Cardiovascular Medicine

Third Edition
James T. Willerson, Jay N. Cohn, Hein J.J. Wellens,
and David R. Holmes, Jr. (Eds)

Cardiovascular Medicine
Third Edition
James T. Willerson, MD Jay N. Cohn, MD
President Professor of Medicine
The University of Texas Health Science Director
Center in Houston Rasmussen Center for Cardiovascular
President-Elect and Medical Director Disease Prevention
Texas Heart Institute Cardiovascular Division
Houston, TX, USA University of Minnesota
Minneapolis, MN, USA

Hein J.J. Wellens, MD David R. Holmes, Jr., MD

Emeritus Professor Consultant
Department of Cardiology Cardiovascular Medicine
University of Maastricht Professor of Medicine
Masstricht, The Netherlands Scripps Professor in Cardiovascular
Medicine
Mayo Clinic College of Medicine
Rochester, MN, USA

Credits for figures and tables appear after the index.

British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library

Library of Congress Control Number: 2006935533

ISBN-10: 1-84628-188-1 3rd edition eISBN-10: 1-84628-725-1

ISBN-13: 978-1-84628-188-4 3rd edition eISBN-13: 978-1-84628-725-1
ISBN 0-443-07000-8 2nd edition, published in 2000 by Churchill Livingstone

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 Preface
T
he third edition of Cardiovascular Medicine is the product of our continuing
effort to provide an authoritative and comprehensive review of important,
clinically relevant cardiovascular disease topics. As compared to the second
edition, this third edition contains 27 new chapters and a 30% expansion and update
of mechanistic, diagnostic, and therapeutic approaches to cardiovascular medicine.
Each chapter is written by one or more experts on the topic. We have also added
two additional editors, Dr. Hein J.J. Wellens, a leading worldwide authority on
cardiac arrhythmias, their recognition and treatment, and Dr. David Holmes, Jr.,
a worldwide leader in interventional cardiovascular medicine.
The continued rapid growth of new knowledge and new techniques has chal-
lenged the physician with a wide array of management options. We believe the third
edition of Cardiovascular Medicine will guide the dedicated physician to more
knowledgeable and effective preventive and therapeutic efforts in patients with car-
diovascular disease.
The specialty of cardiovascular medicine has become increasingly international.
Advances in basic science and clinical research are not restricted to national bound-
aries. Global interaction among scientists and physicians has rapidly expanded, as
a result of major improvements in rapid communication, and the growing recogni-
tion of our interdependence in advancing clinical science. We have therefore main-
tained our commitment to include contributions from American, European, and
Asian-Pacific experts to provide a balanced discussion of opinions from gifted physi-
cians active worldwide in the care and treatment of patients with cardiovascular
diseases.
We hope that the organization of the third edition will enhance its value. Diag-
nostic approaches are considered from a methodological perspective in separate
chapters in the beginning of the book, but are readdressed later in separate chapters
dealing with specific disease categories. Chapters on clinical syndromes are designed
to incorporate anatomic, mechanistic, diagnostic, and treatment considerations.
Whether using the book as a quick reference guide or as a source for comprehensive
coverage of a topic, the reader should have access to up-to-date information in an
accessible format.
We are committed to a long-term effort to update this book so that it keeps
abreast of new and important advances. We shall therefore provide our readers access
to a Web site that will update as necessary all clinically related chapters every three
months by adding new diagnostic and therapeutic information of importance.
The third edition of Cardiovascular Medicine is accompanied by a CD-rom that
presents the entire book on-line, but that also includes an introductory section on
heart sounds of virtually every conceivable cardiovascular abnormality and associ-
ated echocardiographic images. These images serve as an outstanding educational
opportunity for physicians in training, cardiovascular nurses, and cardiovascular
technical associates who are involved in cardiovascular imaging procedures and for
physicians updating their auscultatory and echocardiographic skills in cardiovascu-
lar diagnosis.
We wish to express our appreciation to our editors at Springer for the oppor-
tunity to present the third edition of Cardiovascular Medicine and for their assis-
tance and patience in bringing it to fruition. Our heartfelt thanks go to our families
and our collaborators at the Texas Heart Institute and The University of Texas
Health Science Center in Houston, Texas; the University of Minnesota Medical
School in Minneapolis, Minnesota; the Mayo Clinic College of Medicine in Roch-
ester, Minnesota; and Maastricht University in Maastricht, The Netherlands. We
deeply appreciate the expertise and dedicated assistance of Suzy Lanier at the Texas
Heart Institute and The University of Texas Health Science Center in Houston;
Amy Brown and Cheryl Tincher at the University of Minnesota Medical School

v
vi pr eface

in Minneapolis; and Karyn Hughes and Ann Turner at the Mayo Clinic in
Rochester.
We are very grateful to our colleagues throughout the United States and around
the world who have contributed important chapters. Finally, we express our great
appreciation to our teachers, students, and patients from whom we have learned
so much. It is to them and our families that we dedicate the third edition of
Cardiovascular Medicine.

James T. Willerson, MD
Jay N. Cohn, MD
Hein J.J. Wellens, MD
David R. Holmes, Jr., MD
 Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii
ACC/AHA Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxix

SECTION I Introduction: Cardiac Signs and

Symptoms, and Selected Noninvasive
Diagnostic Methods
1 Anatomy of the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
L. Maximilian Buja

2 The History and Physical Examination . . . . . . . . . . . . . . . . . . . . 19

Thomas C. Smitherman and James T. Willerson

3 Electrocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Anton P.M. Gorgels

4 Chest X-Ray. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Mary Ella Round

5 Introduction to Echocardiography. . . . . . . . . . . . . . . . . . . . . . . . . 93
Raymond F. Stainback

6 Nuclear Cardiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

Arthur Iain McGhie, K. Lance Gould, and
James T. Willerson

7 Cardiovascular Magnetic Resonance Imaging. . . . . . . . . . . . . . . 161

Warren J. Manning

8 Computed Tomographic Cardiovascular Imaging . . . . . . . . . . . . 181

Matthew J. Budoff

SECTION II Congenital Heart Disease in the Adult

9 Normal and Abnormal Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . 205

Robert H. Anderson and Anton E. Becker

10 Pathophysiology, Clinical Recognition, and Treatment of

Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Steven R. Neish and Jeffrey A. Towbin

11 Echocardiography in the Adult with Congenital

Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
Julie A. Kovach

12 Congenital Heart Disease in the Adult:

Interventional Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
Charles E. Mullins

vii
viii contents

13 Surgical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341

Magdi Habib Yacoub, Anselm Uebing,
Rosemary Radley-Smith, and Michael A. Gatzoulis

SECTION III Valvular Heart Disease

14 Valvular Heart Disease: Anatomic Abnormalities . . . . . . . . . . . 369

Hugh A. McAllister, Jr., L. Maximilian Buja, and
†
Victor J. Ferrans

15 Aortic Valve Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381

Blase A. Carabello

16 Pulmonary and Tricuspid Valve Disease . . . . . . . . . . . . . . . . . . . 393

Otto M. Hess, Urs Scherrer, Pascal Nicod, and
Blase A. Carabello

17 Mitral Valve Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397

Maurice L. Enriquez-Sarano and Robert L. Frye

18 Rheumatic Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431

Y.S. Chandrashekhar and Jagat Narula

19 Infective Endocarditis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443

Walter R. Wilson and Eddy Barasch (Second Edition),
revised for The Third Edition by Layne O. Gentry and
Temple W. Williams, Jr.

20 The Assessment and Therapy of Valvular Heart

Disease in the Cardiac Catheterization Laboratory . . . . . . . . . . 463
Paul Sorajja and Rick A. Nishimura

21 Echocardiographic Assessment of Valvular Heart Disease . . . . 487

Raymond F. Stainback

22 Magnetic Resonance Imaging of Valvular Disease . . . . . . . . . . . 537

Scott D. Flamm and Raja Muthupillai

23 Balloon Dilatation of the Cardiac Valves . . . . . . . . . . . . . . . . . . . 557

Igor F. Palacios and Pedro L. Sánchez

24 Valvular Heart Disease: Surgical Treatment . . . . . . . . . . . . . . . . 581

William E. Cohn, O.H. Frazier, and Denton A. Cooley

SECTION IV Coronary Artery Disease

25 Coronary Artery Disease: Pathologic Anatomy

and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
L. Maximilian Buja and Hugh A. McAllister, Jr.

26 Inflammation, C-Reactive Protein, and

Vulnerable Plaques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
Paolo Calabró, James T. Willerson, and
Edward T.H. Yeh
†
Deceased.
 contents ix

27A Atherosclerotic Vulnerable Plaques: Pathophysiology,

Detection, and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
Mohammad Madjid, Samuel Ward Casscells, and
James T. Willerson

27B Biomarkers of Inflammation as Surrogate Markers in

Detection of Vulnerable Plaques and Vulnerable Patients . . . . . 641
Mohammad Madjid, Samuel Ward Casscells, and
James T. Willerson

28 Global Differences in Atherosclerosis . . . . . . . . . . . . . . . . . . . . . 653

Philip A. Poole-Wilson

29 Coronary Artery Disease: Regulation of Coronary

Blood Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
Robert J. Bache

30 Coronary Heart Disease Syndromes: Pathophysiology and

Clinical Recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
James T. Willerson, Attilio Maseri, and Paul W. Armstrong

31 Silent Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699

Matthew B. O’Steen and Neal S. Kleiman

32 Coronary Disease in Women. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713

Allen P. Burke, Frank D. Kolodgie, and Renu Virmani

33 Exercise Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 729

Bernard R. Chaitman, Masarrath J. Moinuddin, and
Junko Sano

34 Coronary Angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 745

Robert F. Wilson and Carl W. White

35 Echocardiographic Evaluation of Coronary Artery Disease . . . . 811

Stephanie A. Coulter

36A Myocardial Perfusion Imaging Utilizing Single Photon

Emission Computed Tomography Techniques. . . . . . . . . . . . . . . 841
George A. Beller

36B Cardiac Positron Emission Tomography. . . . . . . . . . . . . . . . . . . . 855

K. Lance Gould

37A Magnetic Resonance Imaging of the Myocardium . . . . . . . . . . . 871

Raymond J. Kim, Igor Klem, and Robert M. Judd

37B Magnetic Resonance Angiography and Evaluation of

Vulnerable Plaque . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 897
Javier Sanz, Marc Sirol, Zahi A. Fayad, and
Valentin Fuster

38 Medical Treatment of Stable Angina . . . . . . . . . . . . . . . . . . . . . . 911

James J. Ferguson III, Dipsu D. Patel, and
James T. Willerson
x contents

39 Medical Treatment of Unstable Angina, Acute

Non–ST-Elevation Myocardial Infarction, and
Coronary Artery Spasm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937
James T. Willerson and Paul W. Armstrong

40 Treatment of Acute ST-Elevation Myocardial Infarction . . . . . . 963

Paul W. Armstrong and James T. Willerson

41 Kawasaki Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 979

Hirohisa Kato

42 Percutaneous Coronary Intervention and Stable Angina . . . . . . 995

David R. Holmes, Jr.

43 Percutaneous Coronary Intervention for Unstable

Coronary Artery Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005
Pim J. de Feyter and Peter P.T. de Jaegere

44 Percutaneous Coronary Intervention for Acute

Myocardial Infarction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1021
David R. Holmes, Jr.

45 Drug-Eluting Coronary Stents. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1031

Carey D. Moyer, Peter B. Berger, and Christopher J. White

46 Surgical Treatment of Coronary Artery Disease. . . . . . . . . . . . . 1051

William E. Cohn, O.H. Frazier, and Denton A. Cooley

47 Coronary Artery Bypass Surgery and Percutaneous

Coronary Revascularization: Impact on Morbidity and
Mortality in Patients with Coronary Artery Disease . . . . . . . . . 1073
James M. Wilson, James J. Ferguson III, and Robert J. Hall

48 Cardiac Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1113

Michael X. Pham, Jonathan N. Myers, and Victor F. Froelicher

SECTION V Basic Aspects of Myocardial Function,

Growth, and Development
49 Cardiac Development: Toward a Molecular Basis for
Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1135
Michael D. Schneider and Eric N. Olson

50 Fueling the Heart: Multiple Roles for Cardiac Metabolism. . . . 1157

Heinrich Taegtmeyer

51 Cardiac Hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1177

Ali J. Marian and James T. Willerson

52 Regulation of Cardiac Contraction and Relaxation . . . . . . . . . . 1189

Arnold M. Katz

53 Pathophysiology and Clinical Impact of Diastolic

Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201
Gilles W. de Keulenaer and Dirk L. Brutsaert
 contents xi

SECTION VI Myocardial Disease

54 Myocardial Disease: Anatomic Abnormalities . . . . . . . . . . . . . . 1219

Hugh A. McAllister, Jr., L. Maximilian Buja, and
†
Victor J. Ferrans

55 Dilated Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1233

Biykem Bozkurt and Douglas L. Mann

56 Hypertrophic Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . 1261

Diane Fatkin, J.G. Seidman, and Christine E. Seidman

57 Restrictive Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1285

James T. Willerson, L. Maximilian Buja, and
†
John Goodwin

58 Other Cardiomyopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1301

James T. Willerson and L. Maximilian Buja

59 Myocarditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1313
Jay W. Mason, Sanjeev Trehan, and Dale G. Renlund

60 Evaluation of Myocardial Disease in the Cardiac

Catheterization Laboratory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1349
James J. Ferguson III and Tomas Klima

61 Echocardiography in the Evaluation of

the Cardiomyopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1359
Stephanie A. Coulter

62 Pathophysiology and Clinical Recognition of Heart Failure . . . 1379

Jay N. Cohn

63 The Medical Management of Heart Failure. . . . . . . . . . . . . . . . . 1397

Jay N. Cohn

64 Heart Transplantation: Indications, Outcome, and

Long-Term Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1417
Leslie W. Miller

65 Heart Transplantation: Pathogenesis, Immunosuppression,

Diagnosis, and Treatment of Rejection. . . . . . . . . . . . . . . . . . . . . 1443
Leslie W. Miller

66 Surgical Treatment of Advanced Heart Failure . . . . . . . . . . . . . . 1461

O.H. Frazier, Igor D. Gregoric, and William E. Cohn

SECTION VII Pericardial Disease

67 Pericardial Disease: Anatomic Abnormalities. . . . . . . . . . . . . . . 1479

Hugh A. McAllister, Jr., L. Maximilian Buja, and
†
Victor J. Ferrans

68 Pericardial Disease: Etiology, Pathophysiology, Clinical

Recognition, and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1483
Ralph Shabetai

†
Deceased.
xii contents

SECTION VIII Vascular Disease

69 Molecular and Cellular Physiology of Differentiated

Vascular Smooth Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1511
Michael Sturek, Eric A. Mokelke, Jürgen R. Sindermann,
Leonard P. Adam, and Keith L. March

70 Cardiovascular Regulation: Basic Considerations . . . . . . . . . . . . 1525

Giuseppe Mancia, Thomas F. Lüscher, John T. Shepherd,
George Noll, and Guido M. Grassi

71 Vascular Remodeling in Health and Disease. . . . . . . . . . . . . . . . 1541

Luis G. Melo, Massimiliano Gnecchi, Christopher A. Ward,
and Victor J. Dzau

72 Vascular Endothelial Cell Function and Thrombosis . . . . . . . . . 1567

H. Roger Lijnen, Jef M. Arnout, and Désiré Collen

73 Atherosclerosis: Pathologic Anatomy and Pathogenesis . . . . . . . 1581

L. Maximilian Buja and Hugh A. McAllister, Jr.

74 Atherosclerosis: Pathogenesis, Morphology, and

Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1593
Antonio M. Gotto, Jr., and John A. Farmer

75 Detection of Early Cardiovascular Disease . . . . . . . . . . . . . . . . . 1615

Daniel A. Duprez and Jay N. Cohn

76 Diseases of the Aorta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1623

James T. Willerson, Joseph S. Coselli, Scott A. LeMaire,
Ross M. Reul, Igor D. Gregoric, George J. Reul, and
Denton A. Cooley

77 Aneurysms of the Peripheral Arteries . . . . . . . . . . . . . . . . . . . . . 1663

Paul W. Wennberg and Henna Kalsi

78 Peripheral Arterial Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1681

Alan T. Hirsch, Henna Kalsi, and Thom W. Rooke

79 Venous Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1705

Samuel Z. Goldhaber

80 Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1717
Pinak B. Shah and Douglas W. Losordo

81 Carotid Artery Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1741

Christopher J. White

82 Endovascular Procedures for the Treatment of Peripheral

Vascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1755
Kathryn G. Dougherty and Zvonimir Krajcer

83 B-Mode Ultrasound: A Noninvasive Method for

Assessing Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1783
John R. Crouse, Curt D. Furberg, Mark A. Espeland, and
Ward A. Riley
 contents xiii

84 Intravascular Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1797

Seung-Ho Hur, Yasuhiro Honda, Peter J. Fitzgerald, and
Paul G. Yock

85 Arterial Compliance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1811

Gary E. McVeigh, Alan J. Bank, and Jay N. Cohn

86 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1833
Bernard Waeber, Hans-Rudolph Brunner, Michel Burnier, and
Jay N. Cohn

87 Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1871
Henry S. Loeb and Jay N. Cohn

88 Autonomic Dysfunction and Hypotension . . . . . . . . . . . . . . . . . 1883

Christopher J. Mathias

89 Cerebrovascular Disease/Transient Ischemic Attack . . . . . . . . . 1911

Hashem M. Shaltoni and Frank M. Yatsu

SECTION IX Electrical Disturbances of the Heart

90 Sinus Node Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1925

David G. Benditt, Scott Sakaguchi, Keith G. Lurie,
and Fei Lu

91 Supraventricular Tachycardias . . . . . . . . . . . . . . . . . . . . . . . . . . . 1943

Hein J.J. Wellens

92 Atrial Fibrillation and Flutter . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1955

Peter A. Brady and Bernard J. Gersh

93 Preexcitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979
Hein J.J. Wellens

94 Atrioventricular Nodal and Subnodal

Conduction Disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1991
Hein J.J. Wellens

95 Transesophageal Echocardiography for Patients with

Atrial Fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1999
Warren J. Manning

96 Broad QRS Tachycardias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2007

Hein J.J. Wellens

97 Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2019
David G. Benditt and Scott Sakaguchi

98 Sudden Cardiac Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2039

Abdi Rasekh, Mehdi Razavi, and Ali Massumi

99 Antiarrhythmic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2085

Dan M. Roden, Dawood Darbar, and Prince J. Kannankeril
xiv contents

100 Cardiac Pacemakers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2103

Sanjay Dixit and Francis E. Marchlinski

101 The Implantable Cardioverter-Defibrillator . . . . . . . . . . . . . . . . . 2119

William H. Sauer and David J. Callans

102 Catheter Ablation of Supraventricular and

Ventricular Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2139
Luz-Maria Rodriguez, Carl Timmermans, and
Hein J.J. Wellens

103 Surgical Treatment of Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . 2163

Spencer J. Melby, James L. Cox, and
Ralph J. Damiano, Jr.

SECTION X Cardiac Effects of Systemic Disorders,

Pregnancy, Aging, and Environmental
Changes
104 Pulmonary Thromboembolism . . . . . . . . . . . . . . . . . . . . . . . . . . . 2177
Herbert L. Fred, Shahzad Hashim, and Fady A. Joudah

105 Pulmonary Arterial Hypertension . . . . . . . . . . . . . . . . . . . . . . . . 2203

Evangelos D. Michelakis and Stephen L. Archer

106 Chronic Obstructive Pulmonary Disease . . . . . . . . . . . . . . . . . . 2247

Rosa Maria Estrada-Y-Martin and Steven D. Brown

107 Tumors of the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2267

Raymond F. Stainback, Yasmin S. Hamirani,
Denton A. Cooley, and L. Maximilian Buja

108 Endocrine Disorders and the Heart. . . . . . . . . . . . . . . . . . . . . . . . 2295

Victor R. Lavis, Michalis K. Picolos, and
James T. Willerson

109 Connective Tissue Diseases and the Heart . . . . . . . . . . . . . . . . . 2331

Frank C. Arnett and James T. Willerson

110 Substance Abuse and the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . 2357

Paul A. Grayburn and Eric J. Eichhorn

111 Cardiovascular Involvement in Acquired Immune

Deficiency Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2371
Melvin D. Cheitlin, Priscilla Hsue, and Merle A. Sande

112 Cardiac Involvement in Skeletal Myopathies and

Neuromuscular Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2385
Ali J. Marian and James T. Willerson

113 Hematologic Disease and Heart Disease . . . . . . . . . . . . . . . . . . . 2409

Martin D. Phillips and James T. Willerson

114 Hypercoagulable State . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2423

Andrew I. Schafer
 contents xv

115 Aging and the Cardiovascular System . . . . . . . . . . . . . . . . . . . . . 2439

Samer S. Najjar, Gary Gerstenblith, and
Edward G. Lakatta

116 Pregnancy and the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2453

Susan Wilansky, Christina S. Reuss, and
James T. Willerson

SECTION XI Surgery and the Heart

117 Evaluation of Patients for Noncardiac Surgery . . . . . . . . . . . . . . 2487

James B. Froehlich and Kim A. Eagle

118 Anesthesia for Cardiovascular Operations. . . . . . . . . . . . . . . . . . 2501

N. Martin Giesecke and John R. Cooper, Jr.

119 Intraoperative Hemodynamic Monitoring . . . . . . . . . . . . . . . . . . 2515

Rebecca A. Schroeder, Shahar Bar-Yosef, and
Jonathan B. Mark

SECTION XII The Genetic Basis for

Cardiovascular Disease
120 Classification of Genetic Disorders . . . . . . . . . . . . . . . . . . . . . . . 2551
Dianna M. Milewicz

121 Inherited Disorders of Connective Tissue . . . . . . . . . . . . . . . . . . 2557

Dianna M. Milewicz

122 Muscular Dystrophies Affecting the Heart . . . . . . . . . . . . . . . . . 2567

C. Thomas Caskey

123 Genetic Basis for Cardiac Arrhythmias . . . . . . . . . . . . . . . . . . . . 2577

Connie R. Bezzina and Arthur A.M. Wilde

124 Genetic Aspects of Congenital Heart Disease. . . . . . . . . . . . . . . 2599

Dianna M. Milewicz

SECTION XIII Preventive Cardiology

125 Coronary Risk Factors: An Overview . . . . . . . . . . . . . . . . . . . . . 2609

Donald M. Lloyd-Jones and William B. Kannel

126 Preventive Cardiology: The Effects of Exercise . . . . . . . . . . . . . . 2631

Amit Khera, Jere H. Mitchell, and Benjamin D. Levine

127 Smoking, Secondhand Smoke, and

Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2649
Joaquin Barnoya and Stanton A. Glantz

128 Management of Cholesterol Disorders . . . . . . . . . . . . . . . . . . . . . 2667

Scott M. Grundy
xvi contents

129 Cardiovascular Complications of Obesity and the

Metabolic Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2693
Paul Poirier and Robert H. Eckel

130 Gene Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2721

Robert D. Simari and Elizabeth G. Nabel

131 Molecular Biology for the Clinician . . . . . . . . . . . . . . . . . . . . . . . 2731

Sara Arab, Liyong Zhang, Yuichiro Maekawa,
Urszula Zurawska, and Peter P. Liu

132 Stem Cell Therapy for Cardiac Diseases . . . . . . . . . . . . . . . . . . . 2745

Emerson C. Perin, Guilherme V. Silva, and
James T. Willerson

133 Cost-Effectiveness Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2771

William S. Weintraub

134 Erectile Dysfunction and Cardiovascular Disease . . . . . . . . . . . 2791

Sanjay Kaul and James S. Forrester

135 Cardiovascular Disease and Insulin Resistance . . . . . . . . . . . . . 2803

Ramzi A. Ajjan and Peter J. Grant

136 The Heart and the Kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2819

Martin R. Cowie

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2839
Credits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2907
 Contributors
Leonard P. Adam, PhD
Cardiovascular Drug Discovery
Bristol-Myers Squibb
Pennington, NJ, USA
Ramzi A. Ajjan, MRCP, MMed.Sci,
PhD
Molecular Vascular Medicine
Faculty of Medicine and Health
University of Leeds
Leeds, UK
Robert H. Anderson, BSc, MD,
FRCPath
Cardiac Unit
Institute of Child Health
University College
London, UK
Sara Arab, MD
Toronto General Hospital
Research Institute
University Health Network
Toronto General Hospital
Toronto, Ontario, Canada
Stephen L. Archer, MD
Department of Medicine
University of Alberta,
Edmonton, Alberta, Canada
Paul W. Armstrong, MD
Department of Medicine
University of Alberta
Edmonton, Alberta, Canada
Frank C. Arnett, MD
Internal Medicine, Pathology
The University of Texas
Houston Medical School
Houston, TX, USA
Jef M. Arnout, PhD
Faculty of Medicine
Center for Molecular and Vascular
Biology
University of Leuven
Leuven, Belgium
Robert J. Bache, MD
Department of Medicine
University of Minnesota
Minneapolis, MN, USA
Alan J. Bank, MD
Department of Cardiology
St. Paul Heart Clinic
St. Paul, MN, USA
Eddy Barasch, MD
St. Francis Hospital
The Heart Center
Roslyn, New York, USA
Joaquin Barnoya, MD, MPH
Department of Epidemiology
University of California,
San Francisco
San Francisco, CA, USA
and
Departamento de Investigacion y
Docencia
Unidad de Cirugía Cardiovascular
de Guatemala
Guatemala
Shahar Bar-Yosef, MD
Department of Anesthesiology
Duke University Medical Center
and
Anesthesiology Service
Veterans Affairs Medical Center
Durham, NC, USA
Anton E. Becker, MD, PhD
Academic Medical Center
University of Amsterdam
Amsterdam, The Netherlands
George A. Beller, MD
Department of Internal Medicine
Cardiovascular Division
University of Virginia
Health System
Charlottesville, VA, USA
xvii
xviii con tr ibu tors
David G. Benditt, MD, FACC, FRCPC,
FHRS
Department of Medicine
Cardiovascular Division
University of Minnesota Medical
School
Minneapolis, MN, USA
Peter B. Berger, MD
Interventional Cardiology
Geisinger Clinic
Danville, PA, USA
Connie R. Bezzina, PhD
Experimental and Molecular
Cardiology Group
Department of Clinical and
Experimental Cardiology
Academic Medical Center
Amsterdam, The Netherlands
Biykem Bozkurt, MD, FACC
MEDVAMC Cardiology
Michael E. DeBakey Veterans Affairs
Medical Center and Baylor College
of Medicine
Houston, TX, USA
Peter A. Brady, MD, FRCP
Division of Cardiovascular Diseases
Mayo Clinic and Mayo Foundation
Rochester, MN, USA
Steven D. Brown, MD
Department of Medicine
The University of Texas Health Center
at Tyler
Tyler, TX, USA
Hans-Rudolph Brunner, MD (Retired)
Riehen, Switzerland
Dirk L. Brutsaert, MD, PhD
Cardiology Department
AZ Middelheim Hospital
University of Antwerp
Antwerp, The Netherlands
Matthew J. Budoff, MD, FACC, FAHA
Division of Cardiology
Harbor-UCLA Medical Center
Torrance, CA, USA
L. Maximilian Buja, MD
The University of Texas Health Science
Center at Houston
Houston, TX, USA
Allen P. Burke, MD
Medical School
University of Maryland School of
Medicine
Baltimore, MD, USA
Michel Burnier, MD
Nephrology
Department of Medicine
University Hospital
CHUV
Lausanne, Switzerland
Paolo Calabró, MD
Department of Cardiothoracic
Science
Second University of Naples
Naples, Italy
David J. Callans, MD
Cardiology, Medicine
Hospital of the University of
Pennsylvania
Philadelphia, PA, USA
Blase A. Carabello, MD
Department of Medicine
Houston Veterans Affairs Medical
Center
Houston, TX, USA
C. Thomas Caskey, MD
The University of Texas Health
Science Center
Houston, TX, USA
Samuel Ward Casscells, MD
The University of Texas Health
Science Center at Houston
Texas Heart Institute
Houston, TX, USA
Bernard R. Chaitman, MD
Cardiovascular Research
Division of Cardiology
Saint Louis University School of
Medicine
St. Louis, MO, USA
Y.S. Chandrashekhar, MD, DM
Department of Medicine/Division
of Cardiology
Vetrans Affairs Medical Center
Minneapolis, MN, USA
Melvin D. Cheitlin, MD
Department of Medicine
San Francisco General Hospital
San Francisco, CA, USA
Jay N. Cohn, MD
Rasmussen Center for
Cardiovascular Disease
Prevention
Cardiovascular Division
University of Minnesota
Minneapolis, MN, USA
 con tr ibu tors
William E. Cohn, MD
Minimally Invasive Surgical
Technology
Texas Heart Institute
Houston, TX, USA
Désiré Collen, MD, PhD
Center for Molecular and Vascular
Biology
University of Leuven
Leuven, Belgium
Denton A. Cooley, MD
Texas Heart Institute
Houston, TX, USA
John R. Cooper, Jr., MD
Cardiovascular Anesthiology
Texas Heart Institute
Houston, TX, USA
Joseph S. Coselli, MD
Division of Cardiothoracic Surgery
Michael E. DeBakey Department of
Surgery
Baylor College of Medicine
and
Adult Cardiac Surgery;
Cardiothoracic Surgery
Texas Heart Institute at St. Luke's
Episcopal Hospital
Houston, TX, USA
Stephanie A. Coulter, MD
Department of Adult Cardiology
Texas Heart Institute
Houston, TX, USA
Martin R. Cowie, MD, MSc, FRCP
National Heart and Lung Institute
Imperial College
London, UK
James L. Cox, MD
Surgery
Washington University School of
Medicine/Barnes Jewish Hospital
St. Louis, MO, USA
John R. Crouse, MD
Internal Medicine
Wake Forest University School of
Medicine
Medical Center Boulevard
Winston Salem, NC, USA
Ralph J. Damiano, Jr., MD
Surgery
Washington University School of
Medicine/Barnes Jewish Hospital
St. Louis, MO, USA
xix
Dawood Darbar, MBChB, MD
Medicine
Vanderbilt University School of
Medicine
Nashville, TN, USA
Sanjay Dixit, MB BS
Department of Medicine
University of Pennsylvania Health
System
Philadelphia, PA, USA
Kathryn G. Dougherty, CRTT, CVT
Clinical Research
St. Luke’s Episcopal Hospital
Texas Heart Institute
Houston, TX, USA
Daniel A. Duprez, MD, PhD
Cardiovascular Division
University of Minnesota
Minneapolis, MN, USA
Victor J. Dzau, MD
Department of Medicine
Duke University Medical Center
Durham, NC, USA
Kim A. Eagle, MD
Department of Internal Medicine
University of Michigan Medical
School
Ann Arbor, MI, USA
Robert H. Eckel, MD
Division of Endocrinology, Metabolism
and Diabetes
University of Colorado at Denver and
Health Sciences Center
Aurora, CO, USA
Eric J. Eichhorn, MD
Medical City/Baylor Plano Hospital
Dallas, TX, USA
and
University of Colorado Health Science
Center
Denver, CO, USA
Maurice L. Enriquez-Sarano, MD
Department of Cardiovascular
Diseases and Internal Medicine
Mayo Clinic
Rochester, MN, USA
Mark A. Espeland, PhD
Department of Biostatistical Sciences
Wake Forest University Health
Sciences
Medical Center Boulevard
Winstom-Salem, NC, USA
xx con tr ibu tors
Rosa Maria Estrada-Y-Martin, MD
Division of Pulmonary, Critical Care
and Sleep Medicine
The University of Texas Health Science
Center at Houston
Houston, TX, USA
John A. Farmer, MD
Medicine
Baylor College of Medicine
Houston, TX, USA
Diane Fatkin, MD, BSc (Med), FRACP
Molecular Cardiology
Victor Chang Cardiac Research
Institute
Darlinghurst, NSW, Australia
Zahi A. Fayad, PhD
Cardiovascular Institute
Mount Sinai School of Medicine
New York, NY, USA
James J. Ferguson III, MD
Cardiology Research
Texas Heart Institute
Houston, TX, USA
†
Victor J. Ferrans, MD, PhD
Pim J. de Feyter, MD, PhD
Department of Cardiology
Erasmus MC-Thorax Center
Rotterdam, The Netherlands
Peter J. Fitzgerald, MD, PhD, FACC
Division of Cardiovascular Medicine
Stanford University Medical Center
Stanford, CA, USA
Scott D. Flamm, MD
Departments of Radiology and
Cardiology
Texas Heart Institute
Houston, TX, USA
James S. Forrester, MD
Department of Cardiology
Cedars-Sinai Medical Center
Los Angeles, CA, USA
O.H. Frazier, MD
Cardiopulmonary Transplantation
Texas Heart Institute
and
Division of Thoracic and
Cardiovascular Surgery
The University of Texas Medical School
Houston, TX, USA
†
Deceased.
Herbert L. Fred, MD, MACP
Internal Medicine
The University of Texas Health
Science Center at Houston
Houston, TX, USA
James B. Froehlich, MD, MPH
Department of Internal Medicine
University of Michigan
Ann Arbor, MI, USA
Victor F. Froelicher, MD
Cardiology
Department of Veterans Affairs
Palo Alto Health Care System
Palo Alto, CA, USA
Robert L. Frye, MD
Cardiovascular Diseases
Mayo Clinic
Rochester, MN, USA
Curt D. Furberg, MD, PhD
Public Health Sciences
Wake Forest University School of
Medicine
Winston-Salem, NC, USA
Valentin Fuster, MD, PhD
Cardiovascular Institute
Mount Sinai Hospital
New York, NY, USA
Michael A. Gatzoulis, MD, PhD,
FACC, FESC
National Heart and Lung Institute
Royal Brompton Hospital
Sydney Street
London, UK
Layne O. Gentry, MD
St. Luke’s Episcopal Hospital
Houston, Texas, USA
Bernard J. Gersh, MB, ChB,
DPhil
Division of Cardiovascular Diseases
and Internal Medicine
Mayo Clinic
Rochester, MN, USA
Gary Gerstenblith, MD
Medicine
The Johns Hopkins University
School of Medicine
Baltimore, MD, USA
N. Martin Giesecke, MD
Texas Heart Institute
Houston, TX, USA
 con tr ibu tors
Stanton A. Glantz, PhD
Medicine (Cardiology)
University of California,
San Francisco
San Francisco, CA, USA
Massimiliano Gnecchi, MD
Cardiology
University of Pavia and
IRCCS Policlinico San Matteo
Pavia, Italy
Samuel Z. Goldhaber, MD
Cardiovascular Division
Department of Medicine
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA, USA
†
John Goodwin, SPK, MD, FRCP,
FACC, FESC
Anton P.M. Gorgels, MD, PhD
Department of Cardiology
Cardiovascular Research Institute
Maastricht, The Netherlands
Antonio M. Gotto, Jr., MD, DPhil
Weill Medical College of Cornell
University
New York, NY, USA
K. Lance Gould, MD
Department of Medicine
The University of Texas Medical
School
Houston, TX, USA
Peter J. Grant, MD, FRCP
Molecular Vascular Medicine
Faculty of Medicine and Health
University of Leeds
Leeds, UK
Guido M. Grassi, MD
Clinica Medica
University of Milano-Bicocca
Monza, Milan, Italy
Paul A. Grayburn, MD
Internal Medicine
Baylor University Medical Center
Dallas, TX, USA
Igor D. Gregoric, MD
Mechanical Circulatory Support
Texas Heart Institute
Houston, TX, USA
†
Deceased.
xxi
Scott M. Grundy, MD, PhD
Center for Human Nutrition
The University of Texas Southwestern
Medical Center at Dallas
Dallas, TX, USA
Robert J. Hall, MD (Retired)
Houston, TX, USA
Yasmin S. Hamirani, MD
St. Agnes Hospital
Baltimore, MD, USA
Shahzad Hashim, MD
Internal Medicine
The University of Texas Health Science
Center at Houston
Houston, TX, USA
Otto M. Hess, MD
Department of Cardiology
Swiss Cardiovascular Center
Bern, Switzerland
Alan T. Hirsch, MD
Epidemiology, Medicine, and Radiology
Abbott Northwestern’s Vascular Center
and
Division of Epidemiology and
Community Health
Minneapolis Heart Institute
University of Minnesota School of
Public Health
Minneapolis, MN, USA
David R. Holmes, Jr., MD
Cardiovascular Medicine
Mayo Clinic College of Medicine
Rochester, MN, USA
Yasuhiro Honda, MD, FACC
Division of Cardiovascular Medicine
Stanford University Medical Center
Stanford, CA, USA
Priscilla Hsue, MD
Department of Medicine
San Francisco General Hospital
San Francisco, CA, USA
Seung-Ho Hur, MD, PhD
Division of Cardiovascular Medicine
Stanford University Medical Center
Stanford, CA, USA
Peter P.T. de Jaegere, MD, PhD
Intervention Cardiology
Erasmus MC
Rotterdam, The Netherlands
xxii con tr ibu tors

Fady A. Joudah, MD Igor Klem, MD

Internal Medicine DCMRC
Houston Veterans Affairs Medical Duke University Medical Center
Center Durham, NC, USA
Houston, TX, USA
Tomas Klima, MD
Robert M. Judd, PhD Department of Pathology
Duke Cardiovascular Magnetic Texas Heart Institute
Resonance Center Houston, TX, USA
Duke University
Durham, NC, USA
Frank D. Kolodgie, PhD
Cardiovascular Pathology Institute
Henna Kalsi, MD
Gaithersburg, MD, USA
Cardiovascular Medicine
Mayo Clinic
Rochester, MN, USA Julie A. Kovach, MD
Division of Cardiology
Prince J. Kannankeril, MD, MSCI University of Michigan Health
Department of Pediatrics System
Vanderbilt University Ann Arbor, MI, USA
Nashville, TN, USA
Zvonimir Krajcer, MD
William B. Kannel, MD, MPH, FACC Peripheral Vascular Program
Preventive Medicine Texas Heart Institute
Boston University School of Medicine Houston, TX, USA
Boston, MA, USA
Edward G. Lakatta, MD
Hirohisa Kato, MD, PhD, FACC Laboratory of Cardiovascular
Cardiovascular Research Institute Science
Kurume University National Institute on Aging,
Kurume, Japan National Institute of Health
Baltimore, MD, USA
Arnold M. Katz, MD (Retired)
Norwich, VT, USA Victor R. Lavis, MD
Internal Medicine (Endocrinology)
Sanjay Kaul, MD The University of Texas-Houston
Division of Cardiology Medical School
Cedars-Sinai Medical Center Houston, TX, USA
Los Angeles, CA, USA
Scott A. LeMaire, MD
Gilles W. de Keulenaer, MD, PhD
Division of Cardiothoracic Surgery
Department of Cardiology
Michael E. DeBakey Department of
AZ Middelheim Hospital
Surgery
University of Antwerp
Baylor College of Medicine
Antwerp, Belgium
and
Cardiovascular Surgery
Amit Khera, MD
Texas Heart Institute
Division of Cardiology
St. Luke's Episcopal Hospital
The University of Texas Southwestern
Houston, TX, USA
Medical Center
Dallas, TX, USA
Benjamin D. Levine, MD
Raymond J. Kim, MD Institute for Exercise and
Departments of Medicine and Environmental Medicine
Radiology Presbyterian Hospital of Dallas
Duke University Dallas, TX, USA
Durham, NC, USA
H. Roger Lijnen, PhD
Neal S. Kleiman, MD Center for Molecular and Vascular
Cardiac Catheterization Laboratory Biology
Methodist DeBakey Heart Center KU Leuven
Houston, TX, USA Leuven, Belgium
 con tr ibu tors
Peter P. Liu, MD
Toronto General Hospital
University of Toronto
Toronto, Ontario, Canada
Donald M. Lloyd-Jones, MD, ScM
Department of Preventative Medicine
Northwestern University Feinberg
School of Medicine
Chicago, IL, USA
Henry S. Loeb, MD
Department of Cardiology
Edward Hines JR VA Hospital
Hines, IL, USA
Douglas W. Losordo, MD
Cardiovascular Medicine
Caritas St. Elizabeth’s Medical Center
Boston, MA, USA
xxiii
Keith L. March, MD, PhD
Medicine, Cellular and Integrative
Physiology, and Biomedical
Engineering
Indiana University School
of Medicine
Indianapolis, IN, USA
Francis E. Marchlinski, MD
Department of Medicine
University of Pennsylvania Health
System
Philadelphia, PA, USA
Ali J. Marian, MD
The University of Texas Health
Science Center at Houston
Texas Heart Institute
Houston, TX, USA

Fei Lu, MD, PhD Jonathan B. Mark, MD

Department of Medicine Department of Anesthesiology
University of Minnesota Medical Duke University Medical Center
School and
Minneapolis, MN, USA Anesthesiology Service
Veterans Affairs Medical Center
Keith G. Lurie, MD Durham, NC, USA
Medicine and Emergency Medicine
University of Minnesota Medical
School Attilio Maseri, MD
Minneapolis, MN, USA Cardiothoracic and Vascular
Department
Thomas F. Lüscher, MD, PhD University Vita-Salute San Raffaele
Internal Medicine Milan, Italy
Department of Cardiology
University of Zurich Jay W. Mason, MD
Zurich, Switzerland Department of Cardiology
Covance Cardiac Safety Services
Mohammad Madjid, MD Reno, NV, USA
Internal Medicine
The University of Texas Health Science Ali Massumi, MD
Center at Houston Baylor College of Medicine
Houston, TX, USA St. Luke’s Episcopal Hospital
and
Yuichiro Maekawa
Texas Heart Institute
University of Toronto
Houston, TX, USA
Toronto, Canada

Giuseppe Mancia, MD, PhD Christopher J. Mathias, DPhil, DSc,

Clinica Medica
University of Milano-Bicocca
Monza, Milan, Italy
Douglas L. Mann, MD
Baylor College of Medicine
Texas Heart Institute
Houston, TX, USA
Warren J. Manning, MD
Cardiovascular Division
Beth Israel Deaconess Medical Center
Boston, MA, USA
FRCP, FMedSci
Autonomic Unit and University
Department of Clinical
Neurology
National Hospital for Neurology and
Neurosurgery and Institute of
Neurology
London, UK
and
Neurovascular Medical Unit
Imperial College Faculty of Medicine
at St. Mary’s Hospital
London, UK
xxiv con tr ibu tors
Hugh A. McAllister, Jr., MD (Retired)
Previously at Baylor College of
Medicine and The University of
Texas-Houston Medical School and
Texas Heart Institute
Houston, Texas, USA
Arthur Iain McGhie, MD
Department of Internal Medicine
Division of Cardiology
University of Missouri—Kansas City/
Mid America Heart Institute
Kansas City, MO, USA
Gary E. McVeigh, MD, PhD
Department of Therapeutics and
Pharmacology
Queen’s University Belfast
Belfast, Northern Ireland
Spencer J. Melby, MD
Department of Surgery
Washington University School of
Medicine/Barnes Jewish Hospital
St. Louis, MO, USA
Luis G. Melo, PhD
Department of Physiology
Queen’s University
Kingston, Ontario, Canada
Evangelos D. Michelakis, MD
Division of Cardiology
University of Alberta
Edmonton, Alberta, Canada
Dianna M. Milewicz, MD, PhD
Internal Medicine
The University of Texas Medical
School at Houston
Houston, TX, USA
Leslie W. Miller, MD
Department of Medicine
George Town University
George Town, WA, USA
Jere H. Mitchell, MD
Internal Medicine and Physiology
Moss Heart Center
Department of Internal Medicine
Division of Cardiology
The University of Texas Southwestern
Medical Center
Dallas, TX, USA
Masarrath J. Moinuddin, MD, MPH
Department of Cardiology
Wright State University
Dayton, OH, USA
Eric A. Mokelke, PhD
Cellular and Integrative Physiology
Indiana University School of Medicine
Indianapolis, IN, USA
Carey D. Moyer, MD
Cardiology Associates of West Reading
The Reading Hospital and Medical
Center
West Reading, PA, USA
Charles E. Mullins, MD
Department of Pediatrics
Baylor College of Medicine/Texas
Children’s Hospital
Houston, TX, USA
Raja Muthupillai, PhD
Clinical Science—MR and Department
of Radiology
Philips Medical Systems and Baylor
College of Medicine
Houston, TX, USA
Jonathan N. Myers, PhD
Department of Cardiology
Department of Veterans Affairs Palo
Alto Health Care System
Palo Alto, CA, USA
Elizabeth G. Nabel, MD
National Heart, Lung, and Blood
Institute
National Institutes of Health
Bethesda, MD, USA
Samer S. Najjar, MD
Laboratory of Cardiovascular Science
National Institute on Aging
Baltimore, MD, USA
Jagat Narula, MD, PhD
Department of Medicine
University of California Irvine School
of Medicine
Orange, CA, USA
Steven R. Neish, MD
Department of Pediatrics
Texas Children’s Hospital
Houston, TX, USA
Pascal Nicod, MD
Department of Internal Medicine
University of Lausanne
Lausanne, Switzerland
Rick A. Nishimura, MD
Division of Cardiovascular Diseases
Mayo Clinic
Rochester, MN, USA
 con tr ibu tors
George Noll, MD
Internal Medicine
Department of Cardiology
University of Zurich
Zurich, Switzerland
Eric N. Olson, PhD
Molecular Biology
The University of Texas Southwestern
Medical Center
Dallas, TX, USA
Matthew B. O’Steen, MD
Department of Cardiology
Baylor College of Medicine
Houston, TX, USA
Igor F. Palacios, MD
Interventional Cardiology
Harvard Medical School
and
Massachusetts General Hospital
Boston, MA, USA
Dipsu D. Patel, MD, MPH
Department of Cardiology
St. Luke’s Episcopal Hospital
Houston, TX, USA
Emerson C. Perin, MD, PhD
Stem Cell Center
Texas Heart Institute
Houston, TX, USA
Michael X. Pham, MD, MPH
Department of Cardiology
Department of Veterans Affairs Palo
Alto Health Care System
Palo Alto, CA, USA
Martin D. Phillips, MD
Senior Medical Director
Aventis Behring, LLC
King of Prussia, PA, USA
Michalis K. Picolos, MD
Medicine Division of Endocrinology
The University of Texas-Houston
Medical School
Houston, TX, USA
Paul Poirier, MD, PhD, FRCPC
Department of Cardiology
Quebec Heart Institute/Laval Univer-
sity Faculty of Pharmacy
Ste-Foy, Québec, Canada
xxv
Philip A. Poole-Wilson, MD, FRCP,
FMedSci
National Heart and Lung Institute
Faculty of Medicine
Imperial College London
London, UK
Rosemary Radley-Smith, FRCP
Department of Pediatrics
Harefield Hospital
Middlesex, UK
Abdi Rasekh, MD
Texas Heart Institute
Houston, Texas, USA
Mehdi Razavi, MD
Department of Cardiology
Cleveland Clinic
Cleveland, OH, USA
Dale G. Renlund, MD
Division of Cardiology
University of Utah School
of Medicine
Salt Lake City, UT, USA
George J. Reul, MD
Department of Surgery
Texas Heart Institute
Houston, TX, USA
Ross M. Reul, MD
Department of Surgical Innovation
Texas Heart Institute
Houston, TX, USA
Christina S. Reuss, MD
Division of Cardiology
Mayo Clinic Scottsdale
Scottsdale, AZ, USA
Ward A. Riley, BA, MS, PhD
Wake Forest University Health
Sciences
Winston-Salem, NC, USA
Dan M. Roden, MD
Clinical Pharmacology
Vanderbilt University School of
Medicine
Nashville, TN, USA
Luz-Maria Rodriguez, MD, PhD
Department of Cardiology
Faculty of Medicine
University of Maastricht
Maastricht, The Netherlands
xxvi con tr ibu tors
Thom W. Rooke, MD
Vascular Center
Mayo Clinic
Rochester, MN, USA
Mary Ella Round, MD
Department of Radiology
St Luke’s Episcopal Hospital
Houston, TX, USA
Scott Sakaguchi, MD, FACC
Department of Medicine
Cardiovascular Division
University of Minnesota
Minneapolis, Minnesota, USA
Pedro L. Sánchez, MD, PhD
Instituto de Ciencias del Corazón
(ICICOR)
Hospital Clínico Universitario de
Valladolid
Valladolid, Spain
Merle A. Sande, MD
Infectious Diseases/Internal Medicine
Harborview Medical Center/University
of Washington
Seattle, WA, USA
Junko Sano, MD
Division of Cardiology
St. Louis University School
of Medicine
St. Louis, MO, USA
Javier Sanz, MD
Cardiovascular Institute
Mount Sinai School of Medicine
New York, NY, USA
William H. Sauer, MD
Department of Medicine
University of Colorado
Denver, CO, USA
Andrew I. Schafer, MD
Department of Medicine
University of Pennsylvania
Philadelphia, PA, USA
Urs Scherrer, MD
Department of Cardiology
University of Lausanne
Lausanne, Switzerland
Michael D. Schneider, MD
Medicine, Molecular and Cellular
Biology, and Molecular Physiology
and Biophysics
Baylor College of Medicine
Houston, TX, USA
Rebecca A. Schroeder, MD
Department of Anesthesiology
Duke University Medical Center
and
Anesthesiology Service
Veterans Affairs Medical Center
Durham, NC, USA
Christine E. Seidman, MD
Department of Genetics
and Medicine
Howard Hughes Medical Institute
Harvard Medical School
Boston, MA, USA
J.G. Seidman, PhD
Department of Genetics
and Medicine
Howard Hughes Medical Institute
Harvard Medical School
Boston, MA, USA
Ralph Shabetai, MD, FACC
Department of Cardiology
VA Health Care System
La Jolla, CA, USA
Pinak B. Shah, MD
Cardiovascular Medicine
Caritas St. Elizabeth’s Medical Center
Boston, MA, USA
Hashem M. Shaltoni, MD
Neurology—Stroke Program
The University of Texas Health
Science Center at Houston
Houston, TX, USA
John T. Shepherd, MD, PhD
Department of Physiology
Mayo Clinic Foundation
Rochester, MN, USA
Guilherme V. Silva, MD
Stem Cell Center
Texas Heart Institute
Houston, TX, USA
Robert D. Simari, MD
Division of Cardiovascular Diseases
Mayo Clinic College of Medicine
Rochester, MN, USA
Jürgen R. Sindermann, MD
Krannert Institute of Cardiology
Indianapolis, IN, USA
Marc Sirol, MD
Cardiovascular Institute
Mount Sinai School of Medicine
New York, NY, USA
 con tr ibu tors
Thomas C. Smitherman, MD
Department of Internal Medicine
Division of Cardiology
and the Cardiovascular Institute
University of Pittsburgh School of
Medicine and University of
Pittsburgh Medical
Center-Presbyterian
Pittsburgh, PA, USA
Paul Sorajja, MD
Division of Cardiovascular Diseases
and Internal Medicine
Mayo Clinic College of Medicine
Rochester, MN, USA
Raymond F. Stainback, MD, FACC,
FASE
St. Luke’s Episcopal Hospital
Texas Heart Institute
Houston, TX, USA
Michael Sturek, PhD
Cellular and Integrative Physiology
Indiana University School
of Medicine
Indianapolis, IN, USA
Heinrich Taegtmeyer, MD, DPhil
Internal Medicine
Division of Cardiology
The University of Texas-Houston
Medical School
Houston, TX, USA
Carl Timmermans, MD, PhD
Department of Cardiology
Faculty of Medicine
University of Maastricht
Maastricht, The Netherlands
Sanjeev Trehan, MD
Cardiology of Tulsa
Tulsa, OK, USA
Jeffrey A. Towbin, MD
Department of Pediatric Cardiology
Baylor College of Medicine
Houston, TX, USA
Anselm Uebing, MD
Adult Congenital Heart Disease Unit
Royal Brompton Hospital and Harefield
NHS Trust
London, UK
Renu Virmani, MD
CVPath Institute, Inc.
International Registry of Pathology
Gaithersburg, MD, USA
xxvii
Bernard Waeber, MD
Division of Clinical
Pathophysiology
Department of Medicine
University Hospital
CHUV
Lausanne, Switzerland
Christopher A. Ward, PhD
Department of Physiology
Queen’s University
Kingston, Ontario, Canada
William S. Weintraub
Department of Medicine
Christian Care Health System
Newark, DE, USA
Hein J.J. Wellens, MD
Department of Cardiology
University of Maastricht
Maastricht, The Netherlands
Paul W. Wennberg, MD
Section of Vascular Medicine
Mayo Clinic
Rochester, MS, USA
Carl W. White, MD
Department of Medicine
University of Minnesota
Minneapolis, MN, USA
Christopher J. White, MD
Department of Cardiology
Ochsner Clinic Foundation,
New Orleans, LA, USA
Susan Wilansky, MD, FACC, FASE
Department of Cardiology
Mayo Clinic
Scottsdale, AZ, USA
Arthur A.M. Wilde, MD, PhD
Experimental and Molecular
Cardiology Group
Department of Clinical and
Experimental Cardiology
Academic Medical Center
Amsterdam, The Netherlands
James T. Willerson, MD
The University of Texas Health
Science Center at Houston
Texas Heart Institute
Houston, TX, USA
Temple W. Williams, Jr., MD
The Methodist Hospital
Corporation
Houston, Texas
xxviii con tr ibu tors

James M. Wilson, MD Edward T.H. Yeh, MD

Department of Cardiology Department of Cardiology
St. Luke's Episcopal Hospital The University of Texas, MD Anderson
Texas Heart Institute Cancer Center
Houston, TX, USA Houston, TX, USA

Robert F. Wilson, MD, PhD Paul G. Yock, MD

Department of Medicine Department of Bioengineering
University of Minnesota Stanford University
Minneapolis, MN, USA Stanford, CA, USA

Walter R. Wilson, MD Liyong Zhang, MD

Mayo Clinic and Foundation The Heart and Stroke and Richard
Rochester, NY, USA Lewar Center of Excellence
University of Toronto
Magdi Habib Yacoub, FRS Toronto, Canada
Heart Science Centre
Imperial College London Urszula Zurawska
Harefield, Middlesex, UK University of Toronto
Toronto, Canada
Frank M. Yatsu, MD
Neurology—Stroke Program
The University of Texas Health Science
Center at Houston
Houston, TX, USA
 ACC/AHA
Guidelines
Many of the topics covered by chapters in Cardiovascular Medicine, Third
Edition, are researched by writing groups of the American College of Car-
diology and the American Heart Association, and the research results in
guidelines that are prepared jointly by these groups. Members of the writing
groups are experts in their cardiovascular specialties, and the guidelines
undergo a rigid review process before being approved and published in the
ACC/AHA Joint Guidelines collection.

A direct link to the Guidelines collection is provided below:

http://www.americanheart.org/presenter.jhtml?identifier=3004542

References to the guidelines and applicable chapters are listed below.

ACC/AHA/ESC 2006 Guidelines for Management of Patients with Ventric-

ular Arrhythmias and the Prevention of Sudden Cardiac Death. Executive
Summary (Circulation. 2006;114:1088–1132)
Chapters 94, 96, 97, 98, 99, 101, 102.

ACC/AHA/ESC 2006 Guidelines for the Management of Patients with

Atrial Fibrillation. Executive Summary (Circulation. 2006;114:700–752)
Chapters 92, 93, 95, 99, 103.

AC/AHA 2006 Guidelines for the Management of Patients with Valvular

Heart Disease. Executive Summary (Circulation. 2006;114:450–527) and
Full Text.
Chapters 15, 16, 17, 23, 24.

AHA/ACC 2006 Guidelines for Secondary Prevention for Patients with

Coronary and Other Atherosclerotic Vascular Disease (Circulation. 2006;
113:2363–2372)
Chapters 26, 27a, 27b, 28, 30, 74, 128.

AHA/ACC 2006 Guideline Update on Perioperative Cardiovascular Evalua-

tion for Noncardiac Surgery: Focused Update on Perioperative Beta-Blocker
Therapy (Circulation. 2006;113:2662–2674)
Chapter 117

ACC/AHA 2006 Clinical Performance Measures for Adults with ST-Eleva-

tion and Non ST-Elevation Myocardial Infarction. A Report of the ACC/
AHA Task Force on Performance Measures (Circulation. 2006;113:607–
608)
Chapters 39, 40

xxix
xxx acc /a h a gu i de l i n e s

ACC/AHA 2005 Guidelines for the Management of Patients with Peripheral Arte-
rial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic). Executive
Summary (Circulation. 2006;113:1474–1547) and Full Text (Circulation. 2006;113:
463–654)
Chapters 77, 78, 80, 81, 82.

ACCF/AHA 2005 Clinical Competence Statement on Cardiac Imaging with

Computed Tomography and Magnetic Resonance (Circulation. 2005;112:
598–617)
Chapters 7, 8, 22.

ACC/AHA 2005 Guideline Update for the Diagnosis and Management of

Chronic Heart Failure in the Adult (Circulation. 2005;112:e154–e235)
Chapters 62, 63, 64.

ACC/AHA 2005 Key Data Elements and Definitions for Measuring the
Clinical Management and Outcomes of Patients with Chronic Heart Failure
(Circulation. 2005;112:1888–1916)
Chapters 62, 63, 64.

ACC/AHA 2005 Guideline Update for Percutaneous Coronary Intervention.

Summary Article (Circulation. 2006;113:156–175)
Chapters 42, 43, 44, 45.

ACCF/AHA 2005 Clinical Competence Statement on Cardiac Imaging with

Computed Tomography and Magnetic Resonance (Circulation. 2005;112:
598–617)
Chapters 7, 8, 22.

ACC/AHA 2004 Guideline Update for Coronary Artery Bypass Graft Surgery.
Full Text (Circulation. 2004;110:340–437) and Summary Article (Circula-
tion. 2004;110:1168–1176)
Chapter 46, 47.

ACC/AHA 2004 Guidelines for the Management of Patients with ST-Eleva-

tion Myocardial Infarction. Full Text (Circulation. 2004;110:82–293). Execu-
tive Summary (Circulation. 2004;110:588–636)
Chapter 40.

ACC/AHA/ASNC 2003 Guidelines for the Clinical Use of Cardiac Radio-

nuclide Imaging. Full Text and Executive Summary. (Circulation. 2003;108:
1404–1418).
Chapters 6, 36a, 36b.

ACC/AHA/ESC 2003 Guidelines for the Management of Patients with

Supraventricular Arrhythmias. Full Text and Executive Summary (Circula-
tion. 2003;108:1871–1909).
Chapters 90, 91, 92, 93.

ACC/AHA/ASE 2003 Guidelines for the Update for the Clinical Application
of Echocardiography. Summary Article (Circulation. 2003;108:1146) and Full
Text.
Chapters 5, 11,12, 21, 35, 61, 95.

ACC/AHA 2002 Guideline Update for the Management of Patients with

Chronic Stable Angina. Summary Article (Circulation. 2003;107:149) and
Full Text.
Chapter 38.
 acc /a h a gu i de l i n e s xxxi

ACC/AHA 2002 Guideline Update for the Management of Patients with

Unstable Angina and Non-ST Segment Elevation Myocardial Infarction.
Full Text and Summary Article (Circulation. 2002;106:1893)
Chapter 39

ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac

Pacemakers and Antiarrhythmia Devices. Full Text and Summary Article
(Circulation. 2002;106:2145)
Chapters 100, 101.

ACC/AHA 2002 Guideline Update for Exercise Testing. Summary Article

(Circulation. 2002;106:1883)
Chapter 33
SEC TION I

Introduction:
Cardiac Signs
and Symptoms,
and Selected
Noninvasive
Diagnostic
Methods
 1 Anatomy of the Heart
L. Maximilian Buja
Embryologic Development . . . . . . . . . . . . . . . . . . . . . . . . . . 3
External Anatomy of the Heart and Great Vessels . . . . . . 7
Pericardium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Key Points
• External looping and internal septation to form four-
chambered heart.
• Relationship of embryologic defects to congenital heart
disease.
• Structure-function relationships of the pericardium.
• Distribution of the coronary arteries and anatomic
variations.
• Definition of anatomic right and left atria and right and
left ventricles.
• Structure of the four cardiac valves and concept of func-
tional valve apparatus.
• Anatomy of the cardiac conduction system and cardiac
innervation.
This chapter presents basic features of the anatomy of the
heart and great vessels, including the embryologic devel-
opment of these structures and their configuration in the
mature state. Basic knowledge of cardiovascular anatomy is
essential for effective diagnosis and treatment of cardiovas-
cular diseases.
Embryologic Development
Basic Embryology
Development of the cardiovascular system occurs in the
early first trimester fetus. Beginning at about 3 weeks’ gesta-
tion, elements of splanchnic mesoderm differentiate into a
primitive cardiac tube and pericardial cavity, and vascular
channels form and fuse to form blood vessels.1–7 The primi-
tive cardiac tube results from the moving together and fusion
of two lateral endothelial heart tubes. Subsequently, the
epimyocardial mantle and cardiac jelly develop. These com-
ponents differentiate into the endocardium, producing the
internal endothelial lining of the heart, the myocardium
forming the muscular wall, and the epicardium or visceral
pericardium producing the outside covering of the heart. The
Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
recently formed cardiac tube is a single chambered structure
and is composed of the following components, extending
from inferior (caudal) to superior (cephalad): the sinus
venosus, which connects to the major veins; the atrium; the
ventricle; the bulbus cordis or conus; and the truncus arterio-
sus, which connects through six pairs of aortic arches to two
dorsal aortae1–7 (Fig. 1.1).
Initially, the single chambered heart is a straight tube
residing in the pericardial cavity. The bulboventricular por-
tion grows much more rapidly than the pericardial cavity. As
a result, further extension in a longitudinal direction cannot
occur, and the heart tube is forced to bend. The cephalic
ventricular portion of the tube bends in a ventral and caudal
direction and to the right, whereas the caudal atrial portion
progresses in a dorsal and cranial direction and to the left.
This process, known as d(dextro)-bulboventricular looping,
results in the atrial region establishing a position superior to
the ventricular region and the cardiac apex being pointed to
the left (Fig. 1.1).
The external shape changes are accompanied by a
complex process of internal septation that leads to the for-
mation of a four-chambered heart (Fig. 1.2). In the atrium,
a septum primum forms and then develops two openings:
ostium primum and ostium secundum. A septum secun-
dum then develops on the right of the septum primum.
The foramen ovale is formed in the midportion of the devel-
oping interatrial septum as a result of the growth and
positioning of the septum secundum adjacent to the
septum primum. The sinus venosus is incorporated into the
superior portion of the developing atria. Ventricular septa-
tion is partially accomplished by the upward growth of
muscular tissue to form the muscular interventricular
septum. Endocardial cushion tissue develops and provides
the essential tissue for formation of the atrioventricular
valves, the closure of the ostium primum in the atrial
septum, and the formation of the membranous interven-
tricular septum.
The primitive bulbus cordis contributes several key
components of the forming heart. The proximal third of the
3
4 chapter
I II
I II
Truncus
Conoventricular
arteriosus At.r Tr.
s
sulcus
s
nu
nu
Co
Co
Ventricle
Atrium
A 2.08 mm B 3.0 mm
III
IV
VI
Tr.
At.r Art. At.l. At.r
s as the atrium receiving the systemic venous drainage. The
nu
us
Co
Con
Vent.r. Vent.l. Vent.r.
D 6.0 mm E 8.8 mm
FIGURE 1.1. Ventral views of human embryonic hearts that show
bending of cardiac tube and establishment of major anatomic com-
ponents. At., atrium; l., left; r., right; Tr. Art., truncus arteriosus.
bulbus cordis forms the trabeculated part of the right ven-
tricle; the midportion, or conus cordis, forms the outflow
tracts of both ventricles; and the distal part, the truncus
arteriosus, forms the proximal parts of the aorta and pulmo-
nary artery. The junction between the primitive ventricle
and the bulbus cordis is designated the primary interven-
tricular foramen. While the ventricular septation process
proceeds, the primitive ventricle develops into the major
component of the definitive left ventricle, and the proximal
one third of the bulbus cordis gives rise to the major compo-
nent of the definitive right ventricle.
Separate aortic and pulmonary channels are formed by
separation of the truncus arteriosus by a spiral aorticopul-
monary septum (Fig. 1.3). As a result of extensive remodeling
of the double aortic arch system, the definitive major vessel
system develops into a single aorta with left-sided aortic
arch, a pulmonary trunk with right and left main pulmonary
arteries, and the ductus arteriosus, which connects the aortic
arch and the left pulmonary artery.
The heart develops in the fetus as myocardial contractile
activity commences, and a functional circulation is estab-
lished. The foramen ovale in the interatrial septum and the
ductus arteriosus remain open. In the fetus, pulmonary vas-
cular resistance is high in the unexpanded lungs and sys-
temic vascular resistance is low. As a result of these anatomic
and physiologic features, the fetal circulation involves right
to left shunting of blood across the open foramen ovale and
the patent ductus arteriosus to provide oxygenated blood
from the placenta to the general circulation (Fig. 1.4). After
birth, the lungs expand, pulmonary vascular resistance
drops, and systemic vascular resistance increases. This leads
1
I to functional closure of the foramen ovale and ductus arte-
III riosus and, subsequently, fibrous closure of these structures.
IV These closures establish complete separation of the right-
sided and left-sided circulations in the mature cardiovascular
Art. At.l.
system.
s
nu
Co
Ventricle
C 5.2 mm
Relationship to Congenital Heart Disease
III Knowledge of normal and abnormal embryologic develop-
IV
VI ment of the heart and blood vessels provides an essential
basis for and understanding of the morphogenesis of congeni-
Tr.
Art. tal heart disease.8,9 The position of the atria is determined
by general body habitus. The anatomic right atrium is defined
At.l.
anatomic left atrium is defined as the atrium receiving the
pulmonary venous drainage. In situs solitus, the right atrium
Vent.l. is on the right and the left atrium on the left side of the body.
In situs inversus, the anatomic right atrium is on the left side
and the anatomic left atrium is on the right side of the body.
The right and left ventricles are normally connected to the
corresponding atria, but the ventricles may be inverted.
Inversion of the ventricles is a major feature of a condition
known as congenitally corrected transposition of the great
vessels. This condition arises when the primitive heart
undergoes levo(l)-bulboventricular looping rather than the
usual dextro(d)-bulboventricular looping; hence, the alterna-
tive designation of corrected transposition as l-transposition.
Other positional anomalies of the heart include dextrocardia
and right-sided aortic arch.
Abnormalities in atrial septation give rise to three types
of atrial septal defects; in order of frequency they are the
ostium secundum defect, ostium primum defect, and sinus
venosus defect. Ostium secundum defects are located in
the midportion of the interatrial septum and result from
inadequate formation of septum secundum and/or septum
primum to cover the foramen ovale. Ostium primum defects
are located in the inferior portion of the interatrial septum
and result from a defect in formation of endocardial cushion
tissue. Severe endocardial cushion deficiency can lead to
a common atrioventricular canal anomaly with ostium
primum atrial septal defect, membranous ventricular septal
defect, and abnormal atrioventricular valve. The sinus
venosus atrial septal defect is located in the superior portion
of the interatrial septum and results from defective incor-
poration of the primitive sinus venosus into the forming
heart; this defect is often associated with partial anomalous
pulmonary venosus drainage into the right atrium. Abnor-
malities in ventricular septation give rise to ventricular
septal defects, usually in the region of the membranous
septum. Formation of the membranous interventricular
septum involves contributions from the conal ridges of the
bulbus cordis and the endocardial cushions. Deficiencies in
contributions from these embryonic structures leads to the
formation of membranous ventricular septal defects. Abnor-
malities in septation of the great vessels give rise to con-
genital complete transposition of the great vessels, or
d-transposition, since the abnormal septation of the great
vessels occurs with normal dextro-bulboventricular looping
and the atria and ventricles are in normal position. Con-
genital complete transposition is often accompanied by
 a natom y of t h e h e a rt 5

Septum spurium

Interatrial
septum primum
Ostium I

Atrio-vent. canal

Intervent. septum

A 4–5 mm B 6–7 mm

Septum II
S. sp.
Septum Septum I
Ostium II spurium Ostium II
(opening)
Septum I Ostium I
Right Ostium I
atrium Septum II (closed)
(closing)
(caudal limb)
A_V. canal cushion
Intervent. foramen
(closes at 15–17 mm.)
Left
ventricle

C 8–9 mm D 12–15 mm

Septum II Crista
S. sp. Ostium II terminalis
in septum I
S II Functional
outlet F.O.
Foramen
ovale Septum I
(valvula F.O.)
S II

Atriovent.
valves

Bundle
of his

E 25–30 mm F 100 mm. to birth

FIGURE 1.2. Longitudinal sections of embryonic heart in frontal
plane that show extent of growth of various cardiac septa at progres-
sive stages of development. These diagrams depict the stages of
partitioning of the human embryo. Stippled areas indicate the dis-
tribution of endocardial cushion tissue; muscle is shown in diagonal
hatching, and epicardium in solid black. The lightly stippled areas
in the atrioventricular canal in B and C indicate location of dorsal
and ventral endocardial cushions of the atrioventricular canal before
they have grown sufficiently to fuse with each other in the plane of
the diagram.

atrial or ventricular septal defects or other congenital
lesions. Severe maldevelopment of the heart can give rise to
a hypoplastic left heart or hypoplastic right heart and asso-
ciated valvular atresia. Other anomalies include vascular
rings, persistent patent ductus arteriosus, and coarctation of
the aorta.
Cardiovascular malformations occur in about 0.8% of
live births.10 However, the incidence of congenital heart
disease is significantly higher because cardiac malforma-
tions occur 10 times more often in stillborn than in liveborn
infants. Children with congenital heart disease are predomi-
nantly male. However, specific defects have a definite sex
preponderance: females have a higher incidence of patent
ductus; arteriosus and atrial septal defect are more common
in females; and males have a higher incidence of valvular
aortic stenosis, congenital aneurysm of the sinus of Valsalva,
coarctation of the aorta, tetralogy of Fallot, and congenital
complete transposition of the great arteries.10
6 chapter 1

Pulmonary
Dextrodorsal channel S.-v. truncus
Truncus ridge
arteriosus truncus ridge
communis Aortic
channel
Dextrodorsal
conus ridge
Right S.-v.
atrium conus
Conovent. flange ridge
Left Arrow
Conus atrium in aortic
art. channel Ventral
atriovent.
Atrioventricular canal
canal cushion

Dorsal atriovent.
canal cushion
Right
ventricle Left
Interventricular ventricle
septum
A B
FIGURE 1.3. Frontal plane dissections of developing heart show upward, in order to show the absence of truncus ridges in the early
important relations in establishing aortic and pulmonary outlets. stages and their relationships in later stages.
The truncus arteriosus has been drawn with its cut end turned

Septum I
Superior vena cava (remnant)
Crista Margin of interatrial
terminalis foramen II

Septum II Septum I = valvula

foraminis ovalis

Limbus of
foramen Orifices of
ovale pulmonary veins

Valve of Left atrium

inferior
vena cava
Mitral valve
Valve of
coronary
sinus Tendinous
Tricuspid valve cords
Septum
membranaceum Papillary
muscle
Interventricular septum
(muscular portion)
Trabeculae
carneae of
Right ventricle left ventricle

FIGURE 1.4. Schematic drawing to show interrelations of septum
primum and septum secundum during the latter part of fetal life.
Note especially that the lower part of septum primum is positioned
so as to act as a one-way valve at the oval foramen in septum secun-
dum. The split arrow indicates that a considerable part of the blood
from the inferior vena cava passes through the foramen ovale to the
left atrium while the remainder eddies back into the right atrium
to mix with the blood being returned by way of the superior vena
cava.
 a natom y of t h e h e a rt 7

External Anatomy of the Heart and Pericardium

Great Vessels
The anatomy of the heart and great vessels has been well
documented in previous publications.11–17 The normal loca-
tion of the heart is in the mediastinum to the left of the
midline with the cardiac apex pointed to the left (Fig. 1.5).
The heart is rotated and tilted in the chest, and as a result
about two thirds of the anterior surface of the heart is com-
posed of the right ventricle, and the left third of the anterior
surface is composed of the left ventricle. The right inferior
border (obtuse border) of the heart is formed by the right
ventricle and the left lateral border is formed by the left
ventricle. Located superior to the right and left ventricles
are the right and left auricles of the right and left atria,
respectively. The anterior superior surface of the heart is
constituted by the outflow portion (conus) of the right
ventricle and the pulmonary trunk, which extends from
right to left as it exits the pericardium. The pulmonary
trunk then gives rise to the left and right main pulmonary
arteries. The aorta is located posterior to the pulmonary
trunk. The aorta takes origin from the left ventricle and is
oriented from left to right as it exits the pericardium. The
aorta then curves to the left and inferiorly, creating a left-
sided aortic arch. The aortic arch gives origin to the right
innominate, left common carotid, and left subclavian arter-
ies. The aorta then continues inferiorly as the descending
thoracic aorta.
The pericardial cavity is a fluid-filled space that surrounds
the heart and proximal great vessels. The pericardial space
is enclosed by a thin layer of connective tissue that is lined
by a single layer of mesothelial cells. There are two compo-
nents: the visceral and parietal pericardium. The visceral
pericardium covers the epicardium of the heart, and the
parietal pericardium forms the outer layer. The superior
extent of the pericardial cavity representing the transition
of visceral to parietal pericardium occurs approximately 2 to
3 cm superior to the heart at the level of the great vessels,
thereby enclosing the proximal aorta and pulmonary trunk
in the pericardial cavity (Fig. 1.5). The pericardial cavity
normally contains about 20 cc of serous fluid, which serves
to lubricate the heart and facilitate cardiac motion.
The pericardium can be affected by a variety of inflam-
matory and neoplastic conditions. Hemorrhage into the peri-
cardium may occur as a result of cardiac rupture, usually
secondary to acute myocardial infarction, or rupture of the
proximal aorta following aortic dissection. The severity of
cardiac dysfunction secondary to pericardial disease is influ-
enced acutely by the amount and rapidity of fluid accumula-
tion in the pericardial cavity and chronically by the severity
of inflammation and fibrosis. Rapid accumulation of 100 to
200 mL of fluid or blood in the pericardial cavity can induce
cardiac tamponade, whereas the slow accumulation of
several hundred milliliters can be accommodated in the

Innominate Left subclavian artery

artery
Right innomi-
nate vein Left innominate vein
R. int. mam. vein
Pleura
Thymus gland
Reflection of
pericardium
Vena cava
sup. Pulmonary
Asc. aorta artery
Pleura
Probe in Fibrous
transv. pericardium
sinus Serous
Right pericardium
auricle Conus
arteriosus

Right Left
atrium auricle

Coronary
sulcus
Margo
Right obtusus
ventricle

Left
ventricle
Anterior
Margo longi-
acutus tudinal
Incisura sulcus
apicis Apex
cordis
Pleura
FIGURE 1.5. Ventral view of heart in situ
with the pericardial sac opened.
8 chapter
cavity with stretching of the pericardial lining before
impaired cardiac function develops.
Heart
Basic Structure
The anatomy of the heart has been documented in detail.11–17
The heart is composed of three layers: the epicardium, the
myocardium, and the endocardium. The epicardium consists
of fatty connective tissue and is lined by the visceral peri-
cardium. The major coronary arteries and veins traverse the
epicardium. The myocardium constitutes most of the mass
of the heart and is composed of cardiac myocytes, vessels,
and connective tissue. The cardiac myocytes represent
approximately 80% of the mass but only 20% of the number
of cells in the myocardium. The endocardium is divided into
the nonvalvular (visceral) and valvular endocardium. The
endocardium consists of thin fibrocellular connective tissue,
which is lined by a single layer of endothelial cells.
Cardiac Dimensions
Several sources have provided information regarding dimen-
sions and measurements of the heart.11–17 The weight of the
heart varies in relationship to body dimensions, including
length and weight. Hudson11 has published a useful guide
regarding fresh heart weight in males and females. The adult
male heart weight has the following parameters: 0.45% of
body weight, average 300 g, range 250 to 350 g. The adult
female heart weight has the following parameters: 0.40% of
body weight, average 250 g, range 200 to 300 g. Selective mea-
surements of right ventricular and left ventricular weights
can be made, and ranges have been established for determina-
tion of selective enlargement of right and left ventricles as
Right pulmonary veins Left pulmonary veins
Vena cava superior
Aorta
Posterior and
left aortic semi-
lunar valves
Right aortic
semilunar valve
Right coronary
artery
Small cardiac
vein
Anterior cardiac
veins
Preventricular.
arteries
Right marginal
artery
Right ventricle
Incisura apicis cordis
1
well as biventricular enlargement.15 The thickness of the
walls of the cardiac chambers is as follows: right and left
atria, 0.1 to 0.2 cm; right ventricle, 0.4 to 0.5 cm; left ventri-
cle, 1.2 to 1.5 cm (free wall, excluding papillary muscles and
large trabeculae). The average circumferences of the cardiac
valves are as follows: aortic, 7.5 cm; pulmonic, 8.5 cm; mitral,
10.0 cm; and tricuspid, 12.0 cm.
Coronary Vasculature
The anatomy and physiology of the coronary circulation have
been described in detail.18–25 In the normal heart, oxygenated
blood is supplied by two coronary arteries that are the first
branches of the aorta. The origin of the left and right coro-
nary arteries from the aorta is through their ostia positioned
in the left and right aortic sinuses of Valsalva, which are
located just distal to the left and right cusps, respectively, of
the aortic valve (Figs. 1.5, 1.6, and 1.7). The left main coro-
nary artery is a short vessel with a length of 0.5 to 1.5 cm.
The left main coronary artery divides into left anterior
descending and left circumflex branches and, occasionally, a
left marginal branch. The left anterior descending coronary
artery and its left diagonal and septal branches supply the
anterior portion of the left ventricles and interventricular
septum. The left circumflex coronary artery and its circum-
flex marginal branches supply the lateral left ventricle. The
right coronary artery supplies the right ventricle and, in
about 90% of hearts, it extends posteriorly to give rise to the
posterior descending coronary artery.
There is considerable variation in the anatomic distribu-
tion of the coronary arterial branches. However, in most
hearts, branches from both the left circumflex and right
coronary arteries contribute to the blood supply of the pos-
terior left ventricle, resulting in a so-called balanced circula-
tion. In about 10% of hearts, the right coronary artery is
small, and the left circumflex coronary artery gives origin
Left auricle
Left atrium
Circumflex branch
Left coronary
artery
Left aortic sinus
Great cardiac vein
Left pulmonary
semilunar valve
Right and anterior
pulmonary semilunar
valves
Pulmonary artery
Conus arteriosus
Anterior descending
branch of left
coronary artery
Left ventricle
Anterior longitudinal
sulcus
FIGURE 1.6. Cephalic view of the heart with
the epicardium removed to expose the injected
coronary vessels.
 a natom y of t h e h e a rt 9

Vena cava superior

Superior Superior right
left pulmonary pulmonary vein
vein
Inferior right
pulmonary vein
Inferior left
pulmonary vein Terminal
Left atrium sulcus
Oblique vein of
left atrium Right atrium
Interatrial sulcus Vena cava
inferior
Great cardiac vein Valvula venae
cavae
Small
Coronary sinus cardiac vein
Right
coronary
Posterior vein of artery
left ventricle Right
ventricle
Middle cardiac
vein
Diaphragmatic Posterior descend-
surface of left ing branch of right
ventricle coronary artery

FIGURE 1.7. Dorsocaudal view of the heart Posterior longitudinal sulcus

with the epicardium removed to expose the
injected coronary vessels.

to the posterior descending coronary artery and provides the cardiac collaterals); and intramural branches, which com-
sole blood supply for the posterior left ventricle, creating a municate with the cardiac cavities (arterioluminal vessels).
left dominant circulation. Rarely, the converse right domi- In the normal adult heart, the collateral vessels are thin
nant circulation exists when the left circumflex is small and walled, small channels, usually less than 50 μm in diameter,
the posterior left ventricle is supplied primarily by left ven- and they contribute little to total coronary blood flow. In
tricular branches of the right coronary artery. response to coronary arterial narrowing and myocardial
The major blood supply to the sinoatrial node via the ischemia, the capacity of the coronary collateral system can
sinus node artery is derived from the proximal right coro- greatly increase. The myocardial collateral vessels can
nary artery in about 60% of hearts and from the left circum- increase in diameter into the range of 200 to 600 μm or
flex coronary artery in about 40% of hearts.18 The major
atrioventricular nodal artery is derived from the coronary
artery that gives rise to the posterior descending branch,
which is the right coronary artery in about 90% and the left
circumflex coronary artery in about 10% of hearts. Endocardium Myocardium Epicardium
The epicardial coronary arteries deliver oxygenated blood Arterioluminal
to the intramyocardial arteries, arterioles, and capillaries vessel
leading to oxygen and substrate extraction in the myocar- Myocardial sinusoid
dium (Fig. 1.8). A small amount of unoxygenated blood flows Intertrabecular space Coronary artery
directly into the ventricular cavities via the thebesian veins. Anastomoses
Anastomosis between
However, most desaturated blood traverses the myocardial myocardial sinusoids between
coronary arteries
venules and veins into the epicardial veins, which drain into Arteriosinusoidal
vessel
the coronary sinus located in the inferoposterior region of
Trabeculae carneae Arteriovenous
the right atrium. anastomosis
Collateral blood vessels form during embryologic devel- Capillary bed
opment of the heart, and they connect different components Myocardial sinusoid Venovenous
of the coronary arterial circulation.18–25 The coronary collat- Capillaries emptying into anastomosis
eral system is composed of four types of vessels: intramural myocardial sinusoids
Thebesian vein Coronary vein
branches of the same coronary artery (homocoronary collat-
erals); intramural branches of two or more coronary arteries Anastomosis between
thebesian veins
(intercoronary collaterals); atrial branches, which connect FIGURE 1.8. Diagram of the ventricular wall, showing the relation-
with the vasa vasorum of the aorta and other vessels (extra- ship between the various intramural vascular channels.
10 chapter 1

greater, develop muscular media, and transport significant

amounts of blood flow (Fig. 1.9). In addition to the types of
collateral vessels described above, collateral channels also
can develop proximal and distal to a stenosis in a given coro-
nary artery.

Right and Left Atria and Ventricles

FIGURE 1.9. Radiograph of postmortem coronary arteriogram dem-
onstrating an extensive coronary collateral system in a case of coro-
nary heart disease. The proximal part of the left anterior descending
artery is obliterated by old disease (O). The more distal part of the
anterior descending artery (A) has filled through a rich anastomotic
network (X) that has formed in the substance of the interventricular
septum between branches of the anterior (A) and posterior (P)
descending arteries.
The right and left atria and right and left ventricles have
distinctive anatomic features (Figs. 1.10 to 1.17). The ana-
tomic right ventricle is characterized as follows: distinct
muscular infundibulum (conus) arteriosus, which separates
the right semilunar (pulmonary) valve and the right atrioven-
tricular (tricuspid valve); single large anterior papillary
muscle; and coarse trabecular muscles (trabeculae carneae
cordis) at the apical and inflow portion of the chamber.11–17
Key landmarks of the right ventricular infundibular (conus)
region from inferior to superior are the membranous inter-
ventricular septum; the crista supraventricularis, an inverted
V-shaped structure with parietal and septal limbs; and the
pulmonic valve. The anatomic left ventricle has the follow-
ing features: fibrous continuity of annulus of left semilunar
(aortic) valve and anterior leaflet of left atrioventricular
(mitral) valve, two well-developed papillary muscles (antero-
lateral and posteromedial), and fine trabecular muscles at the
apical and inflow portion of the chamber.11–17 These features
allow determination of the anatomic right ventricle and ana-
tomic left ventricle in complex congenital anomalies involv-
ing displacement of the various components of the heart.
Cardiac Valves
The four-chambered heart has four valves: the right semilu-
minar or pulmonic valve; the right atrioventricular or tricus-
pid valve; the left semilunar or aortic valve; and the left

Ligamentum arteriosum

Left pulmonary artery Aorta

Probe in transverse sinus

Right pulmonary
artery
Right auricle
Left pulmonary Vena cava superior
veins
Left atrium Right ventricle
Foramina Crista terminalis
venarum
minimarum
Right pulmonary Left ventricle
veins
Interatrial
sulcus Right atrium
Limbus fossae Tricuspid
ovalis valve:
Fossa ovalis Anterior cusp
Orifice of coronary sinus Medial cusp
Valvula sinus coronarii
Posterior cusp
Valvula venae cavae
Vena cava inferior Musculus pectinatus
FIGURE 1.10. Right anterior oblique
Right coronary artery view of the excised heart, with the right
Small cardiac vein atrium opened to show its internal
configuration.
 a natom y of t h e h e a rt 11

Ascending aorta Right coronary artery

Superior
vena cava Pulmonary cone
Right auricular
appendage Crista supraventricularis
Crista
terminalis Papillary muscle
of conus
Pulmonary
vein
Interventricular septum
membranaceum
Limbus
fossae ovalis Septal cusp of
tricuspid valve
FIGURE 1.11. Right side of the heart Valve of inferior (cut)
opened in a plane approximately parallel vena cava
to the septa, to show the interior of the (eustachian v.) Anterior
right atrium and the right ventricle. A papillary
segment of the septal leaflet of the tri- Inferior vena cava muscle (cut)
cuspid valve has been removed to expose
more fully the region of the membra- Valve of coronary Posterior
nous portion of the interventricular sinus (thebesian v.) papillary
septum. muscle (cut)

Aorta Papillary muscle of conus

Crista supraventricularis Conus arteriosus
Pulmonary artery
Anterior pulmonary semilunar valve
Vena cava superior

Crista terminalis
Limbus fossae
ovalis
Fossa
ovalis

Right
atrium
Right
coronary artery
Vena cava inferior Anterior
FIGURE 1.12. Ventral view of the heart Tricuspid valve: Anterior cusp papillary
muscle
with the walls of the right atrium and of left
ventricle opened to show their internal Posterior cusp ventricle
configuration. This heart has an unusu- Medial cusp
ally well-developed moderator band, and Trabecula carnea Moderator band Left ventricle
Posterior papillary muscle Muscular interventricular septum
the position of the foramen ovale is Chorda tendineae Anterior papillary muscle
somewhat more cephalic than usual.
12 chapter 1

FIGURE 1.13. Photograph of opened right heart demonstrating conus arteriosus, i.e., infundibulum; CS, coronary sinus; PV, pul-
actual structures depicted in the illustrations. Note the muscular monic valve; RA, right atrium; RV, right ventricle.
infundibulum separating the tricuspid and pulmonic valves. CA,

Aorta
Pulmonary trunk
Superior
vena cava
Great cardiac vein
Orifice of right
coronary artery
Left coronary artery
Right superior
Right semilunar pulmonary vein
valve of aorta
Adherent
Interventricular margin of
septum valv. foram ov.
membranaceum
Interventricular Mitral valve (cut)
septum
musculare
Coronary sinus
Papillary
muscle Inferior
(cut) vena cava

FIGURE 1.14. Left side of the heart opened in a plane approximately been removed to expose more fully the region of the membranous
parallel to the septa, to show the interior of the left atrium and left portion of the interventricular septum and the aortic orifice.
ventricle. A portion of the anterior leaflet of the mitral valve has
 a natom y of t h e h e a rt 13

Left atrium
Valve of inferior
vena cava
Septum membra-
naceum
(atriovent. part.)
Septum membra-
naceum (interven-
tricular part.) Mitral
Atrioven- valve
tricular
bundle
Tricuspid
valve

Papillary
muscle Papillary
muscles

Interventricular
septum

FIGURE 1.15. Frontal section through a heart fixed in

diastole, showing a ventral view of the dorsal portion.
The plane of section passes through the septum mem-
branaceum and both atrioventricular ostia.

FIGURE 1.16. Photograph showing the relationship of the membra-

nous interventricular septum (lighted) to the tricuspid annulus and
septal leaflet of the tricuspid valve. While the membranous interven-
tricular septum is entirely contained in the left ventricle, the supe-
rior portion of the interventricular septum extends superior to the
tricuspid annulus. This anatomic relationship allows for left ven-
tricular to right atrial shunts in certain pathologic states, such as
infective endocarditis of the aortic valve. MIS, membranous inter-
ventricular septum; SLTV, septal leaflet of the tricuspid valve.
FIGURE 1.17. Photograph of opened left ventricle showing continu-
ity of the anterior mitral leaflet and the annulus of the aortic valve.
AML, anterior mitral leaflet; LC, left cusp of aortic valve; NCC,
noncoronary cusp of aortic valve; PPM, posterior papillary muscle;
RC, right coronary cusp of aortic valve.
14 chapter 1

Pulmonary annulus fibrosus Conus ligament

Ant. descending br.

Right coronary art.

Left coronary art.

Aortic
Circumflex br. annulus fibrosus

Left fibrous
triangle Atrioventricular
bundle
Right fibrous
friangle
Annulus fibrosus
Annulus fibrosus of tricuspid valve
of mitral orifice

Anastomosing branch Post. descending br. of right coronary a.

FIGURE 1.18. Ventricular portion of the heart viewed from above tricular musculature to them. Epicardial fat has been removed from
with the atria removed, to show the four cardiac valves and the the atrioventricular sulcus in order to show the coronary arteries.
fibrous triangles, the annuli fibrosi, and the attachment of the ven-

atrioventricular or mitral valve (Figs. 1.18 to 1.21). The pul-
monic and aortic semilunar valves each have three cusps
separated by three commissures, and the cusps insert into a
fibrous connective tissue annulus. The aortic valve cusps are
designated as the left and right cusps in relationship to the
coronary ostia and a third, noncoronary cusp. With valve
closure during diastole, the cusps of the aortic and pulmonic
valves make contact along a line about 1 to 2 mm below the
free margin. The central points of maximal contact are espe-
cially prominent and are known as the noduli of Arantius.
The most common congenital valve lesion is a malformed
aortic valve, either a unicuspid or bicuspid valve.
The tricuspid or right atrioventricular valve has three
leaflets (cusps) that are separated by three commissures and
insert into a fibrous annulus. The leaflets are designated as
the lateral, medial, and anterior leaflets. The leaflets are
attached to the ventricular muscle by multiple chordae ten-
dineae, which extend from the ventricular surfaces of the

Ant. desc. branch of

Pulmonary
left coronary art.
semilunar valve

Pulmonary
Noncoronary cusp of
conus
aortic semilunar v.

Septum
Septal cusp of
membranaceum
tricuspid valve

Bundle of his
Muscular part of
interventricular
septum Mitral valve

FIGURE 1.19. Interior of the ventricular base of the heart, exposed interventricular septum membranaceum, and the mitral, the tricus-
by removal of the apical half of the ventricles. The interventricular pid and the aortic valves.
septum has been partially removed to show the relations of the
 a natom y of t h e h e a rt
leaflets to the mural ventricular wall as well as a well-
developed anterior papillary muscle and a diminutive struc-
ture, the papillary muscle of the conus.
The mitral or left atrioventricular valve has a highly
developed and coordinated group of structures that are
referred to as the mitral valve apparatus (Figs. 1.18 to 1.21).
The mitral valve apparatus consists of fibrous annulus, ante-
rior and posterior leaflets, anterior and posterior commis-
sures, multiple chordae tendineae, and anterolateral and
posteromedial papillary muscles. Chordae tendineae extend
from the ventricular surfaces of both leaflets and attach to
both papillary muscles. Chordae tendineae exhibit a branch-
ing pattern with primary chordae arising from the papillary
muscles and branching into secondary and then tertiary
chordae, which insert into the valvular leaflets. Mitral valve
dysfunction can result from a wide variety of pathologic
processes affecting any component of the mitral apparatus,
including the myocardium.
The anterior mitral leaflet is usually a single structure,
whereas the posterior leaflet may be divided into two or three
scallops (Fig. 1.21). The anterior mitral leaflet normally has
a significantly larger area and longer length from annulus to
free margin that the posterior mitral leaflet. As a result, the
anterior leaflet contributes about two thirds of the area of
leaflet tissue involved in closure of the mitral orifice during
systole. Expansion of the posterior leaflet to equal the length
FIGURE 1.20. Photograph of left ventricle showing aortic valve and
a portion of the mitral apparatus, including the anterior mitral
leaflet, chordae tendineae, and papillary muscles. AML, anterior
mitral leaflet; APM, anterior papillary muscle; CT, chordae tendin-
eae; LC, left cusp of aortic valve; PPM posterior papillary muscle.
15
FIGURE 1.21. Photograph of mitral valve showing a portion of the
anterior mitral leaflet and the posterior leaflet consisting of multiple
scallops. AML, anterior mitral leaflet; PML, posterior mitral leaflet.
of the anterior leaflet from annulus to free margin is an
important anatomic feature of myxomatous degeneration of
the mitral valve. Other features include general redundancy,
thickening, and a glistening white appearance of leaflet
tissue and chordae tendineae.
Cardiac Conduction System and
Cardiac Innervation
The anatomy of the cardiac conduction system has been
defined by meticulous study (Fig. 1.22).26,27 The sinoatrial
node is located in the superficial subepicardium of the
superior right atrium at the junction of the superior
vena cava and the right auricular appendage. The sinoatrial
node contains myocytes that are specialized for the genera-
tion of electrical impulses and constitute the cardiac
pacemaker. The electrical impulse propagates selectively
along certain paths in the atria; however, the existence of
anatomically distinct conduction pathways in the atria is
difficult to demonstrate. Atrioventricular conduction is
accomplished by specialized structures, the more proximal
atrioventricular node (node of Tawara) and the more
distal atrioventricular bundle (bundle of His). The atrioven-
tricular node is positioned in the inferior interatricular
septum just anterior and medial to the ostium of the coro-
nary sinus. The specialized conduction tissue then extends
through the fibrous skeleton separating the atria and ven-
tricles to connect to the bundle of His, which is located at
the apex of the muscular interventricular septum. The His
bundle gives origin to the right and left bundle branches,
which extend through the subendocardium of the interven-
tricular septum into the right and left ventricular free
walls.
The heart has a dual innervation from the sympathetic
(thoracolumbar) and parasympathetic (craniosacral) divisions
of the autonomic nervous system (Fig. 1.23). These nerves
interact with the conduction tissue to provide neural modu-
lation of cardiac function.
16 chapter 1

Superior Right pulmonary

vena cava vein Left pulmonary
vein
Sino-atrial
node
Left
atrial wall
Fossa
ovalis

Coronary Mitral
orifice valve

Inferior
vena cava Septum
membranaceum
Atrio-ventricular
node Bifurcation
of bundle

Main atrio-
ventricular bundle
(bundle of his) Left
branch of
bundle
Right branch
of bundle
Purkinje
fibers under
Branch of bundle in endocardium
moderator band of papillary musc. FIGURE 1.22. Schematic diagram of heart
opened frontally, demonstrating the location
Branch under septal endocard. and relations of the several parts of the sino-
atrial and atrioventricular conduction system.

Superior cardiac
Superior cervical nerve
ganglion

Superior cardiac
nerve Middle cardiac nerve
Inferior cervical Superior cardiac branch
ganglion
Vagus nerve Inferior cervical ganglion
First thoracic ganglion
Ansa of vieussens

Inferior
cardiac
branch Superficial
cardiac
plexus
Ganglion of
Deep cardiac wrisberg
plexus

Pulmonary
plexus

Right
coronary
plexus Left
coronary
plexus

FIGURE 1.23. Ventral view of thorax to show

the nerve supply to the heart.
 a natom y of t h e h e a rt
Summary
This chapter presented a description and illustration of the
embryologic and anatomic features of the heart and great
vessels. The embryologic development of the cardiac struc-
tures was presented, and the relationship of cardiac develop-
ment to congenital heart diseases was discussed. Key
components of the mature heart were described and illus-
trated, including the pericardium, the coronary arteries, the
four cardiac valves, the right and left atria and ventricles, and
the cardiac conduction system and cardiac innervation. The
relationship of structure to function was considered. Under-
standing cardiovascular anatomy is important for the diag-
nosis and treatment of cardiovascular diseases.
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cular Pathology, 2nd ed. New York: Churchill-Livingstone,
1991:1367–1428.
 2 The History and Physical
Examination
Thomas C. Smitherman and James T. Willerson
Importance of the Patient History . . . . . . . . . . . . . . . . . . . 19
Differential Diagnosis of the Signs and Symptoms
Commonly Seen in Heart Disease. . . . . . . . . . . . . . . . 19
Importance of the Patient History
The importance of a carefully obtained and accurate history
from the patient with cardiovascular disease cannot be over-
emphasized. In many instances, such a history enables the
examiner to recognize the etiology of the problem relatively
rapidly. Without it, evaluation of the patient’s problem is
much less effective and definitive.
The patient’s general appearance often helps the physi-
cian to focus questions so as to obtain a meaningful history.
The patient’s family history may also assist the physician in
the history-taking process, given that the genetic risks for
cardiovascular disease are very important, especially when
cardiovascular disease has occurred at a relatively young age
in a patient’s father, mother, siblings, or grandparents. Risk
factors for specific cardiovascular diseases enable the physi-
cian to elicit specific complaints related to the patient’s car-
diovascular problem. A history of substance abuse should
lead to specific questions. Cardiovascular abnormalities
detected on physical examination should also help the exam-
iner to elucidate a meaningful history.
We have found it useful to focus on a set of questions
immediately directed at an apparent or a suspected cardio-
vascular abnormality during the first few minutes of the
patient interview. General questions may be asked later.
The examiner must try to obtain both subjective and
objective, even quantitative, answers to specific questions.
Although it is necessary to know about the presence of chest
pain, dyspnea, and easy fatigability, it is also necessary to
determine the specific type of pain present and what pro-
vokes and relieves it. Similarly, learning the amount of effort
required before dyspnea occurs or the amount of effort
required before the patient tires is useful in determining
specific etiologies for a particular cardiovascular problem
and in determining the severity of the patient’s limitation.
In evaluating the patient with chest pain, one must deter-
mine whether the pain is anginal or pleuritic in quality.
Pleuritic pain raises questions concerning pulmonary or
pericardial pain, whereas anginal pain suggests the presence
of one of the coronary artery disease (CAD) syndromes or
Physical Examination of the Patient with
Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
severe left ventricle (LV) outflow obstruction or severe LV
hypertrophy. Dyspnea may be caused by pulmonary or
cardiac problems but sometimes is simply a manifestation
of anxiety. Easy fatigability can be caused by heart or lung
disease or by extracardiac factors, such as anemia, thyrotoxi-
cosis, obesity, renal disease, or a systemic malignancy.
A careful history should elucidate the patient’s family
history, any substance abuse, any evidence of syncope,
dyspnea, orthopnea, chest pain, abdominal pain, discomfort
in the legs while walking, headaches, muscle weakness,
hemoptysis, tiring unduly rapidly with physical effort, palpi-
tations, fever, diaphoresis, loss of appetite, weight loss or
gain, and history related to the presence or absence of risk
factors for cardiovascular diseases.
A carefully obtained history from a patient with cardio-
vascular disease almost always leads the knowledgeable
physician toward a more rapid and correct diagnosis of the
patient’s cardiovascular problem and the development of an
effective treatment plan. When an accurate and careful
history is not or cannot be obtained, it is often difficult to
identify the correct etiology of a cardiovascular problem, and
can lead to the use of less than optimal diagnostic and thera-
peutic interventions.
Heart disease is manifested by various signs and symp-
toms. Cardiac dysfunction influences many organ systems,
and many noncardiac illnesses are expressed in findings
similar to those produced by cardiovascular disease.
Differential Diagnosis of the Signs and
Symptoms Commonly Seen in Heart Disease
Dyspnea
Dyspnea, the labored breathing usually referred to as short-
ness of breath, is a distressful sensation of air hunger. It is
abnormal only when the sensation of breathlessness is inap-
propriate to the level of physical activity that provoked it. The
major causes of dyspnea are listed in Table 2.1. Although sub-
stantial information is available on the normal control of
19
20 chapter
TABLE 2.1. Causes of dyspnea
Heart disease
Left ventricular failure
Restrictive cardiomyopathy
Constrictive pericarditis
Pulmonary venous obstruction
Mitral stenosis
Cor triatriatum
Left atrial myxoma
Left atrial thrombus
Tamponade
Pulmonary disease
Obstructive airways disease
Chronic obstructive pulmonary disease
Asthma
Restrictive lung disease
Interstitial or diffuse alveolar lung disease
Disorders of chest wall and bellows function
Kyphoscoliosis
Arthritis
Neuromuscular disease
Obesity
Vascular disease
Pulmonary embolism
Primary pulmonary hypertension
High altitude exposure
Anemia
Anxiety (hyperventilation syndrome)
ventilation, the mechanism of the uncomfortable breathless-
ness of dyspnea is unclear. It is notable that some causes of
marked hyperpnea, such as metabolic acidosis, do not cause
dyspnea. The same can be said of the hyperpneic phase of
Cheyne-Stokes respiration. However, the examination can
point to some abnormalities that eventually lead to dyspnea.
When left-sided congestive heart failure (CHF) and
obstruction to filling of the left side of the heart develop, as
occurs with mitral stenosis and left atrial myxoma, pulmo-
nary venous and pulmonary capillary pressures are chroni-
cally elevated, causing interstitial and intraalveolar edema.
This interferes with normal pulmonary compliance and
reduces airway size and oxygen diffusion. Disorders associ-
ated with intracardiac right-to-left shunts are accompanied
by chronic systemic hypoxia. With uncomplicated right ven-
tricle (RV) outflow obstruction, there is hypoperfusion of the
pulmonary vasculature. In pulmonary disease, ventilatory
impairment is present; this can be attributed to either an
obstructive or a restrictive phenomenon. Pulmonary embo-
lization is followed by a reduction in pulmonary flow in the
affected segments, with consequent ventilation-perfusion
abnormalities. Bronchospasm may occur in the wake of a
pulmonary embolus, probably mediated by the release of
substances that lead to contraction of smooth muscle. The
dyspnea that may occur with pulmonary hypertension with
a normal cardiac output is not well understood but may be
related in part to reflex-stimulated hyperventilation. There
may be hypoxemia with severe anemia and at high altitudes,
especially during exertion.
Cardiac and pulmonary disorders account for the vast
majority of cases of dyspnea. When either system is involved
in the absence of disease of the other, differentiation of the
cause of dyspnea is usually not difficult. When both the heart
2
and the lungs are abnormal, differentiation of the etiology
of the dyspnea is difficult but imperative. To differentiate
cardiac from pulmonary dyspnea, associated signs and symp-
toms of heart disease should be sought. Progressive dyspnea
over a relatively short time is usually an important clue to
cardiac dyspnea, as opposed to the generally long-standing
symptoms of pulmonary disease. The presence of pulmonary
disease is usually obvious from the history and physical
examination. Chronic progressive shortness of breath with a
productive cough, chronic rhonchi and wheezes, diminished
breath sounds, and respiratory capacity, with abnormal pul-
monary function test values and the absence of evidence of
heart disease, help to confirm pulmonary disease as the chief
cause of dyspnea. Radiologic evidence of specific cardiac or
pulmonary disease may provide cogent evidence for the
cause of dyspnea.
Evidence of acute infection should be sought because it
is frequently the cause of worsening symptoms in chronic
lung diseases. Redistribution of pulmonary blood flow to the
upper lung fields, usually a sign of increased pulmonary
venous pressure and, hence, evidence of cardiac dyspnea,
must be interpreted cautiously in the face of chronic obstruc-
tive lung disease, which may cause this radiologic change
without raised pulmonary venous pressure.
Pulmonary emboli frequently cause dyspnea. The pres-
ence of conditions favoring venous thromboembolism or
hemoptysis, pleuritic chest pain, fever, tachycardia, and jaun-
dice from the history and physical examination, coupled
with evidence of acute right heart strain on examination and
electrocardiogram (ECG), and atelectasis or a pleural-based
parenchymal radiodensity with a rounded profile toward the
hilus (Hampton’s lump) on chest radiography, may provide
clues to pulmonary emboli, especially large ones. If emboli
are small, however, there may be insufficient clinical clues
to establish the diagnosis, and helical (spiral) computed
tomographic scanning of the pulmonary arteries and lungs
or perfusion and ventilation lung scintigraphy of the lungs
may be necessary. Pulmonary arteriography may be required
rarely.
The characteristic features of disorders with an intracar-
diac right-to-left shunt (e.g., pulmonary stenosis, pulmonary
hypertension, and severe anemia) usually facilitate the estab-
lishment of the cause of dyspnea in patients with these
disturbances. Patients with psychogenic dyspnea tend to
demonstrate prominent sighing respiration with large and
erratic title volumes. Other symptoms of hyperventilation
and neurotic behavior may also be present.
Orthopnea is dyspnea in the recumbent posture. It is
usually due to LV failure or inflow obstruction. More of the
lung is below the level of the heart during recumbency, and
consequently pulmonary capillary pressure is further raised.
Patients can often approximately quantify its severity on the
basis of the number of pillows necessary to achieve relief.
Resumption of upright posture provides quick relief. Similar
symptoms may be encountered in patients with pulmonary
disease. The mechanisms involved are probably less efficient
movement of the ventilatory apparatus and pooling of secre-
tions in the recumbent position.
Paroxysmal nocturnal dyspnea occurs several hours after
assumption of a recumbent position. It, too, is usually due
to LV failure or inflow obstruction. Pulmonary venous pres-
 t h e h istory a n d ph ysica l e x a m i nat ion 21
sure is raised by the lowered position of the lungs relative to Angina Pectoris
the heart and by return of extravascular fluid to the intravas-
cular space. Typically, the patient wakes, sits upright, and Angina pectoris results from an imbalance between myo-
seeks fresh air. Pulmonary disease may cause a similar syn- cardial oxygen demand and oxygen delivery by coronary
drome, probably for the same reason that it may cause artery flow. It is most commonly due to a significant reduc-
orthopnea. tion in coronary blood flow. Coronary atherosclerosis is the
most common cause of this reduction. However, angina
may also be caused by disorders that increase myocardial
Chest Pain oxygen demand, such as aortic stenosis and hypertrophic
Pain from different sources may be expressed as chest dis- obstructive cardiomyopathy, or by disorders that both
comfort. Visceral pain is noted in the somatic area with increase myocardial oxygen demand and decrease coronary
which it shares a final common pathway. The demarcation artery flow, such as aortic regurgitation. The characteristic
of visceral pain, however, is less precise than that of somatic findings on physical examination and the ECG in patients
pain because of the distribution of visceral pain to several with aortic valvular and subvalvular disease usually make
adjacent spinal cord segments. Chest pain due to cardiac it easy to differentiate angina complicating these disorders
disease consequently must be differentiated from that due from angina caused by CAD. Angina is typically described
to disorders of other thoracic viscera and the upper as substernal squeezing, pressure, heaviness, burning,
abdomen. Some of the important causes of chest pain are aching, or a bursting sensation. The patient may describe it
listed in Table 2.2. graphically with a clenched fist over the midchest (Levine’s
sign). (Interestingly, patients often insist that the sensation
is a discomfort, not pain.) Radiation of the pain occurs
often, usually to the left shoulder, neck, jaw, and ulnar dis-
TABLE 2.2. Causes of chest pain
tribution of the left arm. Radiation to the same areas on the
Heart disease right side and to the epigastrium also occurs. Pain referral
Angina pectoris to the interscapular or left scapular regions occurs less
Atheromatous coronary artery disease
Nonatheromatous coronary artery disease commonly.
Aortic stenosis Typical stable angina is precipitated by exertion, emo-
Aortic insufficiency tional upsets, cold exposure, or eating and is usually relieved
Idiopathic hypertrophic subaortic stenosis (hypertrophic by rest or nitroglycerin within 5 minutes. It may be accom-
obstructive cardiomyopathy)
panied by dyspnea when myocardial ischemia is associated
Myocardial infarction
Congestive cardiomyopathy with LV dysfunction (diastolic, systolic, or both) or mitral
Pulmonary hypertension regurgitation. Stable angina is predictable in both its fre-
Mitral valve prolapse (click-murmur) syndrome quency and case of provocation. We find it useful to use the
Pericarditis Cedars-Sinai grading system to classify possible anginal dis-
Dissection of the aorta comfort into three categories—typical angina, atypical
Pulmonary disease angina, and nonanginal chest discomfort—based on a simple
Pulmonary embolism three-point system. The location and nature of the discom-
Pleuritis
Pneumothorax fort, its provocation by stressors, and its prompt relief with
Pneumonia rest and nitrates are each given one point. Typical angina
Tumor requires 3 points, atypical angina 2 points, and nonanginal
Collagen disease discomfort 0 or 1 point.
Atelectasis
Musculoskeletal disease
Arthritis
Costochondritis (Tietze’s syndrome)
Bursitis Unstable Angina Pectoris and Acute
Intravertebral disk disease Myocardial Infarction
Thoracic outlet syndrome
Muscle spasm Unstable angina refers to pain that occurs at night (nocturnal
Fracture angina), at rest (angina decubitus), with increasing frequency
Metastatic tumor or hematologic (leukemia) or plasma cell or duration, or with less predictable provocation and relief.
(myeloma) malignancy It may be accompanied by either a normal ECG or one with
Neural disease manifestations of ischemia. With acute myocardial infarc-
Intercostal neuritis
tion (MI), the discomfort is similar to that of angina but
Herpes zoster
occurs or continues at rest and is more intense and more
Gastrointestinal disorders (“referred” chest pain)
Hiatal hernia prolonged, often requiring opiate analgesics for relief. It is
Cholecystitis frequently associated with diaphoresis and nausea and vom-
Pancreatitis iting. It can be accompanied by dyspnea or by palpitations or
Ulcer disease syncope when LV failure or cardiac rate or rhythm dis-
Bowel disease
turbances complicate the MI. The ECG and biomarkers for
Neoplasm myocardial necrosis, along with the history, facilitate
Emotional duress or anxiety (e.g., neurocirculatory asthenia, differentiation of stable angina from unstable angina pecto-
DaCosta’s syndrome)
ris and MI.
22 chapter
The Chest Discomfort of Microvascular Angina
(Syndrome X)
The discomfort of microvascular angina must be distin-
guished from angina associated with flow-limiting epicardial
coronary artery disease. This entity is more common in
women than men, especially premenopausal women, and is
often seen in patients who are younger than most patients
with flow-limiting epicardial coronary artery disease. This
disorder is diagnosed when the patient has angina-like dis-
comfort, ST-segment depression with exercise testing, or
other evidence of exercise-induced ischemia, but with normal
coronary arteriograms and no documented propensity to epi-
cardial coronary arterial spasm. In up to half of patients, the
discomfort is similar to typical angina, but in the other half
there are distinctly atypical features, especially prolonged
discomfort and limited relief by nitrates. The causes of this
disorder remain uncertain. Coronary arteriography is often
required to unambiguously distinguish this disorder from
atheromatous coronary artery disease.
Pericarditis
Chest pain resulting from pericarditis is usually pleuroperi-
cardial and increases in severity with coughing; deep breath-
ing; sometimes with swallowing; and movement, especially
assumption of the supine position. A friction rub on exami-
nation and the typical electrocardiographic, echocardio-
graphic, and computed tomographic features usually serve to
differentiate it from angina.
Dissecting Aneurysm of the Thoracic Aorta
Pain caused by a dissecting aneurysm of the thoracic aorta
may also mimic angina, but it is characteristically of a
tearing or ripping quality and is typically most severe in the
suprasternal notch, the neck, the back, or the lumbar region.
It is often excruciatingly severe and requires narcotic anal-
gesics for relief. Associated findings, such as pulse deficits,
acute aortic regurgitation, a widened or disfigured aortic
profile on chest radiography, or new neurologic deficits,
should raise the index of suspicion for this disorder, espe-
cially in the patient with systemic arterial hypertension.
Computed tomography, with special protocols for this order,
transesophageal echocardiography (TEE), or magnetic reso-
nance imaging (MRI) are usually necessary to establish the
diagnosis with certainty.
Other Cardiac Disorders
The chest pain that accompanies prolapse of the mitral valve
(click-murmur syndrome), congestive cardiomyopathy, and
pulmonary hypertension may mimic angina closely, but a
carefully taken history usually reveals atypical features for
angina. Physical, radiographic, echocardiographic, perfusion
scintigraphic, and electrocardiographic examinations usually
clarify the probable cause of the chest discomfort in these
cases. Occasionally, however, only coronary arteriography
will exclude the presence of significant coronary artery
narrowing.
2
Chest Pain of Noncardiac Origin
Patients with pulmonary problems may present with chest
pain. When pain is a manifestation of pneumonia, pleurisy,
pneumothorax, or pulmonary embolus, it is usually pleuritic.
Gastrointestinal disorders, especially those of the esophagus,
may be associated with referred pain to the chest. Although
the pain of inflammation, diffuse spasm, rupture of the
esophagus, peptic ulcer disease, pancreatitis, or cholecystitis
may mimic angina, there are usually sufficiently specific
complaints and atypical features for angina in a well-taken
history to point to a gastrointestinal origin. Proper labora-
tory and radiologic examinations reveal the source of the
pain. It must be remembered that noncardiac disorders can
act as a trigger for angina in the patient with CAD, and the
confirmation of noncardiac disease does not always elimi-
nate the possibility that the patient’s discomfort is angina.
A frequent cause of chest pain of noncardiac origin is
anxiety (DaCosta’s syndrome, neurocirculatory asthenia,
soldier’s heart, cardiac neurosis). Although the pain may
mimic angina, it is typically fleeting and lancinating or a
prolonged aching pain; it usually occurs after rather than
during effort. It is commonly associated with evidence of the
hyperventilation syndrome. Unfortunately, the many prob-
lems and fears that accompany chronic heart disease often
leave anxiety and a cardiac neurosis in their wake, so the
symptoms of cardiac disease and neurosis coexist and must
be carefully ferreted out by the physician.
Occasionally, costochondritis (Tietze’s syndrome), the
thoracic outlet syndrome, intercostal nerve herpes zoster,
chest wall pain, and disorders of the thoracic and cervical
spine may cause chest discomfort that must be differentiated
from pain of cardiac origin; with herpes zoster infection and
chest wall pain, the severe pain may precede the develop-
ment of the characteristic skin rash by several days.
Cough and Hemoptysis
Coughing is a voluntary or reflex act to clear the tracheo-
bronchial tree of secretions or particulate matter. The stimu-
lus for coughing is usually produced by mucosal irritation
from the larynx to second-order bronchi, which are respon-
sive to inflammatory, mechanical, chemical, and thermal
stimuli. The nature of the cough is an important factor in
identifying its cause and the cough should be defined as
productive or nonproductive, with characterization and
quantification of the sputum.
Cough may be an early manifestation of pulmonary
venous hypertension due to LV failure or pulmonary venous
obstruction, as in mitral stenosis. It may be overlooked as a
symptom of heart disease if respiratory infection precipitates
cardiac decompensation. The cough of early heart failure is
nonproductive or productive of only small amounts of whitish
sputum. It most frequently is nocturnal, occurring soon after
the patient assumes the supine position, and may continue
as a prominent symptom interfering with sleep. It is related
to bronchiolar edema and may be present without rales.
Patients with mitral stenosis may also experience bouts of
coughing, which may be confused with chronic bronchitis.
Blood streaking of the sputum may occur after a paroxysm
of coughing related to pulmonary venous congestion. Cough
 t h e h istory a n d ph ysica l e x a m i nat ion
TABLE 2.3. Causes of hemoptysis
Cardiac
Pulmonary venous hypertension
Left ventricular failure
Mitral stenosis
Eisenmenger’s syndrome
Pulmonary
Infection
Pneumonitis
Bronchitis
Bronchiectasis
Abscess
Tumor
Trauma or foreign body
Vascular
Rupture of atrioventricular fistula
Thoracic aortic aneurysm
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu
syndrome)
Primary pulmonary hypertension
Pulmonary embolism
Goodpasture’s syndrome
Vasculitides
Polyarteritis nodosa
Systemic lupus erythematosus
Wegener’s granulomatosis
Bleeding diathesis
may also be a manifestation of CHF in children with large
left-to-right shunts. A chronic nonproductive cough similar
to that noted in early LV failure is common in patients with
pulmonary fibrosis or infiltration and lesions that compress
the trachea and bronchi, such as lung tumors and aortic
aneurysms. Pulmonary infection produces a purulent, exu-
dative cough. In chronic obstructive pulmonary disease
(COPD), the cough is productive, with purulence dependent
on the presence and severity of acute and chronic bronchitis.
The sputum of patients with bronchiectasis is characteristi-
cally mucopurulent, malodorous, and copious.
Hemoptysis is a relatively rare manifestation of cardiac
disease. The important causes of hemoptysis are itemized in
Table 2.3. Occasionally, high pulmonary venous pressure
resulting from chronic CHF or mitral stenosis may lead to
the rupture of pulmonary capillaries and the production of
blood-streaked sputum. Hemoptysis in mitral stenosis may
be small in amount and recurrent or quite brisk when related
to rupture of endobronchial bronchopulmonary venous vari-
cosities. This is particularly likely when an abrupt increase
in pulmonary venous pressure occurs with increased heart
rate. Eisenmenger’s syndrome also is sometimes associated
with prominent hemoptysis; in these patients, hemoptysis
presumably results from rupture of pulmonary arterioles as
a consequence of increased pulmonary artery pressure and
resistance. Encroachment on the tracheobronchial tree by an
aortic aneurysm may lead to either a small amount of hemop-
tysis or fatal exsanguination.
Hemoptysis is usually due to disease in the lungs or
the pulmonary vasculature. It is a relatively common mani-
festation of pulmonary infection, tumors, trauma, pulmo-
nary embolism and infarction, and disorders affecting the
pulmonary vasculature, such as Goodpasture’s syndrome,
23
hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu
syndrome), and several vasculitides (especially Wegener’s
granulomatosis, periarteritis nodosa, and systemic lupus ery-
thematosus). Fortunately, these problems are usually easily
differentiated from cardiac disease because of their charac-
teristic features.
Palpitations
Palpitations are a subjective consciousness of the beating of
the heart (Table 2.4). Alterations in heart rate, rhythm, or
force of contraction may be experienced as palpitation. This
sensation may be appreciated by the patient as a stopping,
skipping, fluttering, jumping, pounding, or racing of the
heart or as nervousness or uneasiness in the chest. With
tachyarrhythmia, the patient may be able to describe the
manner of onset and the rate and regularity of heartbeat. It
is important to note associated symptoms related to the
beating of the heart, particularly any change in the level of
consciousness. Palpitations may be related to the occurrence
of a cardiac arrhythmia but also can be experienced with no
disturbance at all in rhythm or rate. Enhanced contractility
or a heightened awareness of autonomic function with
anxiety may sensitize the individual to the heartbeat.
Premature contractions of supraventricular or ventricu-
lar etiology may be experienced as an early beat, a pause or
skipped beat, or “flopping” or “thudding” related to the
intensely contractile beat after the premature beat.
Paroxysmal bouts of supraventricular tachyarrhythmias
are often appreciated as being abrupt in onset. They may be
irregular, as with atrial fibrillation, atrial flutter, or paroxys-
TABLE 2.4. Causes of palpitations
Extrasystoles
Atrial premature beats
Atrioventricular junctional (nodal) premature beats
Ventricular premature beats
Tachyarrhythmias
Supraventricular
Regular
Sinus tachycardia
Paroxysmal supraventricular tachycardia
Atrioventricular junctional tachycardia
Atrial flutter
Irregular
Atrial fibrillation
Paroxysmal supraventricular tachycardia or atrial flutter with
varying atrioventricular block
Multifocal atrial tachycardia
Ventricular tachycardia
Bradycardia
Sinus bradycardia
Sinus arrest
Second- or third-degree atrioventricular block
Conditions associated with increased force of cardiac
contraction
Thyrotoxicosis
Anemia
Fever
Certain drugs, including catecholamines and cardiac
glycosides
Anxiety states
24 chapter
mal supraventricular tachycardia with variable atrioventric-
ular (AV) block and multifocal atrial tachycardia, or regular,
as with paroxysmal supraventricular tachycardia, or atrial
flutter with a consistent pattern of AV conduction. Cessation
of these arrhythmias is likewise often abrupt. Ventricular
tachycardia is as frequently manifested by its symptoms
than as appreciation of palpitation. Other causes of palpita-
tions include hyperkinetic states (e.g., intense exertion, fever,
thyrotoxicosis, hypoglycemia, anemia, AV fistula, and
pheochromocytoma).
Drugs that may be associated with the production of
palpitations include amphetamines, ephedrine, aminophyl-
line and other sympathomimetic agents, xanthine-contain-
ing beverages (coffee, tea, and cola), alcohol, tobacco, and
excessive digitalis glycosides or thyroid hormone. Hypokale-
mia, hypercalcemia, and hypoxia may produce palpitations
by inducing atrial or ventricular rhythm disturbances.
Anxiety states may be associated with palpitations because
of a heightened appreciation of cardiac function, emotional
duress, hyperventilation, or tachycardia, usually sinus
tachycardia.
In cases where determination of the cause of palpitations
is difficult, the history and physical examination and appro-
priate laboratory data can be greatly aided by dynamic ECG
(Holter) monitoring or event ECG monitoring with a careful
diary of the time and nature of symptoms. We find Holter
monitoring to be helpful mostly in those cases where palpita-
tions occur at least every day or two, and event monitoring
to be more helpful when palpitations are less frequent. Exer-
cise testing also may demonstrate the occurrence of arrhyth-
mia during an increased workload or immediately after its
cessation.
Syncope
Complete AV block is the most common cause of Stokes-
Adams attacks, but markedly fast or slow heart rates of any
cause may be responsible. Unduly rapid or slow supraven-
tricular or ventricular dysrhythmias or second-degree AV
block produces fainting as a consequence of the inability of
the heart to maintain normal cardiac output at these
extremes of heart rate. The patient’s ability to cope with
cardiac dysrhythmia is influenced by the overall status of
the heart and the presence of other forms of disease (e.g.,
cerebral vascular disease, anemia). Syncope may occur either
at the onset of, during, or after the termination of the dys-
rhythmia. Bradyarrhythmias and, occasionally, advanced AV
block are sometimes encountered with vasovagal episodes,
but also may occur with fainting associated with carotid
sinus disease, traction on an esophageal diverticulum, medi-
astinal tumors, gallbladder disease, glossopharyngeal neural-
gia, pleural and pulmonary irritation, and rapid decompression
of pericardium, pleural, and peritoneal spaces by needle or
catheter aspiration of fluid (Table 2.5).
Other forms of heart disease also may be associated with
syncope. Effort syncope is one of the cardinal manifestations
of hemodynamically significant aortic stenosis. Arteriolar
vasodilatation during muscular work or as the result of acti-
vation of high-pressure baroreceptors in the left heart, with
failure to increase cardiac output to balance this fall in
peripheral vascular resistance, results in a reduction in
2
TABLE 2.5. Causes of syncope
Cardiac
Decreased cerebral perfusion due to cardiac dysrhythmia or
conduction defect
Left ventricular outflow obstruction
Valvular aortic stenosis
Supravalvular aortic stenosis
Discrete subvalvular aortic stenosis
Hypertrophic obstructive cardiomyopathy
Tetralogy of Fallot
Orthostatic hypotension
Vasovagal (vasodepressor, psychogenic)
Micturition syncope
Cough syncope
Carotid sinus syncope
Glossopharyngeal neuralgia
Metabolic
Hypoglycemia
Hypoxia
Hyperventilation
Central cerebral mechanisms
Cerebrovascular accident
Transient ischemic attacks
Subclavian steal syndrome
Migraine
Vasculitis
Tumor
Seizure disorder
Somatization of symptoms
systemic arterial blood pressure and diminished cerebral
perfusion. Postexertional syncope occurs in hypertrophic
obstructive cardiomyopathy due to an abrupt worsening of
the muscular outflow obstruction that probably results from
a rapid drop in LV filling and blood pressure in the face of a
sustained increased inotropic state that occurs with cessa-
tion of exercise. Sudden and severe valvular obstruction
occurring with left atrial myxoma or ball-valve thrombus or
with thrombosis or malfunction of a prosthetic valve may
also produce syncope. Tetralogy of Fallot is the most common
form of congenital heart disease associated with syncope.
Systemic vasodilatation with increased right-to-left shunting
(probably associated with infundibular spasm) is likely the
mechanism for fainting during “spells” in children with
tetralogy of Fallot. Primary pulmonary hypertension may be
associated with syncope.
The most common cause of fainting is neurocardiac
syncope, which can be either cardioinhibitory (bradycardia,
enhanced parasympathetic tone) or vasodepressor (hypoten-
sion, decreased sympathetic tone) or both in cause. Fre-
quently, there is a history of triggers for syncope, such as
noxious stimuli, venipuncture, heat exposure, emotional
duress, or prolonged standing. Autonomic manifestations are
often present, with pallor, perspiration, epigastric distress or
nausea, pupillary dilatation, yawning and hyperventilation,
visual blurring, auditory diminution, weakness, or confu-
sion preceding actual loss of consciousness.
In some patients, stimulation of the carotid sinus (carotid
sinus hypersensitivity) leads to a profound decrease in sys-
temic arterial pressure or a marked slowing of heart rate or
both. Symptoms may be precipitated by relatively minor
 t h e h istory a n d ph ysica l e x a m i nat ion
stimuli, such as head motion or a tight collar. Fainting is
often precipitous, without presyncopal manifestations.
Orthostatic or postural hypotension with a significant
fall in systemic arterial blood pressure is a result of a failure
of adaptive reflexes or mechanical mechanisms to compen-
sate in the upright posture. It may occur as a result of neuro-
pathic disorders, such as diabetes mellitus, amyloidosis, tabes
dorsalis, and alcoholic neuropathy and in neurodegenerative
disorders, such as pure autonomic insufficiency (Bradbury-
Eggleston syndrome), multiple system atrophy (Shy-Drager
syndrome), dementia with Lewy bodies, and Parkinson’s
disease. In younger patients with otherwise unexplained
orthostatic intolerance and hypotension and exaggerated
sinus tachycardia, the postural tachycardia syndrome (POTS)
should be considered. Tilt-table testing is often required to
confirm the diagnosis. Other common causes of postural
hypotension include dehydration, physical deconditioning or
debilitation, sympathectomy, or the administration of anti-
hypertensive or antidepressant medications.
Cough syncope occurs usually in obese men with COPD
and is rare in women or children. It is caused by interaction
of a number of mechanisms that lead to decreased cardiac
output and central effects; among these are a rise in intra-
thoracic pressure with a fall in venous return, a marked
increase in cerebrospinal fluid pressure and compression of
intracranial vascular beds, a concussive effect produced by
the sudden rise in intracranial cerebrospinal fluid pressure,
an increase in cerebral vascular resistance induced by the
hypocapnia of coughing, and increased vagal tone.
Micturition syncope is a sudden loss of consciousness
after nocturnal voiding. It is probably caused by Valsalva
maneuver–mediated reflex vagal tone and a fall in peripheral
vascular resistance enhanced by the abrupt drop in intraab-
dominal volume. It most commonly occurs after substantial
alcohol consumption.
Glossopharyngeal neuralgia may cause reflex stimula-
tion of the vagus and result in fainting. Profound bradycardia
is often associated with the disorder. In addition, there is
often pain localized to the base of the tongue, pharynx, or
larynx; tonsillar area; and ear; followed by syncope. Pressure
in sensitive areas may also produce fainting.
Metabolic derangements that lead to hypoxia or hypogly-
cemia may cause fainting. Disturbances of the vascular
supply within or leading to the cranial vault may produce
syncope and certainly enhance the ability of other causes
to produce a fainting spell. Vertebrobasilar transient isch-
emic attacks are a common cause of this form of syncope.
Movement of the head into certain positions may cause
obstruction of vertebral flow, particularly in certain spinal
disorders. The subclavian steal syndrome is caused by major
occlusion of the proximal subclavian artery with shunting
of blood via the vertebral artery to the distal subclavian
vessel during exercise as a result of vasodilatation and
reduced resistance in the arterial vascular bed with exercise
of the affected arm. A vascular bruit may be heard in the
supraclavicular area, and there is reduced blood pressure on
the affected side. Aortic arch syndrome (Takayasu’s arteritis,
Oriental pulseless disease) with involvement of the carotid
vertebral system is frequently associated with blackout
spells. Occasionally, cerebral vasospasm with migraine
causes fainting.
25
Seizure disorders are not usually difficult to distinguish
from syncope, with the exception of complex partial sei-
zures. Assistance in differentiating this form of syncope
from other varieties is provided by the presence of aura,
seizure activity, the lack of blood pressure, heart rhythm or
rate disturbance, and the postictal state. Dysrhythmias that
produce fainting may also produce convulsion. An electro-
encephalogram (EEG) can be helpful in establishing the
cause of syncope in some patients.
Conversion disorder may express itself as fainting spells;
these episodes often occur under dramatic circumstances.
There usually is no change in pulse rate, systemic arterial
blood pressure, or skin tone. The fainting can occur with
grace and without injury, most frequently in young women,
often with a degree of detachment in the description of the
event (la belle indifférence).
Differential assistance with the problem of syncope is
provided by noting heart rate and rhythm, systemic arterial
blood pressure, and respiration, as well as skin color and neck
veins, during syncopal attacks. The type of onset, precipitat-
ing and alleviating factors, body position, and duration of
symptoms are also helpful in establishing etiology. Fainting
of cardiac etiology tends to produce pallor and cyanosis,
jugular venous distention, and shortness of breath. Some
abnormality of heart rate or rhythm is common. When periph-
eral mechanisms reduce cerebral flow, pallor is prominent
but not usually accompanied by cyanosis or dyspnea, and
jugular venous pressure is not elevated. Disturbance of
primary cerebral flow often produces florid features and slow,
stridorous respiration. Syncope related to Stokes-Adams
attacks is abrupt and is not posturally related. Fainting with
dysrhythmias most frequently occurs in a sitting or standing
position. Although these characteristics of history and physi-
cal examination are helpful, dysrhythmias and transient
heart block can at times be elusive to document. Dynamic
electrocardiographic (Holter) monitoring, event electrocar-
diographic monitoring and exercise stress testing may uncover
these abnormalities when they are not present at rest.
Cardiac Enlargement
The most common cause of cardiac enlargement is CHF
(Table 2.6). The heart enlarges as a compensatory mechanism
in the face of volume or pressure overload. Cardiac muscle
may hypertrophy and undergo dilatation as contractile
TABLE 2.6. Causes of Cardiac Enlargement
Congestive heart failure
Valvular heart disease
Volume or pressure overload (e.g., left-to-right shunts, systemic
arterial hypertension)
Heart muscle disease (ischemia or cardiomyopathy)
High-output failure
Ventricular aneurysm
Large stroke volume
Athlete’s heart
Complete heart block
Pericardial effusion
Cardiac cysts and tumors
Absence of the pericardium
26 chapter 2

efficiency and ability to do work decline. Valvular heart TABLE 2.7. Causes of murmurs
disease, pressure overload of the systemic or pulmonary Valvular heart disease
circuit, and significant shunting of cardiac output are poten- Stenosis
tial causes of cardiomegaly. Disease of the heart muscle itself Insufficiency of congenital or acquired etiology
due to ischemia or cardiomyopathy may also cause cardiac Nonvalvular outflow obstruction
enlargement—either specific chamber enlargement or the Supravalvular and subvalvular outflow obstruction
Hypertrophic obstructive cardiomyopathy
heart may be generally enlarged. Congestive cardiomyopathy
often produces four-chamber enlargement. High-output Shunts (extracardiac and intracardiac)
states with heart failure due to beriberi heart disease, AV Complex congenital heart disease producing turbulence
fistula, anemia, and thyrotoxicosis may produce cardiac dila- Physiologic murmurs
tation. Long-standing complete heart block with relatively Hyperdynamic states
Anemia
large stroke volume is occasionally associated with enlarge- Fever
ment of the heart without other evidence of heart disease. Thyrotoxicosis
The heart of the normal, well-conditioned athlete may also Pregnancy
enlarge. This normal compensatory dilatation and hypertro- Atrioventricular fistula
Excitement
phy is associated with a large stroke volume and a relatively
Flow across normal valves in high-volume states
slow heart rate. The pericardium may be partly or completely Diastolic rumble in mitral and tricuspid regurgitation, atrial
absent on a congenital basis, which allows some expansion and ventricular septal defect, patent ductus arteriosus
of the heart and may be mistaken for heart disease. Complete heart block
Pericardial effusion with apparent enlargement of the Austin Flint murmur of aortic regurgitation
Innocent murmurs of childhood
heart must be distinguished from cardiomegaly resulting
Anatomic distortion producing turbulence
from CHF. Evidence of significant valvular disease, hyper-
Straight back syndrome
tension, congenital heart disease, or cardiomyopathy is Pectus excavatum
usually absent. A history of pericarditis or of factors predis- Chest deformity
posing to pericarditis may be present. There is no definite High- to low-pressure communication
specific chamber enlargement on chest radiography with Ruptured sinus of Valsalva aneurysm
pericardial effusions; globular cardiac enlargement (“water- Coronary fistula
Anomalous origin of left coronary artery from
bottle heart”) occurs instead. The enlarged globular appear-
pulmonary artery
ance of pericardial effusion most frequently must be Atrioventricular fistula
differentiated radiographically from the cardiac enlargement Arteriopulmonary connection
associated with primary myocardial disease. With pericar- Dilatation or stenosis of large or small vessels
dial effusion, heart sounds are often distant, and a pericardial Aneurysm or dilatation of aorta or pulmonary artery
friction rub may be present. The echocardiogram, radionu- Coarctation
Peripheral pulmonary stenosis
clide ventriculogram, or computed tomography of the chest
Atherosclerotic vascular narrowing
are diagnostic of pericardial effusion when the effusion is Pulmonary embolism
large enough to allow its detection. In patients with primary Alteration of arterial or venous flow in nonconstricted vessels
myocardial disease, the heart sounds are usually of normal Venous hum
intensity, and prominent third and fourth heart sounds (S3 Mammary souffle
and S4 gallops) and murmurs of tricuspid or mitral regurgita- High brachiocephalic flow in children
High flow in collateral vessels
tion, or both, are often present.
Intercostal or bronchial collaterals in coarctation of aorta,
Pericardial cysts most frequently produce a rounded or pulmonic stenosis, or atresia
lobulated radiographic appearance and usually occur at the Aortic regurgitation
right cardiophrenic angle. Sometimes they are confused with Sounds resembling murmurs
cardiomegaly or ventricular aneurysm. They are not usually Fusion of S3 and S4 gallops
associated with symptoms. Tumors invading the pericar- Prolonged gallop sounds
Pericardial and pleural friction rubs
dium are usually metastatic, but primary tumors occur
rarely and may produce pericardial effusion.
Ventricular aneurysm may produce an abnormal bulge
in the cardiac contour, especially along the anterolateral LV
wall. Persistent ST-segment elevation on the ECG occurs in be physiologic, occurring without anatomic abnormalities,
about 25% of these patients. Ventricular aneurysms may be or may be observed in hyperdynamic circulatory states, as
associated with intractable CHF, recurrent ventricular dys- in anemia, fever, and thyrotoxicosis. Murmurs may be inno-
rhythmias, and systemic embolic disease. cent (i.e., occurring without any significant anatomic or
functional abnormality); these are most common in children
and young adults. Murmurs must be distinguished from tur-
Murmurs
bulent flow in veins (venous hum), increased flow during
The generation of a murmur is caused by turbulence of blood pregnancy (mammary souffle), bruits with AV fistulas or
flow within the heart or blood vessels. Murmurs occur due dilated intercostal arterial vessels, or friction rubs. Murmurs
to the disruption of smooth laminar flow and production of should be characterized in terms of their timing, quality,
eddies that generate vibrations. The presence of a murmur pitch and intensity, and point of maximal intensity and radi-
may reflect organic heart disease (Table 2.7). Murmurs may ation and of the effect of various physiologic or pharmaco-
 t h e h istory a n d ph ysica l e x a m i nat ion
logic maneuvers on their intensity. Grade 1 murmurs are
faint and can be appreciated only with careful auscultation;
grade 2 murmurs are relatively soft but readily audible; grade
3 murmurs are prominent and loud; grade 4 murmurs may
be associated with a thrill and are very loud; grade 5 are
extremely loud murmurs; and grade 6 murmurs can be heard
with the stethoscope held above the chest wall or even
without a stethoscope.
Murmurs are classified on the basis of their duration or
timing as being systolic, diastolic, or continuous. Specific
murmurs resulting from heart disease are discussed in other
chapters in this book.
Gallops
Cardiac gallops are low-frequency vibrations that are best
heard with light pressure with the bell of the stethoscope.
Third heart sounds generally occur between 0.12 and 0.24
second after the aortic component of the second heart sound.
Clinically, the third heart sound (S3 gallop) may be a physio-
logic sound in children and young adults. It may be produced
by factors that generate increased rate or volume of flow with
high cardiac output or by conditions associated with cardiac
dilatation and altered ventricular compliance, as in CHF.
Fourth heart sounds (S4 gallop) follow the P wave and precede
the QRS complex. They occur with atrial contraction.
Increased amplitude and audibility of these low-frequency
vibrations are usually associated with increased ventricular
stiffness (decreased compliance) from pressure or volume
overload or with acute mitral regurgitation, systemic arterial
hypertension, cardiomyopathy, or CAD. Audible fourth heart
sounds may also be present during increased ventricular
filling with normal compliance, as in high-output states and
with first-degree heart block. Right-sided gallops are aug-
mented by inspiration. During periods of rapid heart rate,
third and fourth heart sounds may be superimposed to form
a louder single “summation” gallop. Other diastolic sounds
to be differentiated from S3 and S4 gallops are the opening
snap of the mitral valve, the pericardial knock of constrictive
pericarditis, and the “tumor plop” of atrial myxoma. The
opening snap of the mitral (or tricuspid) valve occurs earlier
than the S3 gallop (0.02 to 0.12 second after the onset of the
aortic component of the second heart sound). The sound is
usually a high-pitched, brief, sharp event heard well with the
diaphragm of the stethoscope, and the sound radiates widely
over the left precordium. The tumor plop of atrial myxoma
is an early diastolic sound of relatively low frequency that
may be confused with an opening snap or third heart sound.
Usually, it is of lower frequency and occurs later than most
mitral valve opening snaps and slightly earlier than a S3
gallop. The pericardial knock of constrictive pericarditis is
ordinarily higher pitched, occurs earlier, and is louder than
the S3 gallop. Artificial pacemakers may also produce dia-
stolic sounds that are extracardiac in origin. A sharp, high-
frequency clicking or snapping sound may occur 0.08 to 0.12
second before the first heart sound and may be related to
pacemaker-induced intercostal muscle contraction. In some
instances, this sound signifies penetration of the electrode
tip into or through the myocardium, but it also may be
audible in normally positioned and normally functioning
pacemakers.
27
Edema
Peripheral edema is a relatively late finding in the natural
history of CHF. Right ventricle failure causes edema forma-
tion by elevation of systemic venous pressure. Left ventricle
decompensation results in fluid and salt retention, producing
edema as a result of reduced effective renal perfusion and the
consequently increased renin production and subsequent
aldosterone secretion. Congestive heart failure is also associ-
ated with excessive secretion of antidiuretic hormone, which
leads to water retention. Furthermore, chronic LV failure
may lead to RV failure in the wake of chronic pulmonary
venous and arterial hypertension. The resulting increased
ventricular volumes that follow salt and water retention help
to maintain cardiac output through the Frank-Starling
mechanism but at the cost of an increase in the ventricular
end-diastolic pressures and myocardial oxygen demand.
Peripheral edema formation should lead the physician to
search for other evidence of LV or RV disease, or both. When
these are not present, other etiologic factors must be sought.
Constrictive pericarditis may be manifested by edema, and
many patients have been followed mistakenly with the diag-
nosis of right-sided heart failure of uncertain cause or cryp-
togenic hepatic cirrhosis. Kussmaul’s sign, pulsus paradoxus,
a pericardial friction rub or knock, pericardial calcification,
and a relatively small heart for the degree of edema point to
the correct etiology.
In adults, edema formation occurs in dependent areas
of the body. Some noncardiac diseases may lead to edema
formation with a similar distribution; notable among these
are chronic renal disease, profound hypoalbuminemia,
Cushing’s disease, and premenstrual edema.
Local obstruction of venous or lymphatic drainage usually
causes asymmetric edema collection. In hepatic cirrhosis,
ascites is usually large in volume relative to peripheral edema,
except in the case of “cardiac” cirrhosis, in which peripheral
edema may have been prominent before the onset of ascites.
Facial edema may occur with CHF, but it is more com-
monly caused by trichinosis, renal disease, and superior vena
caval syndrome. It may also follow severe respiratory effort
provoked by asthma or an upper respiratory obstruction.
Rales
Elevation of pulmonary capillary pressure to a level above
the plasma oncotic pressure may be accompanied by transu-
dation of fluid into the alveolar spaces, producing moist rales.
Left ventricle failure and mitral stenosis are the most
common cardiac causes. Pulmonary edema is characterized
by excessive transudation of fluid and moist, bubbling inspi-
ratory rales throughout the lung fields, whereas lesser degrees
of decompensation are characterized by more localized phys-
ical findings with greater involvement of the lung bases.
Noncardiac causes of pulmonary edema include especially
the adult respiratory distress syndrome, but also pulmonary
embolism, exposure to high altitudes, salicylate intoxica-
tion, overdose of narcotic analgesics, neurogenic pulmonary
edema, and reexpansion of a lung after pneumothorax.
Many other disorders produce similar sounds. Atelectasis
is characterized by fine, dry, crackling rales at the lung bases,
which clear with deep breathing or coughing. Pulmonary
28
infection with an inflammatory infiltrate produces evidence
of consolidation in addition to rales. In COPD, somewhat
coarser rales are typical and are usually accompanied by
rhonchi, decreased breath sounds, wheezes, and prolongation
of expiration. Pulmonary fibrosis is accompanied by distinc-
tive dry, fine-to-medium inspiratory rales.
Pleural Effusion
The surfaces of the visceral and parietal pleurae are normally
separated by a thin layer of fluid generated by the visceral
pleura. A number of factors may alter the balance between
production and normal absorption of this fluid (Table 2.8).
The visceral pleura is drained by the pulmonary veins and
lymphatics, and the parietal pleura is drained by systemic
veins and lymphatics. Transudation of fluid into the pleural
space may occur with marked elevation in pressure in either
the systemic or the pulmonary venous beds because pleural
drainage depends on both, but it occurs more frequently
with elevation of both pressures. Therefore, although pleural
effusion may occur with LV or RV failure alone, it is more
frequent with combined LV and RV decompensation. Failure-
induced effusions are commonly bilateral. Unilateral pleural
effusions caused by CHF are usually right-sided.
Pleural effusion related to CHF is usually accompanied
by other signs and symptoms of cardiac decompensation.
Factors that compromise lymphatic clearance may also result
in pleural effusion. Inflammatory involvement of the pleura
or adjacent pleural structures is a common cause of pleural
effusion. In addition to an outpouring of fluid due to the
inflammatory process, the lymphatic drainage may be com-
promised or obstructed by inflammation.
Bacterial, mycobacterial, and, occasionally, fungal and
viral pulmonary and pleural infections produce pleural effu-
sions, as may abdominal inflammatory processes. Lymphatic
TABLE 2.8. Causes of pleural effusions
Congestive heart failure
Left and right heart failure (if unilateral, usually right-sided
effusion)
Pulmonary venous hypertension with right heart failure
Inflammation of pleura and/or lung
Infection
Collagen disease with pulmonary involvement
Systemic lupus erythematosus
Rheumatoid arthritis
Autoimmune phenomena after heart injury
Postpericardiotomy syndrome
Postmyocardial infarction syndrome (Dressler’s syndrome)
Tumor
Primary
Metastatic
Pulmonary embolus with pulmonary infarction
Abdominal ascites
Subdiaphragmatic inflammatory processes
Pancreatitis
Hypothyroidism
Trauma
Disruption of or damage to the thoracic duct
Hypoalbuminemia
chapter 2
drainage from the abdomen passes through the diaphragm;
therefore, direct communication may be present from
abdominal to pleural spaces. Pancreatitis is occasionally
associated with a left pleural effusion that has an increased
amylase concentration. Hypoalbuminemia resulting from
cirrhosis, the nephrotic syndrome, or other etiology may be
associated with right-sided or bilateral pleural effusions.
Tumors (primary or metastatic) to the lung or pleura are fre-
quently associated with pleural effusions, often bloody and
high in protein content and lactate dehydrogenase concentra-
tion. Hypothyroidism may produce large pleural (and peri-
cardial) effusions that have low protein content.
Pulmonary infarction often produces a bloody pleural
effusion, although a nonsanguineous effusion is also compat-
ible with the diagnosis. Collagen vascular or connective
tissue disease, especially systemic lupus erythematosus,
may be accompanied by pleural effusion; the pleural effusion
that occurs in some patients with rheumatoid arthritis typi-
cally has low glucose content. The postpericardiotomy and
post-MI (Dressler) syndromes are often associated with
pleural effusions. Disruption of the thoracic duct by trauma
or tumor produces a chylous effusion; bleeding from thoracic
vascular structures may produce hemothorax or bloody
pleural effusion.
Acute effusions and CHF-associated pleural effusions are
generally transudates. Long-standing pleural effusions often
have increased amounts of protein, regardless of the cause.
Effusions with high specific gravity and increased protein
content are characteristic of tumor and inflammation. The
number and type of cells present in a pleural effusion can
provide helpful information, as can measurements of lactate
dehydrogenase and glucose.
Cyanosis
Desaturation of hemoglobin imparts a bluish coloration to
the skin that is best appreciated in the mucous membranes,
nail beds, conjunctiva, and earlobes. Cyanosis is recognized
when 5 g/dL of unoxygenated hemoglobin is present, and
arterial saturation has fallen to 75% to 85%. Because recog-
nition of cyanosis depends on the absolute quantity of reduced
hemoglobin present per 100 mL of blood, recognition of cya-
nosis in severely anemic patients can be difficult. Occasion-
ally, particularly with polycythemia, it can be recognized at
somewhat higher levels of arterial saturation.
Cyanosis is divided into central and peripheral types
(Table 2.9). Central cyanosis occurs with arterial desatura-
tion because of inadequate oxygenation of hemoglobin due
to pulmonary dysfunction with ventilation-perfusion, oxygen
diffusion, or ventilatory abnormalities; right-to-left shunting
of desaturated venous blood into the systemic arterial circuit;
ambient atmospheric hypoxia; or an abnormality of hemo-
globin itself and its ability to transport oxygen. Central cya-
nosis is seen primarily in the nail beds, face, lips, and tongue.
Patients with cyanotic congenital heart disease usually have
a right-to-left shunt as a consequence of markedly increased
pulmonary vascular resistance, RV outflow obstruction, or
transposition of the great vessels. The most common form
of congenital cyanotic heart disease is tetralogy of Fallot.
Central cyanosis may occur in association with venoarterial
shunting of poorly oxygenated venous blood in patients with
 t h e h istory a n d ph ysica l e x a m i nat ion
TABLE 2.9. Causes of cyanosis
Peripheral cyanosis
Decreased blood flow or vasoconstricted states
Reduced cardiac output
Shock
Congestive heart failure
Cold exposure
Peripheral arterial and/or venous disease
Central cyanosis
Arterial unsaturation due to impaired gas exchange in lungs
Hypoxia due to general hypoventilation with increased PCO2
and decreased PaO2
Regional hypoventilation with respect to perfusion
Perfusion of unventilated regions of lung
Impaired diffusion
Low inspired oxygen tension
Right-to-left shunts
Intracardiac
Extracardiac
Hemoglobinopathy
False cyanosis
Argyria
atrial and ventricular septal defects and patent ductus arte-
riosus when severe pulmonary hypertension causes reversal
of the shunting of blood, formerly from left to right, to right
to left. Differential cyanosis of hands and feet can be expected
when venous and arterial mixing occurs after blood leaves
the heart and pulmonary circuit. Toes, for example, are more
cyanotic than fingers in a patent ductus arteriosus with
right-to-left shunt; fingers may be more cyanotic than toes
with transposition of the great vessels and a reversed shunt
from a patent ductus arteriosus. Cyanosis caused by intra-
cardiac shunt lesions persists with oxygen administration,
whereas that due to pulmonary etiology is often corrected.
Abnormal hemoglobins may produce cyanosis. Clubbing
often is found in association with long-standing central, but
not peripheral, cyanosis. Central cyanosis due to hemoglobin
abnormalities is not usually associated with clubbing.
Peripheral cyanosis unrelated to desaturation of central
arterial blood may be observed in peripheral vascular beds in
states of low flow or vasoconstriction, for example, cardio-
genic shock or severe CHF or with exposure to cold or in the
presence of peripheral venous or arterial disease. It may
occur in vasomotor abnormalities, such as Raynaud’s disease.
It is seen in areas where venous stasis is common, such as
the ear lobes and lower extremities. It is due to extensive
local desaturation of hemoglobin in peripheral extremities.
The bluish skin color in argyria is sometimes mistaken
for cyanosis. It is caused by silver deposition in skin and can
be distinguished from cyanosis by the lack of involvement
of mucosal membranes and failure of the skin to blanch with
pressure. Patients with polycythemia may also exhibit true
cyanosis with lesser degrees of arterial desaturation because
of stagnation and sludging of blood flow in peripheral areas
due to increased blood viscosity.
Clubbing
Clubbing of the fingers and toes has been defined as loss of
the normal angle between the cuticle and the distal end of
29
the fingers or toes (widening of the normal angle of entrance
of the nail into the digit to 180 degrees or more) through
edema, increased vascularization, and fibrous tissue over-
growth in the subungual area. There is bulbous enlargement
of the tips of the digits and sponginess of the proximal nail
bed. Clubbing can be familial or acquired, associated with
an underlying disorder, especially of the heart, lungs, liver,
or alimentary tract. Familial clubbing can occur in other-
wise healthy individuals. Clubbing has been reported to
occur in association with certain occupations, such as jack-
hammer operation. The pathogenesis of clubbing is not clear.
Characteristically, it is associated with systemic arterial
oxygen and desaturation and therefore is most commonly
seen in patients with cyanotic congenital heart disease or
advanced pulmonary disease. It rarely occurs with central
cyanosis due to abnormal hemoglobin and does not occur
with peripheral cyanosis. Asymmetric clubbing may be
found in patients with shunts with unequal distribution of
unsaturated blood, as in reversed shunting from patent
ductus arteriosus. Clubbing without cyanosis is found in
bacterial endocarditis, in chronic suppurative pulmonary
diseases, and with intrathoracic disorders, especially lung
cancer. Clubbing has also been associated with arteriovenous
shunts, cirrhosis of the liver, and ulcerative colitis.
Physical Examination of the Patient with
Heart Disease
The examination of the patient with heart disease is
approached in much the same way as a detective approaches
a criminal problem. Rather than a single sign or symptom
that provides the exact diagnosis, it is usually a combination
of symptoms and physical signs or the absence of such that
enables the examiner to suspect or recognize the presence of
a particular abnormality. The examination is most efficient
if the physician approaches the patient in a logical pattern,
directing full attention to the solution of the problem at
hand. One systematic pattern in which a patient may be
examined is as follows:
1. Inspection of the patient
2. Measurement of systemic blood pressure, pulse rate, and
pulse regularity
3. Examination of the carotid and peripheral arteries
4. Examination of the jugular venous pulse
5. Palpation and inspection of the precordium
6. Auscultation of the heart and lungs
Inspection
Inspection of the patient should include a careful, yet rela-
tively rapid, appraisal of the patient from head to foot. The
examiner is specifically interested in the general appearance
of the patient. Does he or she look ill? Is the patient dyspneic?
Although general impressions can be erroneous, they are
often helpful in corroborating the patient’s previously elic-
ited symptoms. In selected instances, one may be interested
in continuing the inspection by asking the patient to perform
such tasks as walking a certain distance or climbing a flight
or two of stairs in the company of the examiner.
30 chapter
The initial inspection of the patient should assess the
general body configuration. Is the patient abnormally tall or
short? Is he or she obese? Does the appearance suggest the
possibility of Marfan’s syndrome? Are the color, pigmenta-
tion, and texture of the skin normal? Hemochromatosis can
be recognized by the characteristic pigmentation, and sclero-
derma can be recognized by the thickening of the skin over
the hands and fingers and around the mouth and eyes. The
eyelids may be violaceous in dermatomyositis, and there
may be a scaly erythematous eruption over the joints of the
fingers. Episodic flushing of the skin is a hallmark of the
carcinoid syndrome, which can cause tricuspid regurgitation
and pulmonic stenosis. Systolic pulsation in the eyeballs or
ear lobes is sometimes seen in severe tricuspid insufficiency.
Xanthelasma, xanthomata, or both may be manifestations of
hyperlipidemia and are seen in some patients with athero-
sclerotic vascular disease.
The presence or absence of a straight back, as well as the
sternal deformities, such as pectus excavatum, should be
noted because sternal or spine deformities may distort or
displace the heart and lead to erroneous signs of cardiac
enlargement. Telangiectases of the lips, tongue, buccal
mucosa, and fingertips are seen in patients with hereditary
hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome).
Fine linear hemorrhages (splinter hemorrhages) under the
fingernails may be the result of trauma in normal individu-
als but may also be a manifestation of bacterial endocarditis.
Conjunctival petechiae also are present in some patients
with bacterial endocarditis, but they may be seen in a high
percentage of patients immediately after open-heart surgery.
In the latter situation, such petechiae usually are not a mani-
festation of endocarditis.
In female patients, a broad chest with widely spaced
nipples and hypoplastic breast tissue in association with a
webbed neck suggests Turner’s syndrome; defects of the
atrial and ventricular septa and coarctation are the usual
cardiovascular abnormalities seen in these patients. Down
syndrome is recognized by the simian crease in the palms
and by other typical physical features. Atrial septal defects,
ventricular septal defects, AV canal defects, and patent
ductus arteriosus are cardiac abnormalities commonly asso-
ciated with this syndrome.
Cyanosis, as discussed above, when central, may be a clue
to the presence of congenital heart disease or pulmonary
dysfunction. Peripheral cyanosis may be indicative of a low-
flow state, CHF, vasoconstriction, or peripheral arterial or
venous disease.
Clubbing, as discussed above, may be a clue to the pres-
ence of cyanosis related to congenital heart disease or infec-
tious endocarditis, as well as to the presence of advanced
lung disease or lung cancer.
Abnormalities of the extremities may be a clue to the
presence of heart disease in some patients. The Holt-Oram
syndrome is characterized by a thumb resembling a finger
(being hypoplastic and in the same plane as the remainder of
the fingers), short forearms, and a forward thrust of the
shoulders. Atrial septal defects are seen in some patients
with this disorder. Flushing of the nail beds with each heart-
beat (Quincke pulse) is a sign of a hyperkinetic circulation
and is commonly seen in patients with severe aortic regur-
gitation. Anemia may be recognized by noting the pale color
of the nail beds, the conjunctivae, or both.
2
In summary, a general inspection of the patient at rest,
and, where applicable, with stress is of immense importance.
Accuracy in diagnosing the etiology of the abnormality in
a patient with cardiac disease depends largely on having
thought of the appropriate possibilities on the basis of valu-
able clues obtained by a careful and thorough general inspec-
tion of the patient.
Blood Pressure Measurement
The current method of measuring blood pressure depends on
auscultatory detection of the Korotkoff sounds over a periph-
eral artery (usually the brachial artery or the popliteal artery)
at a point distal to the cuff compression of the vessel. The
apparatus for measuring blood pressure consists of a com-
pression bladder within a cloth cuff, a valve that allows
reduction of pressure in the cuff, and a manometer that mea-
sures pressure in the cuff. The bladder and the cuff should
be wide enough to encompass at least half of the forearm (or
thigh) and the length of the bladder should be at least three
quarters of the circumference of the forearm (or thigh) to
which it is applied. Many cuffs are marked to indicate if the
length of the bladder is correct relative to the circumference
of the extremity. If the cuff is too small for the extremity
being examined, false elevations in the blood pressure record-
ing will result. The cuff must be at mid-chest level during
the determination of blood pressure. For each 1.2 cm devia-
tion from mid-chest level, the arterial pressure will be arti-
factually raised or lowered 1 mm of Hg. Measurement of
blood pressure should be made with the patient in a basal
state and as relaxed and comfortable as possible. The cuff is
fully deflated and then applied snugly. Before auscultation
the cuff pressure that is necessary to obliterate the distal
arterial pulse is determined. The stethoscope is then posi-
tioned gently but firmly directly over the artery (either the
brachial or popliteal) and the cuff is inflated to a level in
excess of that required to obliterate the distal pulse. While
listening carefully as the cuff is deflated, the examiner deter-
mines the systolic blood pressure, the point at which the first
tapping sound occurs for several consecutive beats. The dia-
stolic pressure is that point at which definite muffling of the
sounds occurs. One should also note and record the point at
which the sounds totally disappear if it is different from the
pressure level at which they become muffled. Blood pressure
is usually measured with the patient in the seated position
with the arm supported at mid-chest level. Blood pressure
measurements should also be made in both arms. Differ-
ences in systolic blood pressures between the two arms can
be a valuable clue in diagnosing disorders, such as athero-
sclerotic vascular disease involving the arterial supply of one
of the upper extremities; dissecting aortic aneurysm involv-
ing the blood supply to one of the arms, coarctation of the
aorta involving the origin of the left subclavian artery, or
supravalvular aortic stenosis. Blood pressure measurements
should also be made in the supine and upright positions in
selected patients, especially the elderly or in those patients
in whom orthostatic hypotension is suspected. Normally
systolic blood pressure in the supine position is a few mm
Hg higher than in the seated position and diastolic blood
pressure is a few mm Hg lower than in the seated position.
Blood pressure measurements should be made routinely
in the legs of patients with hypertension, suspected coarcta-
 t h e h istory a n d ph ysica l e x a m i nat ion
tion of the aorta, aortic dissection, or peripheral vascular
disease. In the adult, systolic blood pressure is usually 10 to
15 mm Hg higher in the legs compared with that in the arms.
When there are marked pressure differences between the
arms and legs, artifactual differences should also be excluded
(e.g., those produced by improper cuff size). A significantly
higher systolic blood pressure in the legs than in the arms is
often found in patients with severe aortic regurgitation (Hill’s
sign). Lower systolic blood pressures are found in the legs of
patients with coarctation of the aorta and severe aortoiliac
disease.
Normal blood pressure for adults younger than 50 years
old is considered to be below 120 mm Hg systolic and below
80 mm Hg diastolic. In any individual patient, however, tran-
sient fluctuations above or below these normal values, espe-
cially in the systolic blood pressure, are a common occurrence
and probably reflect changes in physiologic state. For example,
systolic blood pressure rises with fever, anxiety, sudden
fright, and exercise. However, with sedation and during sleep,
both systolic and diastolic blood pressures tend to fall. Alter-
ations in pulse pressure (the difference between systolic and
diastolic pressures) may or may not be associated with
cardiac disease (Table 2.10).
In some patients, systolic blood pressure may fall dra-
matically in the erect position, resulting in syncope. Such
postural hypotension not uncommonly occurs even in a
normal person initially arising from bed after a prolonged
illness. In this instance, postural hypotension and syncope
result from pooling of blood in the vessels in the lower
extremities. At present, the most common cause of postural
hypotension is in the use of antihypertensive agents. Addi-
tional causes of postural hypotension are listed in Table
2.11.
Regularity and Configuration of Pulses
Pulse rate and regularity are determined by palpating the
radial artery. The normal adult heart rate varies between 60
TABLE 2.10. Causes of pulse pressure abnormalities
Increased Narrow
Pulse Pressure Pulse Pressure
Sinus bradycardia Severe heart failure
Complete heart block Shock
Emotion Aortic stenosis (usually
Exercise occurs but is not always
present)
Aortic regurgitation
Atrioventricular fistulas Hypovolemia
Fever Vasoconstrictive agents
Anemia
Hyperthyroidism
Beri-beri
Inelastic aorta (elderly patients)
Abnormal connections between
aorta and pulmonary artery
(patent ductus arteriosus,
aorticopulmonary window)
Rupture of sinus of Valsalva
aneurysm
31
TABLE 2.11. Causes of orthostatic hypotension
Idiopathic
Hyponatremia
Hypovolemia
Drugs (e.g., tranquilizers, antihypertensive agents)
Central nervous system disease (e.g., syringomyelia, tabes
dorsalis)
Addison’s disease
Pheochromocytoma
Wernicke’s syndrome
Amyloidosis
Diabetes mellitus
Primary autonomic insufficiency
After sympathectomy
Physical deconditioning
and 100 beats/min, although this is subject to the same physi-
ologic influences as for systemic blood pressure. Sinus tachy-
cardia is diagnosed with a regular sinus rate of more than 100
beats/min, whereas sinus bradycardia refers to a regular sinus
rate of less than 60 beats/min. It may be the result of a slow
sinus, an AV junction, or a ventricular pacemaker. Atrial
fibrillation is a chaotic atrial rhythm recognized on physical
examination by finding an abnormally irregular radial pulse.
Occasional transient irregularity of the radial pulse may
result from either atrial or ventricular premature beats. In
this situation, the pause that follows the premature or early
beat is short in the case of atrial extrasystoles and relatively
long after ventricular extrasystoles. A bigeminal pulse is
made up of coupled beats with regular alteration of the height
of the pressure pulses. This occurs as the result of premature
atrial or, more commonly, premature ventricular contrac-
tions. The height of the radial pulse varies because of the
increased diastolic filling period after the premature ven-
tricular beat, so the subsequent stroke output is greater than
that associated with the ventricular extrasystole.
Pulsus paradoxus (Fig. 2.1) is diagnosed when the systolic
blood pressure falls more than the normal 10 mm Hg during
normal inspiration. The mechanism of pulsus paradoxus is
thought to be predominantly the result of pulmonary vascu-
lar pooling during inspiration and accentuated by conditions
that
1. limit the normal inspiratory increase in blood flow from
the right ventricle to the pulmonary artery,
2. cause a greater-than-normal inspiratory pooling in the
lungs,
3. cause wide extremes of intrathoracic pressure during
inspiration and expiration, or
4. interfere with venous return to the atrium relatively
more during inspiration.
Pulsus paradoxus is seen in patients with pericardial effu-
sion of sufficient size to impede venous return to the heart
during inspiration, that is, pericardial tamponade, less com-
monly with constrictive pericarditis, and in association with
severe asthma or chronic obstructive pulmonary disease and
hypovolemic shock.
Pulsus alternans refers to a pulse pattern in which there
is regular alternation between the heights of the pressure
32 chapter 2

Normal carotid
Start insp. Start exp. DN
140
BA
Pressure–mm Hg

120
LV
100
80
60 Bisferiens carotid
40
20 DN DN
0
1 sec.
FIGURE 2.1. This paradoxical pulse was present in a patient with
pericardial tamponade. Note the marked fall in brachial artery (BA)
and left ventricular (LV) systolic pressure, with inspiration (Insp.)
followed by a rise during expiration (Exp.). Anacrotic carotid

pulses (Fig. 2.2). Such a finding may signify LV dysfunction,
usually severe, and therefore may be associated with any
disease leading to ventricular failure or with events, such as
extreme tachycardia, that might impair ventricular func-
tion, if only temporarily. Pulsus alternans is occasionally
induced by a ventricular ectopic beat.
The equality of pulses should be checked over the carot-
ids and in both the upper and lower extremities. Unilateral
reduction or absence of the pulse over one of these vessels
suggests localized obstruction of that artery.
Pulse configuration may provide an important clue to
cardiac disease. It is best determined by palpitation of the
carotid artery, providing, of course, that the patient does not
have intrinsic carotid arterial disease. The carotid pulse is
best examined with the patient reclining with the trunk of the
body elevated at 15 to 45 degrees to the horizontal plane. The
sternocleidomastoid muscles should be relaxed and the head
either not rotated or rotated very slightly away from the exam-
iner. The forefinger is generally used with light and then, if
necessary, slightly heavier pressure in an attempt to assess the
upstroke, the peak, and the downstroke of the carotid impulse.
For precise separation of the various components of the carotid
contour, listening simultaneously to the heart sounds may be
helpful. The normal configuration of the carotid pulse con-
sists of a smooth and rapid upstroke (Fig. 2.3). The summit of
the carotid pulse is smooth and dome shaped. The descending
limb from the systolic peak is less steep. The carotid incisura
or dicrotic notch is not usually identifiable by palpation. Char-
acteristic abnormalities of the carotid pulse are listed in Table
2.12. Examples of some of these abnormal carotid pulses are
shown in Figure 2.3. An anacrotic carotid pulse is usually
seen in patients who have isolated and hemodynamically sig-
Shudder
Anacrotic DN
AN DN
notch
FIGURE 2.3. Examples of normal, bisferiens, and anacrotic carotid
pulses. The anacrotic carotid pulse with the shudder was obtained
from a patient with severe valvular aortic stenosis. AN, anacrotic
notch; DN, dicrotic notch.
nificant valvular aortic stenosis. In these patients, the carotid
pulse is of small volume and the anacrotic notch is palpable
relatively low on the carotid upstroke. At the summit or peak
of the carotid, a shudder may be felt. The entire carotid
upstroke in these patients is markedly delayed. In the adult
patient, assessment of the carotid upstroke is the single most
valuable clue to the presence of hemodynamically significant
valvular aortic stenosis in the absence of intrinsic carotid
arterial disease. In contrast, in aortic regurgitation, the carotid
upstroke is extremely rapid and the pulse is sometimes
described as a water-hammer pulse. The bisferiens pulse is
found in some patients with severe aortic regurgitation, some
with combined aortic stenosis and regurgitation, and some
patients who have hypertrophic obstructive cardiomyopathy
(HOCM). In patients with HOCM, the carotid upstroke is typi-
cally rapid (Fig. 2.4).
TABLE 2.12. Arterial pulse abnormalities
Abnormality Description

Anacrotic pulse A small, slowly rising pulse with a

200 notch on the ascending limb, such
that there are two deflections on the
upstroke of the carotid
mm Hg

BA Bisferiens pulse Two palpable systolic peaks of almost

100 equal height
Dicrotic pulse A second peak during diastole
LV Water-hammer pulse Characterized by rapid and sudden
0 systolic expansion
FIGURE 2.2. An example of pulse alternans. The brachial arterial
Idiopathic hypertrophic A carotid pulse with a very rapid
(BA) and left ventricular (LV) systolic pressures vary in a regular
Subaortic stenosis pulse upstroke, sometimes having a
manner, such that every other pressure is reduced. Pressure is indi-
bisferiens quality
cated on the vertical axis.
 t h e h istory a n d ph ysica l e x a m i nat ion 33

Carotid 1 A P
DN
2 2

Carotid

A H
V
Jug.
Carotid C
pulse
FIGURE 2.4. Three different examples of carotid pulses in patients
with idiopathic hypertrophic subaortic stenosis. Note the character-
istic rapid upstroke in all three and the “double hump” in the carotid
downstroke in the top two examples. The systolic ejection period is
prolonged in all three. DN, dicrotic notch. Y
X
A systolic thrill may be palpable over the carotid vessels. FIGURE 2.5. A normal jugular venous pulse configuration. Note
the prominence of the A wave and that the X trough is deeper than
This vibration is produced by turbulent blood flow and rep- the Y trough. A 2, aortic valve closing; P2, pulmonary valve closing.
resents the physical counterpart of a loud murmur heard on
auscultation. In general, a thrill over the carotid is transmit-
ted from the aortic root in patients with valvular heart patient sit upright for adequate examination (Fig. 2.6). Light-
disease, especially valvular aortic stenosis. Alternatively, a ing is also of extreme importance; either oblique or tangen-
carotid thrill may represent local arterial disease, in which tial lighting with respect to the vein is helpful. The right
the thrill is usually unilateral and associated heart disease external jugular vein is usually the easier to assess.
is absent. The examiner should also listen with a stethoscope
for bruits over the carotid vessels. A bruit over a carotid
V V
artery may represent a transmitted murmur from the precor-
dium, as occurs in patients with valvular heart disease (espe-
cially aortic valve disease), or it may be a manifestation of
intrinsic occlusive disease of the carotid vessel itself.
Severe
A A
Examination of the Jugular Venous Pulse
V V
The information obtained from examination of the jugular
venous pulse includes an estimation of the level of venous Moderate
A A
pressure and an evaluation of the individual components
(Fig. 2.5). The external jugular vein is generally used to assess Y
both the level and the waveform of venous pressure, although Y
the internal jugular vein can also be used. The jugular veins
reflect right atrial (RA) events with only minimal delay, and Y Y
the venous pulsations can be differentiated from arterial
pulsations in several ways. The pulsation seen at the anterior A Normal
C V C V
border of the sternocleidomastoid muscle is usually arterial,
whereas pulsations at its posterior border are usually venous.
Venous pulsations are influenced by respiration, tending gen-
X Y X Y
erally to fall with inspiration and rise with expiration. Three
separate pulsations can usually be identified in the venous
pulse, in contrast to the single systolic pulsation noted in the
arterial wave configuration (Fig. 2.5). The venous pulsation
can usually be obliterated by light pressure over the external LR LR
jugular vein, whereas the arterial pulsations usually cannot
1 2 3 1 2 3
be so easily obliterated. In examining venous configuration, FIGURE 2.6. The jugular venous pulse configuration in a patient
the position of the patient is important. The higher the with severe tricuspid regurgitation, a patient with moderate tricus-
central venous pressure, the more vertical the subject should pid regurgitation, and a control patient. Bottom, Murmur of tricus-
be so that the venous waveform can be adequately examined. pid regurgitation. Note the prominent V waves in the jugular venous
pulse with severe and moderate tricuspid regurgitation. L and R,
The patient is usually positioned with the trunk at an angle timing of left and right ventricular third heart sounds (S3), respec-
of 15 to 45 degrees to the horizontal plane, although if venous tively, in relation to the jugular venous pulse. Note: A, C, X, V, and
pressure is extremely high, it may be necessary to have the Y waves are all explained on p. 34.
34 chapter
The sternal angle of Louis is used as a reference point for
measurement of venous pressure because it is approximately
5 cm above the level of the right atrium from supine to
upright posture. After positioning the patient appropriately,
so the top of the level of the external jugular venous column
can be identified, the vertical distance between the angle of
Louis and the top of the venous column is measured. Addi-
tion of 5 cm to the value obtained provides an approximation
of venous pressure in centimeters of water. The normal
venous pressure should be no more than 6 to 7 cm when it is
measured in this way. In some patients, the venous pressure
will be so high that, even in the upright position, no definite
upper level of the venous column is apparent. In the normal
patient, venous pressure falls during inspiration, in contrast
to the situation in some patients with cardiac tamponade or
RV failure. Other causes of elevated jugular venous pressure
are listed in Table 2.13.
The normal waveform of the external jugular vein is
demonstrated (see Fig. 2.5). The A wave is the most prominent
positive deflection in the external jugular pulse in the normal
subject. It originates as a result of atrial contraction with a
subsequent rise in RA pressure, which is reflected in the neck
veins. It can be distinguished by its upstroke preceding that
of the carotid arterial pulse palpated simultaneously on the
opposite side of the neck. It is often easier, however, to
compare jugular venous waveforms in conjunction with
timing of the heart sounds. The A wave in the jugular venous
pulse occurs almost simultaneously with the first heart
sound (S1). The size of the A wave depends on several factors,
including the force of RA contraction, the resistance to RA
emptying and RV filling, and the cardiac rhythm. Prominent
A waves occur with tricuspid valve obstruction. Pulmonic
stenosis and pulmonary hypertension in the presence of an
intact septum also result in prominent A waves due to
decreased ventricular compliance. In assessment of the A
wave, the size and contractile strength of the right atrium
must be considered (i.e., if it is large and dilated, it may have
reduced contractile strength). In this situation, the A waves
generated in the jugular venous pulse may not be impressive
despite the presence of conditions, such as significant tricus-
pid valve obstruction or pulmonary hypertension. When
the right atrium contracts during ventricular systole with
a closed tricuspid valve, “cannon A waves” are produced
(Fig. 2.7). This is seen in complete AV block and occurs in
other situations where AV dissociation exists (e.g., ventricu-
lar tachycardia or ventricular ectopic beats).
The X descent may be noticeable in other situations where
AV dissociation exists, including ventricular tachycardia (and
TABLE 2.13. Causes of elevated jugular venous pressure
Right ventricular failure
Vascular pulmonic stenosis
Infundibular pulmonary stenosis
Pulmonary hypertension
Tricuspid stenosis or insufficiency
Hypervolemia
Pericardial tamponade
Constrictive pericarditis
Superior vena caval obstruction
2
VPB
Second lSB
(400 cps)
Fourth ISB
(400 cps)
A
Jugular “cannon”
venous pulse A
FIGURE 2.7. A “cannon” A wave is demonstrated. It occurs when
the right atrium contracts on a closed tricuspid valve and is typically
seen after a ventricular premature beat (VPB), as shown here, and in
the patient with complete heart block. LSB, left sternal border.
ventricular ectopic beats), as a result of the reduction in pres-
sure in the jugular veins as blood flows into the right atrium.
Its trough is usually deeper than that of the Y descent. In the
normal jugular venous configuration, it is the most conspicu-
ous wave. The generation of the X descent depends on three
factors: atrial relaxation, the size of the RA cavity, and a
decrease in intrathoracic pressure as a result of LV contractil-
ity. The X descent is usually exaggerated when RV stroke
output is high, as occurs with a left-to-right shunt such as in
atrial septal defect or with exercise, fever, or anxiety. The X
descent may also be very sharp in constrictive pericarditis. In
atrial fibrillation and with tricuspid regurgitation, the X
descent either is not present or is partially abolished so that
the Y trough is the deepest negative deflection.
The origin of the jugular C wave is still disputed.
Although it may be a transmitted impulse from the underly-
ing carotid artery, it most likely represents the rising up of
the tricuspid valve cusps at the onset of RV systole.
The V wave begins during the period of ventricular con-
traction, and it is caused by passive filling of the right atrium
via venous return in the presence of a closed tricuspid valve.
The sudden termination of RA filling associated with opening
of the tricuspid valve represents the descending limb of the
V wave, or Y descent. The amplitude of the V wave depends
on the amount of blood in the right atrium during ventricu-
lar systole. With tricuspid regurgitation (see Fig. 2.6), the
systolic venous wave is due to regurgitation of blood from
the right ventricle into the jugular venous system, so that
the V waves with significant tricuspid regurgitation are very
large and in some instances larger than the A wave. Promi-
nent V waves, equaling the A waves in amplitude, have also
been noted in patients with atrial septal defects. The Y
descent follows the pulmonary component of the second
heart sound (P2) and begins with the opening of the tricuspid
valve (see Fig. 2.5). Because the Y descent is a manifestation
of ventricular filling, abnormalities in RV filling caused by
changes in RV compliance will be reflected in the Y descent.
Friedreich’s sign refers to a prominent Y descent in the
venous pulse seen in constrictive pericarditis, in which
the initial portion of RV filling is rapid after opening of the
tricuspid valve, followed by subsequent sudden resistance to
further filling as the expansion of the right ventricle is
 t h e h istory a n d ph ysica l e x a m i nat ion
abruptly checked. This sign is not specific for constrictive
pericarditis, however, but also may be seen in restrictive
cardiomyopathies. The Y descent in tricuspid stenosis is
markedly prolonged and damped due to the delayed RA emp-
tying resulting from the tricuspid valve obstruction. The end
of the steep Y descent corresponds to the point at which a
third heart sound originating from the right ventricle would
be heard. A LV third heart sound frequently occurs earlier
than the end of the steep Y descent.
After the Y descent, there may be another rise in the
venous pressure just before the A wave; this late positive
wave is known as the H wave (see Fig. 2.5). This rise has been
attributed to the inrush of blood into the right ventricle,
resulting in an upward movement of the tricuspid valve
cusps. It is most likely to be noted with slow heart rates.
One further point must be made about examination of
the cervical veins to warn the reader about venous hums,
continuous murmurs heard over the cervical veins. They are
commonly present in children and in some young adults,
presumably reflecting a hyperkinetic cardiovascular system.
The important point to make is that a venous hum may be
mistaken for a heart murmur. This hum tends to be of low
or medium pitch. It may be heard over the anteroinferior
cervical region and sometimes over the anterior chest. It
tends to become slightly louder during diastole. The inten-
sity of the hum is increased by placing the patient in the
upright position, by inspiration, and by positioning the head
in such a way that the cervical veins become attenuated. It
is reduced in intensity or disappears entirely on the patient’s
assuming the supine position, during expiration, with the
Valsalva maneuver, with direct compression of the veins, and
with positioning the head so that the cervical veins become
kinked or compressed.
Inspection, Palpitation, and Percussion
of the Precordium
Inspection and palpitation of the precordium in the patient
with cardiac disease are important and valuable, but often
overlooked, parts of the physical examination. Percussion
plays a less important role, but can be used in an attempt to
outline the borders of the heart in dextrocardia and
dextroversion.
Inspection and palpation of the precordium can provide
clues to the underlying abnormality in the patient with heart
disease. With the patient supine, the examiner should care-
fully inspect and palpate the precordium, attempting to
determine the presence and location of a LV and a RV impulse.
The normal LV impulse is felt at the cardiac apex near the
area of the left midclavicular line. It usually covers an area no
greater than 3 cm in diameter, and the outward thrust is not
sustained. It is usually best appreciated with the tips of the
fingers. With LV enlargement, the apex impulse may also
become sustained, as in patients with significant aortic ste-
nosis, or it may become more rapid, diffuse, and forceful, as
in patients with significant aortic regurgitation. It may also
consist of a double impulse, representing both a visible coun-
terpart to the fourth heart sound and an apical systolic thrust,
or representing regions of LV dyskinesis. A palpable tactile
counterpart to the fourth heart sound is present in some
patients with LV outflow obstruction, CHD, systemic arterial
hypertension, and myocardial disease of various causes.
35
When palpable, the RV impulse is present in the fourth and
fifth intercostal spaces immediately adjacent to the left
sternal border. It is usually best appreciated with the heel of
the palm. In most adults without RV enlargement, this
impulse is not palpable, although in thin subjects it may be.
The RV impulse is usually palpable in situations where RV
hypertrophy or dilatation is present (e.g., in patients with
mitral stenosis, myocardial disease, severe tricuspid regurgi-
tation, RV outflow obstruction, or pulmonary hypertension).
Abnormal precordial pulsations should also be sought,
such as those that occur after MI or during myocardial isch-
emia. They may be noted in any area between the pulmonary
artery and the cardiac apex and are not uncommonly found
in the left parasternal region, in the fourth and fifth inter-
costal spaces, sometimes making their differentiation from
a RV impulse difficult.
The second and third left intercostal spaces should be
carefully examined for the presence of a pulsation indicative
of pulmonary artery enlargement. The pulmonary artery is
usually not palpable in the absence of pulmonary artery
enlargement except in very thin patients, pregnant patients,
and some patients with the straight back syndrome. In the
absence of these situations, however, a palpable pulmonary
artery pulsation in adults without a hyperkinetic circulation
usually means either a dilated pulmonary artery (secondary
to an increase in pulmonary artery pressure and resistance)
or increased pulmonary artery blood flow.
Heart sounds may have a palpable counterpart. A loud
second heart sound in association with pulmonary or sys-
temic arterial hypertension may be palpable in the second and
third left intercostal spaces just adjacent to the sternum. First
heart sounds may be palpable at the cardiac apex in patients
with mitral stenosis. As already noted, the fourth heart sound,
or presystolic gallop, may be palpable in patients with reduced
LV compliance. A third heart sound, or protodiastolic gallop,
may also be palpable in some patients with conditions, such
as myocardial disease or significant mitral regurgitation.
Systolic and diastolic thrills associated with heart
murmurs are detected by palpation. The finding of a systolic
thrill indicates significant valvular heart disease and is
usually associated with a loud systolic murmur. Systolic
thrills palpable in the second and third intercostal spaces to
the right of the sternum usually indicate hemodynamically
significant valvular aortic stenosis. Those palpable in the
same locations to the left of the sternum may indicate either
hemodynamically significant valvular pulmonic or aortic
stenosis. Systolic thrills along the lower left sternal border
may occur as the result of severe tricuspid regurgitation,
with ventricular septal defects, and occasionally in associa-
tion with hypertrophic obstructive cardiomyopathy. Systolic
thrills at the apex usually indicate hemodynamically signifi-
cant mitral regurgitation or LV outflow obstruction. Dia-
stolic thrills along the lower left sternal border may occur
with either tricuspid or mitral valve obstruction. A diastolic
apical thrill, best appreciated directly over the point of
maximal impulse with the patient in the left lateral decubi-
tus position, usually identifies the presence of hemodynami-
cally significant mitral valve stenosis.
To accurately time a thrill, it is helpful to listen to the
heart sounds or palpate a carotid artery as well as the pre-
cordium, to determine whether the thrill occurs in systole
or diastole.
36 chapter
Auscultation
Auscultation should never be done in isolation from the other
features of the cardiac examination; rather, it is an integral
part of the total examination, and when the information
obtained from auscultation is combined with that obtained
from general inspection, examination of the arteries and
jugular veins, and inspection, palpitation, and percussion of
the precordium, a satisfactory hypothesis regarding the abnor-
mality of the patient in question can usually be formulated.
The examiner should choose a stethoscope that is com-
fortable. The earpieces should fit the ear canal snugly without
penetrating to an uncomfortable depth. The tubing of the
stethoscope should allow maximal sound transmission,
which occurs when the internal diameter of the tubing is
approximately 3 mm. Double-tube stethoscopes are associ-
ated with less distortion of heart sounds than are single tube
models. The basic components of a stethoscope, whether
separate or tunable parts of a single component, are a bell
and a diaphragm, which are used, respectively, for low- and
high-pitched sounds and murmurs.
During auscultation, the examiner should concentrate
solely on listening to and analyzing heart sounds. Ausculta-
tion is most likely to be successful when both physician and
patient are comfortable and auscultation is performed under
very quiet circumstances. Strict attention should be paid to
each of the various heart sound components audible during
systole and diastole. The examiner should listen for the first
heart sound, for systolic murmurs and clicks, for the second
heart sound and its splitting with respiration, for the pres-
ence of a third and fourth heart sound, and for diastolic
murmurs and diastolic clicks, each in turn excluding the
other events of the cardiac cycle, paying strict attention to
that portion of the cycle in which the sound in question is
located. It is easy, unfortunately, to overlook the presence of
gallops, clicks, and even murmurs unless they are listened
for specifically. Several different areas of the precordium
should be examined with both the diaphragm and the bell
and the patient must be in the ideal position to bring out
heart sounds as each circumstance dictates.
The diaphragm of the stethoscope is most effective in
identifying high-pitched sounds, such as systolic clicks,
opening snaps of valves, splitting of the second heart sound,
the first heart sound, certain systolic murmurs, and pulmo-
nary and aortic regurgitation. The diaphragm should be
firmly applied to the chest, and one should listen both to the
right and left of the sternum in the second, third, and fourth
intercostal spaces and at the cardiac apex.
The bell is used to hear low-frequency diastolic murmurs
(i.e., tricuspid and mitral stenosis) and the diastolic gallop
sounds, the third (S3) and fourth (S4) heart sounds (Fig. 2.8).
Diastolic gallop sounds are often best heard with the patient
in the left lateral decubitus position and by listening with
the bell in the third and fourth left parasternal intercostal
spaces and over the apical impulse. Gallop sounds are usually
best heard with application of only very light pressure with
the bell to the skin; firm pressure may result in inability to
hear an S3 or S4 even when it is present.
It is best to establish a routine for the sequence of areas
in which one listens to the heart sounds; this ensures that
each of the important areas will be auscultated. One can
2
Fifth lSB
(25 cps)
S4 S1 S.M. S3
S2
Apex
(25 cps)
Carotid
FIGURE 2.8. The low-frequency fourth (S4) and third (S3) heart
sounds. The S4 precedes the first heart sound (S1), and the S1 occurs
in mid-diastole. S2, second heart sound; LSB, left sternal border; SM,
systolic murmur.
follow whatever pattern one finds easiest, but one approach
is to listen with the diaphragm in the second and third inter-
costal spaces to the right of the sternum initially, followed
by listening to the same areas to the left of the sternum. The
diaphragm can then be moved down the sternal border to the
fourth and fifth intercostal spaces and then to the apex and
from there into the axilla to listen to heart sounds. One can
then switch to the bell of the stethoscope and listen in the
fourth and fifth intercostal spaces to the left of the sternum,
followed by auscultation at the apex. We have found it easier
to have the patient lie in the left lateral decubitus position
at the end of the routine portion of the auscultatory examina-
tion so one can listen with the bell directly over the cardiac
apex and along the left sternal border.
In appropriate situations, a few additional areas require
examination. Specifically, the first and second intercostal
spaces below the left midclavicular area should be auscul-
tated when patent ductus arteriosus is suspected; a continu-
ous murmur audible in this area may represent a patent
ductus arteriosus. The systolic murmur of coarctation of the
aorta may be heard well in the left infraclavicular region, in
the suprasternal notch, or in the back on the midthoracic
region at the level of the fourth or fifth spinous process. The
systolic murmur of mitral regurgitation may radiate to the
axilla and up the vertebral column so as to be audible even
on the top of the head, or it may radiate toward the sternum
and up along the left sternal border. Murmurs resulting from
pulmonary arterial stenosis and pulmonary AV fistulas may
be heard over the lungs. Scars should be examined for the
presence of a continuous murmur suggestive of AV fistulas
(Table 2.18).
After completion of the routine auscultation, in selected
patients it can be helpful to determine how heart sounds
change after mild exercise. This can be done by asking the
patient to perform a few sit-ups and then listening to the
 t h e h istory a n d ph ysica l e x a m i nat ion 37
heart sounds again. Not uncommonly, this will either bring Expiration Inspiration
out or make louder an S3 or S4. It may also help to accentuate 1 22 1 22
the murmur of mitral stenosis when the obstruction across
the mitral valve is not severe. Normal

First Heart Sound A2 P2 A2 P2

Events in the left ventricle and aorta might be, at least in part,
responsible for the genesis of the first heart sound (S1); however,
LBBB
convincing evidence that mitral and tricuspid valve closure
plays a major role in the production of S1 has also been pre-
P2 A2 P2 A2
sented. S1 is often initiated by a low-frequency component
occurring immediately after the onset of rise in LV pressure. FIGURE 2.9. (Top) Normal splitting of the second heart sound.
Bottom: Paradoxical splitting. In normal splitting, pulmonary valve
The first high-frequency component of S1 occurs during the
closure (P2) follows aortic valve closure (A 2), and the splitting
early phase of pressure rise in the left ventricle. The second increases with inspiration. In paradoxical splitting, aortic valve
high-frequency component occurs at the time of opening of the closure follows pulmonic closure, and the splitting is widest during
aortic valve. The next component occurs at the first peak of the expiration. The paradoxical splitting of the second heart sound
aortic pulse, and the final component, when present, appears (bottom) occurred as the result of a left bundle branch block (LBBB).
to coincide with maximal expansion of the aortic wall. S1 may
sound split to the examiner’s ear or may sound as if it is single.
Three general abnormalities can occur with respect to
It decreases in loudness with the following conditions: LV
splitting of S2. First, S2 may be a single sound, with neither
hypertrophy, a dilated left ventricle, a prolonged PR interval,
audible nor detectable splitting. Second, the splitting may be
and reduced strength of contraction of the left ventricle. The
wide during inspiration and may remain wide during expira-
first heart sound increases in amplitude when the LV cavity is
tion, so that the splitting sounds “fixed” to the ear. Third, para-
small, when it is less compliant, when it is hypertrophied but
doxical splitting (i.e., wider splitting of S2 during expiration
the hypertrophy is predominantly the result of increased
and narrowing during inspiration) may occur (Fig. 2.9). A
muscle mass rather than connective tissue, and when LV con-
single S2 (in some instances narrowly split sounds beneath the
tractility occurs rapidly. The first heart sound is usually soft
capability of the human ear to detect splitting) is heard in
in the presence of aortic regurgitation and loud with mitral
elderly people, in patients with truncus arteriosus (although a
stenosis of hemodynamic significance. The first heart sound
split S2 may be occasionally heard in this abnormality), with
varies in intensity with atrial fibrillation, being somewhat
ventricular septal defects complicated by severe pulmonary
softer after a long pause. Short PR intervals (the interval
hypertension, and with severe pulmonary hypertension of any
between atrial systole and ventricular systole) also result in
etiology. Fixed splitting of S2 often but not invariably occurs
increased intensity of the first heart sound. Where complete
with atrial septal defects. Apparent fixed splitting of S2 is
heart block or advanced AV block exists, the first heart sound
sometimes found in patients with right bundle branch block,
varies in intensity on a beat-to-beat basis.
partial anomalous venous return, ventricular septal defect,
and mild pulmonary hypertension. The important causes of
Second Heart Sound
paradoxical splitting of S2 are listed in Table 2.14, and an
The second heart sound (S2) usually has two separate audible example of paradoxical splitting of S2 is shown in Figure 2.9.
components; aortic valve closure provides one component
(A 2) and pulmonic valve closure contributes the second (P2) Clicks
(Fig. 2.9). Splitting of the S2 is best heard in the second and
Systolic and diastolic clicks are high-frequency sounds
third intercostal spaces to the left of the sternum. P2 is not
usually associated with some form of cardiovascular abnor-
usually heard low along the left sternal border or at the
mality. The different types of systolic and diastolic clicks
cardiac apex, except in situations where pulmonary artery
and their distinguishing features and associated cardiovas-
pressure is significantly increased. In the normal situation,
cular abnormalities are listed in Table 2.15. Examples of
the widest splitting of S2 occurs during inspiration (Fig. 2.9).
some of these are shown in Figures 2.10 and 2.11.
During expiration, S2 becomes single, or the splitting between
A 2 and P2 becomes narrower. The amplitude of the A 2 is
proportional to the peak value of the first derivative (dP/dt) TABLE 2.14. Causes of paradoxical splitting of the second heart
of the pressure difference between the aorta and the left sound
ventricle. Correspondingly, the amplitude of the P2 is propor-
Left bundle branch block
tional to the dP/dt between the pulmonary artery and the
Right ventricular ectopic beats
right ventricle. Increased pressure in the aorta or pulmonary
artery is usually accompanied by a louder A 2 or P2, respec- Right ventricular pacing
tively. Systemic hypertension and coarctation cause loud Angina Pectoris
aortic components, whereas pulmonary hypertension results Left ventricular failure
in a loud pulmonary component of the second heart sound. Left ventricular outflow obstruction
Left and right ventricle outflow obstruction, whether valvu- Severe systemic hypertension
lar, subvalvular, or supravalvular, usually results in fainter Paradoxical splitting occurs in some patients with these abnormalities but
components of the S2, and sometimes A 2 or P2 is absent. not in all of them.
38
TABLE 2.15. Systolic and diastolic clicks
Systolic clicks
Early systolic clicks
Valvular aortic stenosis
High-frequency sounds usually occurring
0.02–0.06 s from the initial high-
frequency component of the first heart
sound. These clicks do not change their
timing with respect to the first heart
sound, respiration, or change in position,
nor does the intensity of the click
fluctuate with respiration. The aortic
valve ejection click either slightly
precedes or occurs simultaneously with
the carotid upstroke. This type of
ejection click is commonly heard in the
patient with a bicuspid aortic valve that
is not heavily calcified.
Valvular pulmonary stenosis
An early systolic click with approximately
the same timing as for the aortic click.
These clicks become significantly softer
or disappear during inspiration and
become louder with expiration. One
may also estimate the severity of the
valvular pulmonary stenosis by the
closeness of the pulmonary systolic
click to the initial high-frequency
deflection of S1 with increasing severity.
The click is closer to S1.
Dilated pulmonary artery or dilated aorta
High-frequency clicks occurring with
ejection timing are also heard in some
patients with these abnormalities. The
click occurring with a dilated
pulmonary artery that either is due to
pulmonary hypertension or is idiopathic
usually is not significantly diminished
in intensity during inspiration.
Mitral valve prolapse
Early systolic click or clicks occur in
some patients with this entity.
Typically, these clicks move closer to
the first heart sound with inspiration,
with assumption of the upright
position, with the Valsalva maneuver,
and with amyl nitrate administration.
Their relationship to the carotid
upstroke is variable in that they may
precede, occur simultaneously with, or
follow the carotid upstroke
Ebstein’s anomaly
Early systolic click is audible in some
patients with this abnormality.
Aneurysm of the membranous
ventricular septum
Some patients with this abnormality also
have an early systolic click.
Aortic valve prosthesis
The intensity of the opening click of
disk-and-ball aortic prostheses should
be approximately 50% or more of that of
the closing click in the second right
intercostal space. Abnormal function of
the aortic prosthesis is suggested by
gross reduction in the intensity of the
opening click of the prosthesis.
chapter 2
Mid- and late systolic clicks
Mitral valve prolapse
The most common cause of a high-
frequency click or clicks occurring in
middle to late systole. Usually these
clicks move closer to the first heart
sound with inspiration, with
assumption of the upright position,
with amyl nitrate inhalation, and with
the Valsalva maneuver. The click may
be preceded by, enveloped by, or
followed by a systolic murmur, or there
may be no audible systolic murmur.
Aortic regurgitation
Middle to late systolic clicks occur
rarely in patients with significant
aortic regurgitation.
Diastolic clicks
Opening snaps
Mitral valve
A high-frequency sound audible along
the left sternal border and at the
cardiac apex in patients with mitral
stenosis and in a rare patient without
mitral valve disease. The presence of
large amounts of calcium in the mitral
valve apparatus may result in the
absence of an opening snap even when
significant mitral stenosis is present.
The opening snap of the mitral valve
usually occurs 0.03 to 0.14 s after the
high-frequency component of aortic
valve closure. In mitral stenosis, one
can use the aortic closure and the
mitral valve opening click as an
indication of the severity of the mitral
valve obstruction. With increasing
severity of the mitral valve obstruction,
this interval becomes progressively
shorter.
Mitral disk prosthesis
Also a high-frequency sound, usually
best heard along the left sternal border
or at the cardiac apex. With
malfunction of the prosthesis resulting
from either tissue ingrowth,
paravalvular regurgitation, or thrombus
interference, the opening click may
become markedly reduced in intensity.
With severe mitral paravalvular
regurgitation, the interval from aortic
closure to mitral valve opening may
become markedly reduced, whereas
with tissue ingrowth or thrombus
interference, this interval may be
significantly prolonged.
Tricuspid valve
Some patients with tricuspid stenosis
and patients with tricuspid prostheses
have opening snaps of their tricuspid
valve. This is also a high-frequency
sound audible along the left sternal
border and at the apex.
Mitral valve prolapse
Diastolic clicks have been recorded in
some patients with this abnormality,
but these clicks are extremely unusual.
 t h e h istory a n d ph ysica l e x a m i nat ion 39

FIGURE 2.10. (A) Midsystolic clicks in the recordings of

the heart sounds at the base and apex of the left precor- Second lSB
dium in a patient with mitral valve prolapse. Typically, (400 cps)
Base S1 S1 EC S
S2 2
such a patient has a midsystolic click (MSC) that moves (400 cps) S1 A2 P2 Carotid
closer to the first heart sound (S1) with inspiration and Multiple systolic clicks
with sitting and standing. However, as shown here, some Apex
patients with mitral valve prolapse have early systolic (400 cps) Inspiration Expiration

ejection clicks and early midsystolic ejection clicks. (B)

A middle to late systolic click in another patient with Carotid
mitral valve prolapse. (C) Ejection click in a patient with A C Inspiration Expiration
valvular pulmonic stenosis in the left second intercostal
space. It becomes softer and often disappears with inspi-
ration and is easily audible during expiration. (D) An Second lSB
early systolic ejection click in a patient with a bicuspid (400 cps)
A2 P2
aortic valve. The intensity of this click does not change 2nd LICS
with respiration. The typical systolic ejection murmur in MSC MSC
Apex CL 2 CL 2 CL 2
a patient with an obstructed bicuspid aortic valve is also (40 cps) SM SM SM SM
shown. ECG, electrocardiogram; LICS, left intercostal Carotid ECG
space; LSB, left eternal border; SM, systolic murmur. B D

Murmurs tricuspid regurgitation typically (but not always) increases in

intensity with inspiration (see Fig. 2.6).
Innocent or functional murmurs do not represent pathologic Table 2.16 lists distinguishing features of the common
abnormalities. Innocent murmurs may occur as a result of systolic murmurs. The examiner should remember that more
increased velocity of blood flow across normal valves due to than one murmur indicative of valvular heart disease can
extracardiac factors. They are heard in patients with anemia exist in a given patient. For example, it is not uncommon to
or thyrotoxicosis and after exercise. Innocent murmurs are find systolic and diastolic murmurs indicative of both valvu-
usually short, soft systolic murmurs that often change in lar obstruction and regurgitation. The common types and
intensity or disappear with changes in position, with rest, locations of diastolic murmurs are listed in Table 2.17, and
and/or with correction of an underlying abnormality, such as two examples are shown in Figure 2.11. The common types
anemia. Diastolic murmurs are rarely, if ever, innocent of continuous murmurs are listed in Table 2.18.
murmurs. Innocent murmurs are common in children. Occa-
sionally, the differentiation of an innocent or benign systolic
murmur from one indicative of serious underlying cardiac
pathology is difficult from the physical examination alone. 2 2
ES P ES
Systolic murmurs are classified as either systolic ejection A AP
murmurs, holosystolic murmurs, or continuous murmurs.
Systolic ejection murmurs terminate before the second heart PCG-PA
sound and peak in intensity in early to midsystole, becoming X X
1
softer thereafter. Valvular aortic and pulmonary stenosis SM
MDM MDM
(Fig. 2.10) are characterized by systolic ejection murmurs.
Holosystolic murmurs extend throughout systole, beginning PCG-MA
immediately after the first heart sound and extending up to
the second sound. Continuous murmurs are both systolic
and diastolic with the murmur peaking in late systole, envel-
oping the second sound, and continuing into diastole. The
murmur of mitral regurgitation is an example of a holo-
systolic murmur (Fig. 2.12). The holosystolic murmur of
X
X

ECG
SM
DM
Second
lSB Apex
(HF) S2 (LF)
S1 FIGURE 2.12. The holosystolic murmur typical of mitral insuffi-
A B S1 S2 OSMV
DM ciency is demonstrated at the apex (second panel with heart sounds).
FIGURE 2.11. Two diastolic heart murmurs are demonstrated. (A) The jugular venous pulse is shown in the third panel, and the
A high-frequency (HF) diastolic decrescendo murmur (DM) in a patient’s electrocardiogram (ECG) is shown in the bottom panel. A,
patient with aortic regurgitation. (B) A low-frequency (LF) diastolic aortic closure sound; ES, ejection sound; MA, mitral area; MDM,
rumble typical of mitral stenosis occurring immediately after an mid-diastolic murmur; P, pulmonic closure sound; PA, pulmonary
opening snap of the mitral valve (OSMV). LSB, left sternal border; artery position; PCG, phonocardiogram; SM, systolic murmur; X,
SM, systolic murmur. descent of jugular venous pulse.
40 chapter 2

TABLE 2.16. Systolic ejection murmurs

Location Differential diagnosis

Second and third right and/or
left intercostal spaces
Second to fifth left intercostal
spaces
Cardiac apex
Holosystolic murmurs
Fourth and fifth left intercostal
spaces
A “flow” murmur indicative of either increased stroke volume or turbulence around the aortic valve
but not hemodynamically significant aortic valve obstruction
Valvular aortic stenosis. This murmur is audible anywhere over the left precordium and radiates up
and toward the right shoulder and into both carotid arteries. If the obstruction is due to a bicuspid
aortic valve that is not heavily calcified, there is usually an associated systolic ejection click
Supravalvular aortic stenosis. Usually occurs in children or young adults and can be associated
with a characteristic physical appearance, namely elfin facies, and mental retardation. There is
often a systolic blood pressure difference of greater than 15 mm Hg between the two arms, with
blood pressure being higher in the right arm
Subvalvular aortic stenosis (bar or diaphragm immediately beneath the aortic valve). In addition to
the systolic murmur, there is often an associated diastolic murmur of aortic regurgitation. A
systolic ejection click is usually not present
Valvular pulmonary stenosis. This murmur is usually loudest to the left of the sternum. There is
an associated systolic ejection click that decreases or disappears with inspiration and becomes
prominent during expiration
Coarctation of the aorta. This murmur may also be heard medial to the left scapula posteriorly
and/or under the left clavicle anteriorly. The murmur is usually associated with systemic arterial
hypertension and diminished or absent femoral pulses
Atrial septal defect. Typically, a soft murmur caused by increased blood flow across the pulmonary
valve and often associated with “fixed splitting” of the second heart sound
Infundibular pulmonary stenosis. This murmur is best heard to the left of the sternum. There is
usually no associated ejection click
Peripheral pulmonary stenosis. This murmur may also be heard over the back
Hypertrophic obstructive cardiomyopathy (HOCM)
This murmur usually does not radiate well into the carotid arteries. The murmur typically
increases with Valsalva maneuver and upright position and in the beat following a ventricular
premature beat. It characteristically decreases with squatting. On occasion, however, the
Valsalva maneuver and squatting do not result in the expected changes in intensity of this
murmur
Valvular aortic stenosis. On occasion this murmur may be loudest at the apex rather than at the
base, making its differentiation from mitral regurgitation more difficult
Mitral regurgitation resulting from papillary muscle dysfunction. This murmur often is of ejection
type, beginning after the first heart sound, peaking in midsystole, and ending before the second
sound. On occasion, however, this murmur is holosystolic rather than ejection
Tricuspid regurgitation. This murmur typically increases with inspiration and is associated with
prominent V waves in the jugular venous pulse. Occasionally the inspiratory increase in the
murmur does not occur
Ventricular septal defects. This murmur has no phasic respiratory change and is often associated
with a systolic thrill along the left sternal border
Rheumatic mitral regurgitation and/or mitral regurgitation due to endocarditis
Mitral regurgitation due to ruptured chordae tendineae
Mitral regurgitation secondary to papillary muscle dysfunction. This murmur may have an ejection
quality in some patients
“Relative” mitral regurgitation. This is the mitral regurgitation due to left ventricular failure and
an abnormal spatial relationship of the mitral leaflets and papillary muscles
Mitral regurgitation with HOCM or left atrial myoxma

Friction Rubs Gallop Sounds

Pericardial friction rubs may be mistaken for cardiac
murmurs, but they can be differentiated by their rough,
rubbing, harsh quality, and by the fact that they have at least
two components (systolic and diastolic) and sometimes three
audible components (systolic, diastolic, and presystolic).
They may be audible anywhere over the left precordium.
They are often evanescent. They can occur in the presence
of any disorder that causes pericarditis, for example, with
viral pericarditis, after MI or cardiac surgery, in uremia, after
chest injury, with malignant implants into the pericardium,
and in association with systemic collagen diseases, espe-
cially systemic lupus erythematosus.
The third heart sound, or protodiastolic gallop (S3) may be
physiologic in children and young adults, but is an abnormal
sound in adults older than 30 years. Its origin is most likely
from either the mitral or tricuspid valve leaflets, supporting
structures, the ventricular myocardium, or a combination. It
is found in patients with severe myocardial disease and in
those with hemodynamically significant valvular insuffi-
ciency, including aortic, mitral, tricuspid, and pulmonary
valvular insufficiency. A third heart sound is demonstrated
in Figure 2.8. The presence of a third heart sound is incom-
patible with a diagnosis of hemodynamically severe mitral
obstruction in the absence of substantial coexistent mitral
 t h e h istory a n d ph ysica l e x a m i nat ion 41
TABLE 2.17. Diastolic murmurs
Location Differential Diagnosis

High-pitched diastolic decrescendo
murmurs
Low-pitched diastolic rumbles
Third to fourth left intercostal spaces
Fourth to fifth left intercostal spaces
Cardiac apex
Aortic regurgitation. This is a blowing murmur that immediately follows the second heart
sound. In general, valvular aortic regurgitation murmurs are best heard along the left
sternal border in the second and third intercostal spaces, and aortic regurgitation due to
aortic root disease (e.g., syphilis, spondylitis, dissection) are best heard to the right of the
sternum. Its timing and quality are similar to the murmur of valvular aortic regurgitation
Atrial septal defect. This murmur results from increased flow across the tricuspid valve
Tricuspid stenosis. This murmur may become louder during inspiration and with maneuvers
that increase venous return to the right atrium. Rheumatic fever or right atrial myxoma
may be etiologies
Mitral stenosis. This low-pitched diastolic murmur follows immediately after the opening
snap of the mitral valve when the latter is present. It is often best heard by having the
patient lie on the left side and listening directly over the point of maximal impulse. The
length of the diastolic murmur correlates directly with the severity of mitral obstruction
Flow rumbles due to a large left-to-right shunt, such as with large ventricular septal defects.
These occur just after the second heart sound and are usually short in duration
Austin Flint murmur. Apical diastolic rumble ordinarily of short length occurring in some
patients with severe aortic regurgitation. This murmur usually results from vibration of the
septal leaflet of the mitral valve due to the regurgitation aortic jet. The murmur may rarely
result from late diastolic mitral regurgitation
Carey-Coombs murmur. Short mid-diastolic rumble noted rarely in patients with acute
rheumatic fever; murmur results from inflammation involving mitral valve leaflets
“S3 rumble complex.” Some patients with hemodynamically significant mitral regurgitation
have a short diastolic rumble that follows the third heart sound. The rumble reflects a flow-
related and relative mitral obstruction
Left atrial myxoma may also produce a murmur that mimics mitral stenosis, except that it
ordinarily is not associated with an opening snap of the mitral valve

insufficiency. However, an S3 can be produced by significant
aortic regurgitation or severe tricuspid regurgitation, even in
the patient with severe mitral valve obstruction. An S3 that
is audible or becomes significantly more prominent during
inspiration is likely of RV origin. The tumor plop sound of
atrial myxoma is a high-frequency mid-diastolic sound that
may be mistaken for an S3.
The fourth heart sound, or presystolic gallop (S4), is an
abnormal sound (see Fig. 2.8). It is thought to originate within
the left or right ventricle as a result of the left or right atrium
being forced to contract more vigorously than normally due
to reduced ventricular compliance in the ventricle from
which the sound originates. It is almost always found in
patients with severe CAD, LV outflow obstruction, or sys-
temic arterial hypertension and in patients in sinus rhythm
with substantial mitral regurgitation of recent onset. It is not
present in patients with atrial fibrillation because of the
absence of a discrete forceful atrial contraction.
A summation gallop is a prominent sound that occurs at
rapid heart rates and represents the summation of both a
presystolic and protodiastolic gallop sound. It is recognized
with certainty by demonstrating a single loud gallop sound
at relatively rapid heart rates, which at slower heart rates
resolves into its individual components (i.e., S3 and S4).
Heart Sounds from Prosthetic Valves
Mechanical prosthetic cardiac valves normally produce
clicks that identify their opening and closing. Figure 2.13
identifies the timing of these sounds for both aortic and
mitral prosthetic valves. The opening and closing clicks of
these valves are high-frequency sounds best heard with the
diaphragm of the stethoscope. The opening click of the aortic
prosthesis is best heard along the left sternal border and over
the left precordium. The closing click of the aortic valve is
best heard in the second and third left intercostal spaces.
The opening and closing clicks of the mitral prosthesis are
best heard at the lower left sternal border and the cardiac
apex. In recent decades, tilting disk valves have accounted
for almost all of mechanical valve replacements. The most

TABLE 2.18. Continuous murmurs*

Location Differential Diagnosis

First to second left intercostal spaces (and under left clavicle) Patent ductus arteriosus
Second to fourth left intercostal spaces Aorticopulmonary septal defect
Usually best heard in the second to third left intercostal spaces; occasionally Surgical shunts, such as aortopulmonary anastomoses
may be best heard at the right of the sternum in the same area
Usually best heard along the lower left sternal border, although it may be Rupture of sinus of Valsalva aneurysm
audible over the entire precordium
Audible over the left precordium Coronary arteriovenous fistulas
May be audible anywhere that they occur Atrioventricular fistulas
*Continuous murmurs depend on a continuous pressure gradient in systole and diastole, such as occur in arterial and venous communications.
42 chapter
OCAV CCAV
SEM
CCMV OCMV
S1 S2
FIGURE 2.13. The prosthetic disk valve sounds for aortic and
mitral valves are shown. AV, aortic valve; CC, closing click; MV,
mitral valve; OC, opening click; SEM, systolic ejection murmur.
common change of the clicks with dysfunction of these
valves is a decreased intensity of the opening click.
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guidelines. Circulation 1998;98:1949–1984.
3. Carabello BA. Evaluation and management of patients with
valvular aortic stenosis. Circulation. 2002;105:1746–1750.
4. Otto CM. Clinical evaluation and management of chronic
mitral regurgitation. Circulation 2001;345:740–746.
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the evaluation and management of chronic heart failure in
the adult. Executive summary. J Am Coll Cardiol 2001;38:
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10. Hoit BD. Management of effusive and constrictive pericardial
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cardiac myxoma. A series of 112 consecutive cases. Medicine
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 3 Electrocardiography
Anton P.M. Gorgels
Electrical Activation of the Heart . . . . . . . . . . . . . . . . . . .
The P-QRS-T-U Complex. . . . . . . . . . . . . . . . . . . . . . . . . . .
Recording the Electric Activity . . . . . . . . . . . . . . . . . . . . .
Lead Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
T
his chapter covers basic information about the differ-
ent aspects of the standard electrocardiogram (ECG)
in adult clinical cardiology. Arrhythmias, including
monogenetic forms, conduction disturbances, and ECG find-
ings in congenital cardiology are discussed elsewhere in this
book.
Electrocardiography, more than 100 years after its inven-
tion by Einthoven, remains one of the most frequently used
bedside tools for the evaluation of the cardiac patient. Its old
age does not imply that electrocardiography has become a
rusty static science. On the contrary, along with the develop-
ment of new pathophysiologic concepts, electrocardiography
was reevaluated, resulting in new insights as to the use of
the ECG in current daily practice. Examples of such develop-
ments are new insights into cellular electrophysiology and
cardiogenetics, leading to the definition of new ECG syn-
dromes, such as the Brugada syndrome and better under-
standing of existing syndromes such as the long QT
syndrome. Availability of new imaging techniques has facili-
tated revisiting electrocardiographic–anatomic correlations.
The advent of possibilities to reopen a coronary artery, either
by thrombolytic therapy or by percutaneous coronary inter-
vention, has led to new information in the ECG regarding
ischemia and infarction, as to the site of occlusion within
the coronary system and the area at risk, and to noninva-
sively diagnose reperfusion of the ischemic tissue. Other
features of electrocardiography are its easy and repeated
applicability. This enables, better than any other technique,
the study of the dynamic behavior and natural history of
cardiac diseases.
This chapter discusses new findings in standard electro-
cardiography and the use of the ECG to describe the dyna-
micity of cardiac disease.
Electrical Activation of the Heart
The pump function of the heart is accomplished by electrical
activation of the myocardium. This process occurs through
depolarization of cells, aimed at (1) driving the heart action
43 The Normal Electrocardiogram . . . . . . . . . . . . . . . . . . . . . 47
44 The Abnormal Electrocardiogram . . . . . . . . . . . . . . . . . . . 49
44 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
46
(automaticity), (2) conducting the electrical impulse, and (3)
initiating contraction.
Depolarization and Repolarization
The basic electrophysiologic action is depolarization of cells
that are in a state of polarization. The amount of polarization
differs between automatic cells and conducting and contract-
ing cells. This process is driven by different ion currents,
with sodium, calcium, and potassium being the most impor-
tant ones. Sodium is the ion used for depolarization, calcium
follows thereafter to initiate and maintain contraction, and
potassium is needed to repolarize the cell. During the state
of polarization sodium concentration is high outside and
potassium concentration is high inside the cell. This is phase
4 of the action potential. During depolarization, sodium
enters the cell quickly (phase 0); after a slight repolarization
(phase 1), the plateau phase is reached, during which calcium
influx occurs (phase 2). Finally repolarization occurs through
potassium currents (phase 3). The equilibrium of ion concen-
trations is restored by energy-dependent ion pumps, such as
the sodium/calcium exchanger and the sodium/potassium
pump.
Automaticity
Automatic cells are less polarized than the other cardiac cells
and have the ability of spontaneous depolarization during the
resting phase 4. This leads to spontaneous de- and repolariza-
tion, allowing automatic activity. These cells are located
within the sinus node, the atrioventricular (AV) node, and the
specific distal conduction system. Differences in speed of
phase 4 depolarization lead to a hierarchical organization,
allowing the sinus node to dominate the heart rhythm. The
other potential pacemakers are depressed by the faster activa-
tion rate, a phenomenon, known as overdrive suppression. In
cases of failure of the dominant pacemaker or conduction
block, the secondary pacemakers become active, frequently
after a pause, and prevent in this way the heart from asystole.
The ensuing rhythm is called an escape rhythm.
43
44 chapter
Conduction
Depolarization of a cardiac cell is propagated to a neighbor-
ing cell. In this way propagation of the electrical impulse
occurs, resulting in activation of the whole heart.
Excitation of the cells spreads along myocardial cells
or specifically conducting fibers, such as the Bachmann
bundle in the atria and the His–bundle–branch–Purkinje
system in the ventricles. After atrial activation the impulse
passes through the AV node. Here the impulse is slowed
down, allowing time for the blood to pass to the ventricles.
Also the AV node has the property of decremental con-
duction and block at higher rates, preventing impulses
from passing to the ventricles in cases of atrial tachycardias,
such as atrial fibrillation. In this way the ventricles
are protected in cases of high-imposed rates. Once the
impulse has passed the AV node, conduction through
the distal conduction system, that is, the His bundle, the
right (RBB) and left bundle branch (LBB), and the Purkinje
network, is fast and in an all-or-none fashion. These proper-
ties secure prompt and synchronous activation of both
ventricles.
The P-QRS-T-U Complex
Electrocardiography is the graphic representation of cardiac
electrical activity, registered at the body surface. Cardiac
activation starts with discharge of the sinus node; the
electrical activity spreads over the atria, and passes to the
ventricles through the AV node, the His bundle, and
the bundle branches. Sinus node activity and conduction
through the specific conduction system are electrically
silent. Therefore, the basic electrocardiogram consists of
a P wave as the result of atrial activation, followed by an
isoelectric PQ interval during conduction through the spe-
cific conduction system, the QRS complex because of ven-
tricular myocardial depolarization, the isoelectric ST
segment during homogeneous and simultaneous myocardial
activation, and the T wave as the consequence of repolariza-
tion of ventricles (Fig. 3.1). The T wave has the same polarity
as the QRS complex because the sequence of myocardial
repolarization is reversed. The T wave is followed by a small
final deflection with a similar polarity known as the U
wave.
R
P T
AV conduction Q
S from the positive pole is recorded as a downward deflection. (C)
FIGURE 3.1. The basic electrocardiogram (see text).
3
Recording the Electric Activity
Electrode Leads
The electric activity of the heart is recorded from the body
surface using electrode leads. These consist of a positive pole,
connected to either a negative pole (bipolar leads) or a refer-
ence (zero) pole (unipolar leads). An electrical activation front
with the main direction toward the positive pole, records an
upward deflection (Fig. 3.2A). An activation front going in a
direction opposite to the positive pole, is recorded as a down-
ward deflection (Fig. 3.2B), and activation perpendicular to
this pole is electrically silent (Fig. 3.2C).
Factors Influencing the Amplitude
of Electrocardiogram Deflections
An activation front directly toward the electrode results in a
larger amplitude than an activation front with an angle to
the + pole (Fig. 3.3). Larger amplitudes will also be recorded
in cases of increased wall thickness, such as in myocardial
hypertrophy, because of the larger activation front (Fig.
3.4A,B) or with the electrode located closer to the myocar-
dium (Fig. 3.4C).
Similarly, smaller voltages than usual can be observed
and may include the total P-QRS-T complex (Table 3.1). This
is seen (1) in cases of an electrode more distant to the myo-
cardium (Fig. 3.5B)); (2) in conditions affecting both atrial and
A
+
B
+
+
FIGURE 3.2. (A) Any electrical activity in the hemi-segment
directed toward the positive pole is recorded as an upward deflec-
tion. (B) Any electrical activity in the hemi-segment directed away
Wave fronts perpendicular to the + pole are electrically silent.
 elect roca r diogr a ph y 45

+ +

FIGURE 3.3. The electrode depicts a larger amplitude when the

activation front is directed right toward the + pole, than in case of
an angle with this electrode. B

C
TABLE 3.1. Low-voltage ECG
Low voltage Extremity leads Precordial leads

Global cardiac muscle loss + +

Insulation myofibrils +
Pericardial fluid
Pleural fluid
Emphysema
Obesity FIGURE 3.4. The voltage (A) will be higher when the electrode is
closer to the myocardium (B) or when the myocardial wall thickness
RV dilatation + − is increased (C).

A B

+ +

C D

+ +

FIGURE 3.5. Mechanisms to induce low

voltage ECG. (A) Normal situation. (B) Elec-
trode more distant to myocardium. (C) Decrease +
in myocardial wall thickness. (D) Interposed
tissue or substance between myocardium and
electrode. (E) Storaged substance within the
myocardium causing electrical insulation.
46 chapter 3

A rotation of the dominant vector perpendicular to Einthoven’s

triangle.
R Changes in Electrocardiogram Deflections
2 1 Due to the Activation Sequence
+ Electrical activity recorded from global structures such as
S cardiac compartments are the result of the direction, force,
and timing of activation of the myocardial walls (Fig. 3.6).
Consecutive activation of the proximal vs. the distal wall
will lead to a positive/negative deflection, in cases of ven-
B tricular activation in an RS complex (Fig. 3.6A). In contrast,
activation of the distal wall first and subsequently the proxi-
R mal wall will lead to a QR complex (Fig. 3.6B). Activation of
1 2 both walls simultaneously results in cancellation of both
forces, resulting in no deflection (Fig. 3.6C).
+
Q Lead Systems

The Standard 12 Electrocardiogram

C
1 1
+ ences between the left arm and the right arm, lead II between
FIGURE 3.6. Activation sequence and resulting ECG configura-
tion. See text.
ventricular myocardium, such as in myocarditis, and dilated
cardiomyopathy, where loss of myocardial wall thickness
plays a role (Fig. 3.5C); (3) in the presence of extracardiac
interposing tissue, such as in obesity, pleural or pericardial
effusion, increased air content, for instance, in emphysema,
or pneumothorax (Fig. 3.5D); and (4) in cardiac amyloidosis
or storage diseases, where myocardial cells are insulated by
nonconductive material (Fig. 3.5E). Low voltage restricted to
the QRS complex in the extremity leads, and thus with
normal voltage in the precordial leads, is seen in cardiac
dilatation, especially of the right ventricle (RV). This is the
result of increased intracardiac volumes (Brody effect1) and/or
To enable the heart to be viewed in a standardized way and
from different sites, lead systems were developed. The first
three were the three bipolar leads I, II, and III, based on
Einthoven’s triangle. Lead I measures the potential differ-
the right arm and the left foot, and lead III between the left
arm and the left foot. A simple mathematic relation exists
among these three leads: At every instant during the cardiac
cycle the potential in lead II equals the sum of the voltages
in leads I and III: I + III = II. This basic relation is Einthoven’s
law. These bipolar limb leads were followed by the aug-
mented unipolar limb leads, aVR, aVL, and aVF, aimed at
deriving more local information from different parts of the
heart. These leads were constructed by using one of the limb
electrodes as the positive pole and the combined other two
as the reference electrode. Lead aVR equals the potential dif-
ference between the right arm and the reference potential,
which is the mean of the potentials of the left arm and the
left leg. Lead aVF equals the potential of the left foot minus
the mean of the potentials of the left arm and right arm, and
lead aVL records the potential difference between the left
arm and the mean potential of the left leg and the right arm.
These three bipolar and three unipolar limb leads form the
hexaxial lead system in the frontal plane (Fig. 3.7A,B).
Subsequently, precordial leads V1, V2, V3, V4, V5, and V6
were developed to obtain information in the transversal

A B C aVR aVL
- I + aVR aVL
- - I
I
II III
FIGURE 3.7. Electrode lead system
in the frontal plane. (A) Einthoven’s
+ + triangle. (B) Hexaxial lead system
III II positioned within the ventricles
aVF III II with the electrical center at the
aVF base of the left ventricle (C).
 elect roca r diogr a ph y 47
V9 V8
V7

V6 0˚ V6
V1 V2
V5
V4
V3
V5
30˚
V1 V4 V6r
V2 V3 60˚
120˚ 75˚
90˚
FIGURE 3.8. Precordial leads. Placement on the chest and position V5r
to the ventricles in the transverse plane.
V4r
V3r V1
plane. These leads have their positive pole at a specific pre- V2
cordial site and the combined limb electrodes as a reference FIGURE 3.9. Additional leads. Right precordial and left posterior
electrode. The most common system is the Wilson central leads.
terminal, which consists of inputs from three limbs (right
arm, left arm, and left leg) connected through 5000-Ohm
resistors. In this way six precordial leads are constructed
positioned from the right (lead V1) to the left lateral side (Fig. The Normal Electrocardiogram
3.8). Leads V1 and V2 are located more superiorly on the chest
in the four intercostal space, lead V3 is midway between
The P Wave
leads V2 and V4, and leads V4 to V6 are in the same transversal
plane with V4 being in the fifth intercostal space. It should Atrial activation starts from the sinus node, which is located
be realized that the plane formed by the six precordial leads at the right superior side in the right atrium. Therefore, the
is not in an exactly transverse direction. right atrium is activated first and from right superior to
The frontal leads are more at a distance from the heart, inferior. Thereafter the left atrium is activated, which is a
whereas the precordial leads are located closer to the myo- left posteriorly located structure. The normal P wave is
cardium. This allows the potential in the frontal plane to be therefore in the frontal plane, and is usually positive in I and
analyzed preferably according to a vectorial approach (single II and negative in lead aVR, with an axis in the frontal plane
dipole model). The potentials recorded in the precordial leads between 0 and 90 degrees (Fig. 3.10). In the transversal plane
are determined not only by the global cardiac activation but lead V1 records initial positivity during right atrial activation
also by local events close to their exploring electrode. There- and thereafter negativity during left atrial activation. Lead
fore, the analysis fits also with the multiple dipole array V6 records positive deflections throughout right and left atrial
model.2 activation.
The height of the P wave normally does not exceed
2.5 mm and its duration of 110 ms. Above that latter value
Additional Leads
conditions are present such as left atrial enlargement,
Apart from the standard 12 leads, additional leads are fre- intraatrial fibrosis, or the use of medication, slowing
quently used. Right precordial leads V3R to V6R are placed intraatrial conduction.
opposite to the regular precordial leads (Fig. 3.9). The most
frequently used lead is V4R, which is particularly useful to
The PQ Interval
record right-sided processes such as right ventricular infarc-
tion. Less frequently, leads V7 at the left posterior axillary The PQ or PR interval consists of the time of atrial activa-
line, V8 at the left midscapular line, and V9 left paraverte- tion, for conduction through the AV node, and the distal
brally, all at the V6 level, are used, usually to diagnose pos-
terior wall infarction.

The Format of the 12-Lead Electrocardiogram

The 12-lead ECG is mostly recorded in an order according to
2
their historical sequence of development, that is, first leads 1
2 1
I, II, and III, thereafter the augmented limb leads aVR, aVL,
and aVF, and finally the precordial leads. Especially regard-
ing the frontal plane, a more logical order would be to use
the sequence aVL, I, −aVR, II, aVF, and III. Because this way II
of representing the leads also has disadvantages, in the fol- V1
lowing discussion the traditional representation is used. All
recordings are taken at a paper speed of 25 mm/s and at a FIGURE 3.10. Left and right atrial activation and resulting P wave
calibration of 10 mV/cm. configuration in the frontal and transverse plane.
48 chapter
conduction system, the latter comprising the His bundle,
bundle branches, and Purkinje network, until the ventricular
myocardium becomes activated. The AV node starts to be
activated about midway through the P wave. Atrioventricu-
lar nodal conduction is characterized by its slowness (allow-
ing time for the blood to pass from the atria to the ventricles)
and long refractory period. The latter is useful to prevent fast
atrial activity (such as atrial fibrillation or flutter) to reach
the ventricles. Conduction slowing is decremental, implying
that the higher the imposing rate the more the conduction
will be impaired. Conduction time through the AV node is
at normal rates between 100 and 130 ms.
In contrast, conduction through the distal conduction
system is fast and because of the absence of decremental
conduction properties, the impulse traverses in an all-or-
none fashion, securing prompt and synchronous activation
of both ventricles. Conduction time through the distal con-
duction system is between 35 and 55 ms.
The total PR interval is usually between 120 and 200 ms.
A PR interval above this value is called prolonged conduction
and is due to a number of conditions such as ischemia, fibro-
sis, myocarditis, the use of medication, etc. A prolonged PR
interval should not be called first-degree block because the
impulse is not blocked but only delayed in conduction.
The QRS Complex
The QRS configuration is determined by the activation
sequence and contribution of both ventricles. Under normal
circumstances the thin-walled right ventricle contributes
little to the dominant activation fronts and therefore to the
QRS configuration. Activation mapping of the human heart
has revealed that the first structure to be activated is the
interventricular septum, immediately followed by the domi-
nant activation front, directed laterally, and finally the left
and right posterobasal areas are depolarized.3 Initial septal
activation leads to a negative deflection in leads I and aVL
(septal q), after which the activation spreads to the lateral
and posterior wall. The dominant force in the direction of
these leads results therefore in an R wave (Fig. 3.11). In the
transverse plane this activation sequence leads to an rS,
an RS, and a qR complex in V1, V3 or V4, and V6, respectively
(Fig. 3.11).
The normal QRS width does not exceed 90 ms. The height
of the R wave is less than 25 mm in V5 and V6, and 20 mm in
leads I and aVL. The Q wave is not wider than 40 ms. Widen-
ing of the QRS may be due to sequential activation of both
ventricles in the bundle branch block; intramyocardial con-
2
lead I
2
1 2 V5
1
1
V3
V1
FIGURE 3.11. Normal activation of the ventricles and resulting
QRS configuration in the frontal and transverse plane.
3
-90˚
-120˚ -60˚
aVL
-150˚ -30˚
0˚ EA LAD
180˚ 0˚
RAD NA
150˚ 30˚
60˚
90˚ II
120˚ 60˚
90˚
FIGURE 3.12. Assessment of the QRS axis in the frontal plane.
Left: In this example in lead aVL R height is equal to S depth. The
overall direction is therefore 0 and thus the axis is perpendicular to
aVL. The axis could either be +60 or –120 degrees. Lead II shows a
positive QRS complex, therefore the axis is +60 degrees. Right:
Definition of normal and abnormal QRS axes in the frontal plane.
NA, normal axis; LAD, left axis deviation; RAD, right axis devia-
tion; EA, extreme axis deviation.
duction delay, as seen in ischemia or fibrosis; or prolonged
conduction times due to increased muscle mass, as seen in
hypertrophy or ventricular dilatation.
The height of the QRS complex is dependent on many
factors such as age, thickness of the thoracic wall, and indi-
vidual differences in stature.
The Electrical Axis
In clinical practice the electrical axis is frequently used to
indicate the main electrical activation front. The axis can be
assessed for any part of the P-QRS-T complex. The axis is
defined as the global direction of electrical activation. A
convenient way to determine the axis is to go from a lead
where the global direction is (most) perpendicular to, for
example, an isoelectric segment or a lead with an equal
upward and downward deflection. The next step is to assess
in another lead whether this direction is toward or opposite
from its positive pole (Fig. 3.12).
The QRS axis is normally between −30 and 90 degrees.
Between −30 and −90 degrees left axis deviation is present,
and between 90 and 180 degrees right axis deviation. The
term extreme axis is used in case of an axis between −90 and
180 degrees.
Clinical Significance of the QRS Axis
Axis deviation may occur due to factors such as (1) the ana-
tomic position of the heart; (2) gain of forces in a specific
direction, for instance, right axis deviation in right ventricu-
lar hypertrophy; (3) loss of forces in a localized area, such as
in myocardial infarction; and (4) changes in the activation
sequence such as in conduction delay or block in the bundle
branches or in the left anterior or posterior fascicle.
The ST Segment
The ST segment occurs during calcium influx into the myo-
cardium allowing contraction to occur. This process is
simultaneous and homogeneous throughout the ventricles
and therefore the ST segment is usually isoelectric. In the
normal ECG lead V2 may show some ST elevation, especially
in men.
ST segment deviation may occur as the consequence of
a disease process, such as hypertrophy, ischemia, pericardi-
 elect roca r diogr a ph y
tis, or infarction, and is then called a primary ST segment
change. When ST-T changes occur as the result of a concomi-
tant ECG abnormality, such as in bundle branch block, pre-
excitation, or a paced rhythm, secondary ST-T segment
changes are present.
The T Wave and the QT Interval
The T wave reflects the repolarization of the ventricles and
although it has a similar polarity as the QRS complex, slight
differences in axis may be present, but usually not more than
45 degrees. Changes in polarity and T wave configuration
may be due to many different causes and are outlined in
more detail below.
The duration of the QT interval is generally used to indi-
cate the duration of the repolarization time. This interval is
rate dependent and normalization is done using different
methods, Bazett’s formula [corrected QT interval (QTc) = QT
(ms)/√R − R(s)] being the most frequently used. Normal values
are below 440 ms for men and below 450 ms for women. The
QT interval is prolonged in the setting of the long QT syn-
drome, comprising different congenital and acquired forms.
The U Wave
The normal U waves are likely to be produced by the repo-
larization of the His-Purkinje system, but there is some
doubt about whether large or inverted U waves are produced
in this manner. It is suggested that abnormal U waves are
actually due to split T waves created by two voltage gradients
across the ventricular myocardium. The first voltage gradi-
ent is responsible for the first part of the T wave (the usual
T), and the second voltage gradient is responsible for the
second wave that is currently called an abnormal U wave.4
The Abnormal Electrocardiogram
ECG abnormalities can be divided grossly into (1) configura-
tional changes and (2) time and sequence related changes of
the P-QRS-T complex. The latter changes are disturbances
of the heart rhythm and are discussed elsewhere.
Configurational changes, considered here, are P wave
abnormalities (such as atrial enlargement and hypertrophy,
and atrial infarction), changes in QRS configuration (increase
in QRS voltage, for instance, in hypertrophy, widening of
QRS duration as in bundle branch block, decrease in QRS
voltage, localized changes such as in healed infarction), ST
segment changes (acute coronary syndromes, acute pericar-
ditis), and primary T-wave abnormalities (acute ischemic or
postischemic T-wave changes, electrolyte abnormalities).
In the examples given below one can observe that many
disease states will simultaneously change different parts of
the P-QRS-T complex.
Changes in the P-Wave Configuration
Left Atrial Enlargement
Changes in the P wave, indicating overload of the left atrium,
are due to several factors, such as hypertrophy of the atrial
49
aVL
2 2
1 1
II
V1
FIGURE 3.13. Left atrial hypertrophy. Electrical forces in left atrial
hypertrophy in the frontal and transverse plane and the resulting P
wave configuration.
muscle, enlargement of the atrial compartment, slowing of
conduction, and prolonged conduction time due to the larger
muscular mass.5 This change leads to an increase in voltage
and, in cases of left atrial pathology, to an increase in dura-
tion of the latter part of the P wave. Leads II, aVL, and V1
usually depict these abnormalities best (Figs. 3.13 and 3.14A).
Lead II shows a wide P wave with a prominent second part,
frequently after a notch due to a transition from right to left
atrial activation. In lead aVL typically a late positive deflec-
tion is observed. In lead V1 small initial positivity, due to
right atrial activation, is followed by deep and broad late
negativity. Criteria for left atrial enlargement are P wave
duration in lead II ≥ 110 ms,6 and late negativity in lead V1 ≥
1 mm2 (Table 3.2).7
Another important P wave abnormality in this setting is
interatrial conduction block and retrograde activation of the
left atrium (Fig. 3.14B).8
Diagnosing left atrial enlargement and intraatrial con-
duction block has important clinical implications as it fre-
quently indicates left ventricle (LV) disease, for instance
mitral valve disease, LV hypertrophy, or end diastolic pres-
sure elevation, but it also indicates a substrate for atrial
arrhythmias, such as atrial fibrillation.
Right Atrial Enlargement
In right atrial enlargement mostly the initial part of the P
wave is distorted, because the right atrium is activated before
the left atrium. The increase in voltage and duration will lead
to superposition on left atrial activation in lead II and thus
to a tall P wave (Figs. 3.15 and 3.16). In lead V1 prominent
initial positivity is seen. Criteria for right atrial enlargement
are a P wave in lead II ≥ 0.25 mV (2.5 mm) and lead V1 ≥
0.15 mV (1.5 mm) (Table 3.2). Also criteria in the QRS complex,
and related to RV hypertrophy, have been defined to diagnose
right atrial enlargement. A qR pattern in V1, a QRS voltage
of 4 mm or more, has been found to be very specific.9 Right
atrium (RA) enlargement is present in congenital and valvu-
lar heart disease and in pulmonary hypertension.
Increased sympathetic tone also sometimes results in a
more cranial origin of the sinus, and faster atrial activation
with superposition of right and left atrial activation results
in taller P waves in the inferior leads, mimicking right atrial
enlargement.
50 chapter 3

A B

I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4 FIGURE 3.14. ECG with left atrial hypertro-

phy (A) and interatrial conduction block (B). (A)
Sinus rhythm, 70 beats/min, wide P wave,
120 ms in lead II, with prominent terminal
aVL V5 aVL V5 part, >1 mm2, in V1, indicating left atrial hyper-
trophy, in this case in anterior wall infarction.
(B) Sinus rhythm, P waves with markedly pro-
longed terminal part, negative in leads II, III,
aVF V6 aVF V6 and aVF, due to interatrial conduction block
with retrograde left atrial activation.

TABLE 3.2. Criteria for left and right atrial enlargement

P wave QRS Sens Spec PV

Left atrial enlargement II, III, aVF ≥120 ms 65% 70%

V1 ≥1 mm2 51% 87%
Right atrial enlargement II >2.5 mm Low Low 20%
V1 ≥1.5 mm
qR Low Low
QRS ≤ 4 mm 100%
QRSV2/V1 ≥ 5 46% 90% 80%
Biatrial enlargement V1 pos 1.5 mm
peak neg
peak ≥1 mm2
PV, predictive value; Sens, sensitivity; Spec, specificity.

2 2 I V1
1
1
II II V2

V1

III V3
FIGURE 3.15. Right atrial hypertrophy. Electrical forces in right
atrial hypertrophy in the frontal and transverse plane and the result-
ing P wave configuration.

aVR V4

aVL V5
FIGURE 3.16. Right atrial and ventricular hypertrophy. Sinus
rhythm, rate 75 beats/min electrical axis shifted to the right, +120
degrees, prominent positive P waves in V1 and V2, indicating right
atrial hypertrophy, tall R waves in III and V1, persistent s in V6, sec-
ondary T wave abnormalities indicating severe right ventricular aVF V6
hypertrophy. Case of severe primary pulmonary hypertension.
 elect roca r diogr a ph y 51

A B
I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4

FIGURE 3.17. Biatrial hypertrophy. (A) Sinus

rhythm, rate 75 beats/min, wide and tall P
wave in lead II, prominent biphasic P wave in aVL V5 aVL V5
lead V1, indicating biatrial enlargement, right
axis deviation, s in V1, abnormal ST-T seg-
ments, indicating right ventricular overload.
(B) Same patient in atrial fibrillation. Note
huge fibrillation waves in V1. Case of restric- aVF V6 aVF V6
tive cardiomyopathy.

Biatrial Enlargement
In biatrial hypertrophy features of both right and left atrial
hypertrophy are present (Table 3.2 and Fig. 3.17): (1) P wave
in lead II is taller and wider than normal, 2.5 mm and 0.12 s,
respectively; and (2) left atrial enlargement is combined with
QRS criteria for right atrial enlargement.
Changes in QRS Configuration
Conditions with Voltage Increase
L EFT VENTRICULAR HYPERTROPHY
Left ventricular hypertrophy is an important ECG diagnosis.
The ECG features are based on the pathophysiologic and
structural changes in the left heart. Increased load to the left
ventricle such as in hypertension or aortic valve disease lead
to increased wall thickness and therefore an increase of the
QRS voltage. The hypertrophic process is accompanied by
fibrosis, and impaired cell-to-cell coupling that may cause
impaired intramyocardial conduction and also impaired
bundle branch conduction. This leads to widening of the
QRS complex and altered initial activation. The result will
be disappearance of the septal q and a delayed intrinsicoid
deflection. The latter is assessed as an increase of the qR time
in V5 beyond 50 ms. Increase of dominant forces of the basal
left ventricle due to the larger muscle mass causes the electri-
cal axis to shift leftward. Increased atrial contribution to fill
the less compliant left ventricle leads to left atrial hypertro-
phy, and the presence of subendocardial demand ischemia
leads to secondary ST T abnormalities, apparent as down-
sloping ST depression in the anterolateral leads I, aVL, V5,
and V6. The latter is more frequently present in pressure than
in volume overloaded left ventricles.
Voltage criteria were developed to diagnose left ventricu-
lar hypertrophy (LVH); all have a similar drawback of a high
specificity at the expense of a low sensitivity (Table 3.3).7 The
Cornell voltage criteria for LVH include sex specificity.10

TABLE 3.3. Voltage criteria for left ventricular hypertrophy

Sensitivity (%) Specificity (%) Accuracy (%)

RI+SIII > 25 mm 10.6 100 55

RaVL > 7.5 mm 22.5 96.5 59.5
RaVL > 11 mm 10.6 100 55
RaVF > 20 mm 1.3 99.5 50
SV1 + RV5–6 ≥ 35 mm 42.5 95 74
SV1 + RV5–6 > 33 mm 55.6 89.5 73
In V1 − V5 any S + R > 45 mm 45 93 69
RV5–6 > 26 mm 25 98 62
RaVL + SV3 > 2.8 mV in men 42 96 68
RaVL + SV3 > 2.0 mV in women
Romhilt-Estes score 60 97 78
52 chapter 3

TABLE 3.4. Romhilt-Estes score to diagnose left ventricular hypertrophy (LVH)

QRS changes Points Total

Voltage criteria 3
R or S in frontal plane
≥20 mm
SV1 − V2 ≥ 20 mm
RV5 − V6 ≥ 30 mm
Frontal axis ≥−30 2
ID in V5 − V6 ≥ 0.05 s 1
QRS duration ≥0.09 s 1
ST-T changes ST depression without dig 3
ST depression with dig 1
P wave Terminal part V1 ≥1 mm2 3
LVH probable 4
LVH present 5
Dig, digitalis.

Apart from gender, other factors influence the accuracy of
the ECG, such as obesity decreasing sensitivity and black
race decreasing specificity.11 Combined QRS voltage and
duration criteria, expressed as their product, have been found
to increase sensitivity to 51%.12 To improve the accuracy of
the ECG diagnosis of LVH, scoring systems were developed
(Table 3.4),7 including not only changes in the QRS complex
but also in the P wave and the ST segment. More recently,
continuous rather than dichotomous scoring systems were
developed, increasing the sensitivity without sacrificing spe-
cificity.13 Although echocardiography is more sensitive than
the ECG to diagnose LVH, both techniques contain inde-
pendent prognostic information and, at least in hypertensive
patients, both should be performed to fully assess the
increased risk.14
Unloading the left ventricle can lead to regression of hyper-
trophy and to normalization of the ST segment, and decrease
in the voltage and width of the QRS complex (Fig. 3.18).15
R IGHT VENTRICULAR HYPERTROPHY
Right ventricular pressure and/or volume overload leads to
right ventricular hypertrophy (RVH) and dilatation of the
right ventricle.16 Owing to the thinner wall of the right ven-
tricle, this compartment has less opportunity to be exposed
in the ECG, even when pathologic changes are present. This
holds especially during the regular synchronous activation
of both ventricles. When sequential activation is present,
such as in left- or right-sided aberrant conduction, abnormali-
ties will be apparent more easily. In RVH rightward forces
counteract the left ventricular forces and could even become
the dominant direction of electrical activation (Table 3.5).7 In
the frontal plane this leads to rightward shift of the electrical
QRS axis. In the precordial leads, the QRS configuration in
the V1 lead shows the most pronounced consequence of the
rightward force; this may vary from a diminished depth of
the S wave to the occurrence of a tall R wave and a qR
complex. The latter indicates severe RVH, frequently in the
setting of high pulmonary artery pressures (Fig. 3.19). Another
feature of hypertrophy is conduction delay in the right bundle
or the RV myocardium. This will lead to a secondary R and/
or delayed intrinsicoid deflection of RV, best seen in V1 (Fig.
3.20).
Dilatation of the RV. Dilatation of the RV frequently
accompanies hypertrophy, due to the thin-walled RV not
prepared to generate high pressures. RV dilatation is seen in

A B

I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4 FIGURE 3.18. Left ventricular hypertrophy

(LVH) (A) and regression of LVH (B). Sinus
rhythm, 75/min, electrical axis +30 degrees,
absence of septal q waves, increased QRS
aVL V5 aVL V5 voltage in the precordial leads, ST-T segment
changes in V6, indicating severe LVH. Clini-
cally severe aortic valve stenosis. (B) General-
ized decrease in voltage indicating regression
aVF V6 aVF of LVH 2 months after aortic valve
V6
replacement.
 elect roca r diogr a ph y 53
TABLE 3.5. Criteria for RVH atrial and ventricular premature beats, or atrial fibrillation/
Criterion Sens Spec flutter. Bradycardia is rare and an agonal sign. The P wave is
usually normal and only rarely tall P waves are present. The
V1 R/S V1 ≥ 1 6 98
R ≥ 7 mm 2 99 QRS complex shows a rightward shift and signs of right ven-
QR 5 99 tricular conduction delay, apparent as an S in lead I, a Q in
S < 2 mm 6 98 lead III (McGinn and White’s sign), and a late R in leads aVR
IDT ≥ 0.35 s 8 98 and V1. The amount of right ventricular conduction delay cor-
V5 − V6 R/S ≤ 1 16 93 relates with the extent of obstruction within the pulmonary
R < 5 mm 13 87 circulation. Right ventricle dilatation may cause a general-
S ≥ 7 mm 26 90
ized voltage decrease in the extremity leads and slow R pro-
V1 + V6 RV1 + SV6 > 10.5 18 94
gression in the precordial leads. ST elevation in leads aVR and
QRS axis ≥110 degrees 15 96 V1 is part of the picture, and is probably due to demand isch-
SISIISIII 24 87
emia. In the subacute phase these signs gradually normalize
IDT, intrinsicoid deflection (time from onset to R wave peak). within a few days, but negative T waves develop especially in
leads V1 to V4, which remain for days to weeks.
RV Hypertrophy in Chronic Obstructive Pulmo-
nary Disease. In chronic obstructive pulmonary disease
the extremity leads as a generalized decrease in QRS voltage, (COPD) the ECG is determined by the amount of RVH and
and an undetermined electrical axis. In the precordial leads RV dilatation due to pulmonary hypertension, the increased
RV dilatation is observed as slow R progression and a persist- pulmonary volume due to conditions such as emphysema and
ent S until V6. This is due to extension of the RV anterolater- backward tilt of the apex of the heart as the low diaphragm
ally. ECG signs of RV dilatation may normalize when pulls down on the pericardium. The latter leads to general-
pressure or volume overload in the pulmonary circulation ized decrease in voltage and an upward shift of the QRS axis
improves (Fig. 3.21). in the frontal plane. Sinus tachycardia and not infrequently
atrial fibrillation is present, a QRS axis in the frontal plane
Acute RV Pressure Overload (Pulmonary
pointing in an extreme direction leading to the typical SISIISIII
Embolism). Acute RV pressure overload may occur in several pattern, and in the precordial leads a shallow s wave in V1 as
clinical circumstances, the most important being acute pul-
the consequence of RVH, slow R progression, and a persistent
monary embolism. The ECG is important to support the
s wave in V6 due to RV dilatation (Fig. 3.23).
correct diagnostic workup in a suspicious clinical condition.
The sudden increase of the resistance in the pulmonary cir-
BIVENTRICULAR HYPERTROPHY
culation leads to abrupt changes in the right ventricle, such
as a sudden decrease in stroke volume, dilatation, conduction RV Involvement in LV Disease. Left ventricle disease,
delay, and ischemia. The typical ECG features in the acute such as hypertensive heart disease, myocardial infarction,
phase (Fig. 3.22 and Table 3.6)17 are sinus tachycardia, right and mitral and aortic valve abnormalities, are usually

A B C
I V1 I V1 I V1

II V2 II V2 II V2

III V3 III V3 III V3

aVR V4 aVR V4 aVR V4

aVL V5 aVL V5 aVL V5

aVF V6 aVF V6 aVF V6

FIGURE 3.19. Development of right ventricular hypertrophy (RVH). forces counteracting left ventricle (LV) activation (cancellation), the
Three panels illustrating the development of RVH. All panels show shallow s sign, which is consistent with RVH. (B) Recorded 6 years
sinus rhythm. (A) QRS axis is 35 degrees. A s is present in lead I. later, it shows right axis deviation (+110 degrees), a qR pattern, an s
Also a small s is present in V1, as the result of right ventricle (RV) in V6. Changes are even more pronounced in panel C.
54 chapter 3

A B

I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4

aVL V5 aVL V5

aVF V6 aVF V6

FIGURE 3.20. Right ventricular hypertrophy in right bundle branch synchronous activation of both ventricles. (B) During RBBB, signs
block (RBBB). (A,B) RBBB in the same patient with ischemic heart of RVH are more evident because of the sequential activation of both
disease and mitral regurgitation. Sinus rhythm, left atrial hypertro- ventricles. RBBB has a qR pattern, delayed intrinsicoid deflection
phy, left axis deviation, q wave in V2. (A) Note the shallow S during and tall R.

reflected in the ECG. With increasing severity of these condi-
tions the pulmonary circulation may become pressure or
volume overloaded and in this way the right ventricle
becomes involved. Diagnosing RV involvement in LV disease
is therefore a marker of the severity of the disease process.
The ECG can give clues as to the presence of this situation.
Biventricular hypertrophy (BVH) may occur in hypertensive
heart disease (Fig. 3.24); in valvular heart disease, such as
mitral regurgitation; and in hypertrophic cardiomyopathy
(HCM) (Fig. 3.25; Table 3.7). Next to signs of LVH, frequently
left atrial hypertrophy is present, and signs of RV involve-
ment are present, such as increased voltage signs of hyper-
trophy, the typical feature being a tall R and a deep S in V3
(Katz-Wachtel complex), rightward shift in the frontal plane,

A B
I V1 I V1

II V2 II V2

V3
III V3 III
FIGURE 3.21. RV dilatation and regression
after heart failure treatment. (A) Recorded
V4 during severe congestive heart failure. Sinus
aVR aVR V4 tachycardia, 95 beats/min. Left atrial enlarge-
ment, low voltage in the extremity in contrast
to the precordial leads, slow R progression in
the precordial leads due to RV dilatation. (B)
V5 V5 Recorded after treatment. Slowing of the sinus
aVL aVL
rate, 75 beats/min, no left atrial hypertrophy,
normalization of voltage in the extremity
leads, R progression in the precordial leads.
The dynamic QRS behavior is explained by RV
aVF V6 aVF V6
dilatation and subsequent normalization.
 elect roca r diogr a ph y 55

A B C D

I I

II II

III III

aVR aVR

aVL aVL

aVF aVF

V1 V1

V2 V2

V3 V3

FIGURE 3.22. Acute RV pressure overload. V4 V4

Four panels with ECGs recorded during the
acute, subacute, and later stages of acute pul-
monary embolism. Left ECG shows sinus
tachycardia rightward shift of QRS axis, S1, V5 V5
Q3, T3 pattern, right bundle conduction delay,
S in V6 and ST elevation in aVR and V1. These
changes normalize over time, but T wave nega-
tivity in V1 to V4 remains for weeks to V6 V6
months. 400 ms

increase of the intrinsicoid deflection of the RV (as measured

in lead V1), and dilatation such as decrease of QRS voltage in
the extremity leads and slow R progression in the precordial
leads.
TABLE 3.6. Pulmonary embolism
P wave P pulmonale 8% Hypertrophic Cardiomyopathy. The 12-lead ECG is
Atrial arrhythmias 22% abnormal in 75% to 95% of HCM patients. The abnormali-
QRS complex Frontal axis > 90 degrees 33% ties are related to (1) the involvement of the respective com-
Axis undetermined 31% partments, (2) the hemodynamic consequences, and (3) the
Voltage <5 mm in extremity leads 20% stage and severity of the disease. Involvement of the ventri-
S lead I and/or aVL 73%
Q in lead III and/or aVF 49% cles and/or atria leads to LV and/or RV and LA and/or RA
RBBB incomplete 53% hypertrophy (Fig. 3.25). Abnormal initial activation (pseudo–
RBBB complete 14% ␦-wave), Q waves (pseudo-infarction), and QRS widening
Slow R progression precordial leads 51% (pseudo–bundle branch block) may also be present. ST-T
RBBB, right bundle branch block. abnormalities and prolonged QT interval are not unusual.
56 chapter 3

I
V1 I V1

II V2 II V2

III V3
III V3

V4
aVR aVR V4

aVL V5
aVL V5

aVF V6
aVF V6

FIGURE 3.23. RV hypertrophy and dilatation in emphysema. Sinus

rhythm, generalized decrease in voltage, extreme axis deviation,
small s in V1, slow R progression in the precordial leads, persistent
S in V6.
FIGURE 3.24. Biventricular hypertrophy. Atrial fibrillation, left
axis deviation due to left anterior hemiblock, positive criteria for
LVH, qR in V1 and delayed intrinsicoid deflection, persistent S in V6.
Hypertensive heart disease.

I V1

II V2

III V3

aVR V4

aVL V5

aVF V6

FIGURE 3.25. Sinus rhythm, 75 beats/min, wide P waves, 120 ms in precordial leads, consistent with right ventricular dilatation, tall
in lead II, >1 mm2 in V1, indicating left atrial hypertrophy, electrical R in V1 to V3, suggesting RVH, R in V6 > V5 indicating LVH. Widened
axis in frontal plane perpendicular to all leads (indeterminate axis), QRS complexes. Case of hypertrophic cardiomyopathy.
discrepancy of low voltage in the extremity leads with high voltage
 elect roca r diogr a ph y 57
TABLE 3.7. Right ventricle (RV) involvement in left ventricle
(LV) disease
I V1
LV disease RV involvement

LVH Rightward shift electrical axis

Old infarction Slow R progression precordial leads
II V2
LBBB Low voltage extremity leads
In RBBB tall R´
In RBBB persistent R´ over precordial leads
III V3
In LBBB increased R V1−V2

aVR V4
Marked T-wave inversion in the precordial leads should alert
the clinician to the diagnosis of the apical form of HCM.
Arrhythmias such as atrial fibrillation and ventricular
ectopic activity, and also conduction disturbances such as
AV junctional delay or block and bundle branch block, are aVL V5
seen.

Widening of the QRS Complex aVF V6

L EFT BUNDLE BRANCH BLOCK
In left bundle branch block (LBBB) both ventricles are acti-
vated through the right bundle branch. Slowing of conduc-
tion or complete block may be structural or functional.
Therefore, LBBB may be intermittent, through mechanisms
such as fast (phase 3 block) or slow rate (phase 4 block), ret-
rograde invasion into one of the bundles by premature ven-
tricular beats, or a mechanism called acceleration dependent
block.
The configuration of LBBB in the ECG is explained by
the activation sequence of the ventricles through the right
bundle branch solely. This structure inserts into the right
ventricle anteriorly in the apex. Therefore, the first part to
be activated is the right ventricular anterior wall, which may
result in a tiny r wave in lead V1 (Figs. 3.26 and 3.27). There-
after the interventricular septum is activated from right to
left, resulting in initial positivity in the lateral leads I, aVL,
and V6. The LV apex is the structure next to be activated,
frequently leading to slightly less voltage due to the smaller
amount of tissue. This is typically seen as a notch at the
nadir of the QRS complex. Finally the lateral wall is acti-
vated, producing positivity in the lateral leads. The serial
activation of the LV and the conduction through the myocar-
dium results in a widened QRS complex, but not exceeding
140 ms (Table 3.8). Exceeding this duration suggests addi-
tional reasons for slow or prolonged conduction within the
FIGURE 3.27. Intermittent left bundle branch block. Sinus rhythm,
the first and last two beats show wide QRS, left axis deviation,
absence of the septal q, widened QRS, 140 ms, notch in mid-QRS,
secondary ST-T segment changes, indicating left bundle branch
block. The middle five beats show normal conduction due to slight
slowing in rate. The T wave abnormalities during normal conduc-
tion are caused by the preexisting LBBB, a phenomenon known as
the cardiac memory sign.
myocardium, such as hypertrophy, dilatation, ischemia, or
use of medication, and is termed overcomplete LBBB. A
typical QRS configuration but without widening of the QRS
is named incomplete LBBB.
Additional Heart Disease and LBBB. Additional fea-
tures in the LBBB may unmask concomitant heart disease
(Table 3.9). In LVH the Sokolow index (SV1or2 + RV5or6 ≥ 35 mm)
is valid in LBBB. In old myocardial infarction (MI) and LBBB
the QRS is frequently distorted; slurring in the initial
upstroke in leads I, aVL, and V6 (Chapman’s sign), slurring in
the terminal upstroke in V4 and V5 (Cabrera’s sign), Q waves
in the leads I and aVL, and notches in the leads II, III, and
aVF all indicate scar due to previous MI.
Right ventricular hypertrophy (RVH) is apparent in the
ECG as a rightward shift of the QRS axis and gain of initial
voltage (R wave) in the leads V1 to V3, and RV dilatation as
low voltage in the extremity leads (Fig. 3.28). Acute ischemia
is diagnosed by recording additional ST segment changes

1 3
2
lead I
TABLE 3.8. Criteria for LBBB and RBBB
3 2 3 V6
1 LBBB RBBB

1 Axis −30° to +60° 0°–120°

2 QRS width 120–140 ms 120–130 ms
V1
Septal q wave Absent Present
Late R lateral leads Present Absent
FIGURE 3.26. Left bundle branch block. Directional changes in left V1 rS complex RsR´ complex
bundle branch block in the frontal and transverse plane and the
V6 RR´ complex Rs complex
resulting QRS configuration.
58
TABLE 3.9. LBBB and additional heart disease
LVH
Acute MI
Old MI
Septal MI
Inferior MI
RVH/dilatation
MI, myocardial infarction.
next to the secondary repolarization abnormalities due to the
LBBB. Serial comparison of subsequent ECG's is very helpful
for this purpose. Very specific is ST positivity in leads with
a positive QRS complex.
R IGHT BUNDLE BRANCH BLOCK
In right bundle branch block (RBBB), sequential activation of
the left ventricle and right ventricle occurs due to conduction
delay or block in the right bundle (Fig. 3.29). First the left
ventricle is activated in the usual way, that is, firstly septal
activation from to left to right, leading to a septal q wave in
leads I and aVL, followed by activation of the other parts of
the LV. The dominant direction in the lateral direction
results in a large R wave in these same leads. After this, due
to the right bundle branch block (RBBB) the right ventricle
is activated, leading to a late S, in the leads I and aVL, and a
tall secondary R in lead V1. The s wave in the lateral leads
typically has a rounded shape due to slow activation of the
RV through the myocardium rather than through the
Purkinje network (Table 3.8; Fig. 3.30A).
The RBBB is caused by similar pathologic mechanisms
as in LBBB, such as hypertrophy, dilatation, ischemia, and
A B
I V1
II V2
III V3
aVR V4
aVL V5
aVF V6
FIGURE 3.28. Changes in LBBB due to additional heart disease. (A)
LBBB and right ventricular overload. Sinus rhythm, low voltage in
the extremity leads, indicating right ventricular dilatation, tall R
chapter 3
Sokolow index positive
Additional ST segment changes
Initial slurring I, aVL, V6 (Chapman’s sign)
Slurring S wave V4 − V5 (Cabrera’s sign)
Q wave I, aVL
Notches II, III, aVF
Vertical/right axis
Low voltage extremity leads
Tall R V1–3
the use of medication impairing conduction, such as class IA
and IC drugs and tricyclic antidepressant drugs.
Also concomitant heart disease can influence the typical
RBBB configuration. Examples are the initial r wave in V1
increasing in height and width in old posterior wall infarc-
tion, but disappearing in septal infarction (Fig. 3.30B,C); in
concomitant RVH the secondary R’ wave increases in height
(Fig. 3.20). The RBBB masks left ventricular hypertrophy by
decreasing the Sokolow index (Fig. 3.31).
Distortion of the QRS Complex
The QRS complex will be distorted due to local changes
within the myocardium, such as scar formation, fibrosis,
infiltration by proteins, granulomas, tumor metastases, etc.
This distortion leads to changes of the QRS complex due to
absent, diminished, or delayed local activation. Pseudoin-
farction is diagnosed when one or more of the above-
mentioned QRS distortions are present in the absence of
ischemic heart disease. Examples are infiltrative heart
disease such as cardiac sarcoidosis, hypertrophic cardiomy-
opathy, and preexcitation syndromes.
I V1
II V2
III V3
aVR V4
aVL V5
aVF V6
in V2 to V3, consistent with RVH. (B) LBBB in healed myocardial
infarction. Sinus rhythm, notches in V4 and V5 (Cabrera’s sign) and
Q in V6.
 elect roca r diogr a ph y 59

lead I V1
1 2 I
V6
2
1 3 V2
II
3
V1
III V3

FIGURE 3.29. Right bundle branch block. Directional changes in

the frontal and the transverse plane and the resulting changes in aVR V4
QRS configuration.

aVL V5

HEALED INFARCTION
After acute myocardial infarction the ischemic myocardium
becomes necrotic and heals within weeks with scar forma-
tion. This leads in the QRS to the following possible changes:
(1) decrease of R voltage due to less myocardium to be acti-
vated, (2) a Qr complex due to incomplete loss of myocardium
and slow local conduction, (3) a QS complex in case of loss
of local myocardium (Figs. 3.30B and 3.32). Dependent on the
leads showing these changes, the infarction can be classified
as anterior, inferior, or lateral. The loss of myocardium in
cases of posterior wall infarction leads to a gain of R voltage
in the precordial leads.
Based on the changes in the QRS, complex scoring
systems were developed to estimate the infarct size.18
PSEUDOINFARCTION
The QRS complex will also be distorted due to other local
changes within the myocardium, such as fibrosis, infiltra-
tion by foreign materials, granulomas, and tumor metasta-
ses. This will lead to changes of the QRS complex due to
absent, diminished, or delayed local activation. Pseudoin-
farction is diagnosed when one or more of the above-
aVF V6
FIGURE 3.31. Right bundle branch block masks left ventricular
hypertrophy. Atrial arrhythmia leading to changing RR intervals,
leading to intermittent RBBB. Note the decrease in voltage in lead
I and aVL during RBBB and the positive Sokolow index in the syn-
chronous QRS, which is masked during RBBB.
mentioned QRS distortions are present in the absence of
ischemic heart disease. Examples are infiltrative heart
disease such as cardiac sarcoidosis (Fig. 3.33), hypertrophic
cardiomyopathy, and preexcitation syndromes.
Decrease in QRS Voltage
A number of mechanisms and causes of a decrease in voltage
have been mentioned above. Another not infrequent cause is
starvation, a typical example being anorexia nervosa. Proba-
bly due to protein loss of the myocardium, a generalized
decrease of voltage occurs (Fig. 3.34).19 In addition, the ECG
is characterized by sinus bradycardia and long QT time. The
latter may lead to torsades de pointes and sudden cardiac
death. After refeeding the ECG picture is reversible.

A B C

I V1 I V1 I V1

II V2 II V2 II V2

III V3 III V3 III V3

aVR V4 aVR V4 aVR V4

aVL V5 aVL V5 aVL V5

aVF V6 aVF V6 aVF V6

FIGURE 3.30. Right bundle branch block and changes in configura-
tion due to location of myocardial infarction. (A) Sinus rhythm, QRS
axis +60 degrees, normal initial QRS activation but late right ven-
tricular activation best seen as a late wide S in lead I and aVL (and
typically also in V6) and a late R’ in V1 (rSR’ complex). (B) RBBB in
healed inferoposterior wall myocardial infarction. Sinus rhythm,
left axis deviation due to myocardial loss in the inferior wall, result-
ing in Q waves in leads II, III, and aVF. Complete RBBB with a high
initial R in V1 as the result of posterior wall infarction. (C) Right
bundle branch block in anteroseptal myocardial infarction. Sinus
tachycardia, slightly prolonged PR interval, likely due to distal con-
duction delay. Due to muscle loss in the septum, the initial r in lead
V1 is absent, leading to the typical qR pattern in this situation.
60 chapter
1 STEMI and therefore treatment strategies are more aggres-
2 PCI (percutaneous coronary intervention). Non-STEMI,
3 main and proximal three-vessel disease, and ECG character-
4 rior, lateral, and combinations) and basal versus apical STEMI
1 be identified, all being situations indicating higher risk. The
FIGURE 3.32. Different QRS configurations in healed myocardial
infarction. (1) Normal tissue, qR complex. (2) Subendocardial infarc-
tion, Qr complex as the result of slow conduction and muscle loss.
(3) Transmural infarction, QS complex due to total loss of local
activation. (4) Subepicardial infarction, qr or r complex, as the result
of normal subendocardial activation and epicardial muscle loss.
The ST Segment
The most important cause of ST segment changes, either ST
elevation or depression, is ischemia of the myocardium. This
can either be demand ischemia, occurring during situations
such as exercise, anemia, or tachycardia, but also supply
ischemia in the setting of a critical stenosis frequently due
to plaque instability. This situation is covered by the term
acute coronary syndrome, being further classified as ST ele-
vation acute myocardial infarction (STEMI)20 and non-ST
elevation acute myocardial infarction (non-STEMI).21
Acute Coronary Syndromes
Management of STEMI and non-STEMI strongly depends on
the assessment of the risk of extensive damage to the myo-
cardium and its possible complications such as heart failure,
ventricular arrhythmias, and sudden or nonsudden death.
A B
I V1
I V1
II V2
II
III V3
III
aVR V4
aVR
aVL V5
aVL
aVF
V6
aVF
3
The ECG has proven to be a very useful tool for that purpose.
STEMI usually leads to more immediate damage than non-
sive, including thrombolytic therapy and primary and rescue
however, also comprises high-risk situations, such as proxi-
mal left anterior descending branch (LAD) disease and left
istics have been described for their identification.22 The ECG
also diagnoses anterior versus non-anterior (inferior, poste-
locations. In both instances the former conditions involve
larger areas at risk.23 Right ventricular and atrial infarction
and involvement of the specific conduction system can also
ECG of STEMI has been correlated with the culprit coronary
artery and a proximal or distal site of occlusion in that
vessel. These findings are helpful not only for assessment of
the area at risk but also to guide the interventional cardiolo-
gist to the culprit lesion in cases of multivessel disease. The
ECG also gives information about the acuteness24 and the
severity of STEMI, facilitating in both situations the choice
of the most appropriate treatment strategy.
T HE ISCHEMIA VECTOR
The term ischemia vector implies the direction and magni-
tude of the ST segment deviation during acute ischemia.
Similarly to the QRS vector, the most convenient way to
determine its direction is to go from a lead with an isoelec-
tric ST segment. The ST vector is perpendicular to this lead
and points to the direction of leads with ST elevation. Assess-
ment of the direction of the ischemia vector facilitates
assessing the site of (most) ischemia, and the amount of ST
elevation provides information about its severity. Especially
in the frontal plane, this vector has been shown to be helpful
for this purpose.
STEMI
Occlusion of an epicardial coronary artery or of a side branch
leads to acute transmural myocardial ischemia (also termed
V2
V3
V4
FIGURE 3.33. Distortion of the QRS complex.
Cardiac sarcoidosis. (A) Sinus rhythm, left
V5
atrial hypertrophy, atypical widening of the
QRS complex with pseudoinfarction pattern in
leads II and III. (B) Same patient with RBBB.
V6 Involvement of the conduction system is fre-
quent in cardiac sarcoidosis.
 elect roca r diogr a ph y
A B
I V1 I V1
II V2 II
III V3 III
aVR V4 aVR
aVL V5 aVL
aVF V6 aVF
FIGURE 3.34. Decrease in P-QRS-T voltage. Anorexia nervosa. Before (A) and during (B) an episode of anorexia nervosa. Note sinus brady-
cardia, axis deviation to vertical, generalized loss of voltage, deflections in lead I almost being absent.
acute myocardial infarction). The site and extent of the
ischemic area depends on (1) the artery being occluded, (2)
the perfusion area of the occluded coronary, and (3) the site
of occlusion within the vessel. The system coronary artery
is shown in Figure 3.35.
Anatomy of the Coronary Artery System. The LAD
runs along the anterior part of the interventricular septum
and perfuses the interventricular septum and the anterior
and anterolateral part of the left ventricle. In 40% to 50% of
cases this vessel wraps around the apex and also perfuses the
inferoapical area. The LAD is usually the most dominant
coronary branch, and occlusion leads to the largest infarc-
tions with possible complications such as heart failure, ven-
tricular arrhythmias, and death. By way of the first septal
perforator, it also perfuses the His bundle and the right and
left bundle branch, the latter also being supplied by the right
coronary artery (RCA). As a consequence, RBBB and intra-
Hissian block can occur in LAD occlusion and indicate a
proximal obstruction and therefore a large area at risk.
The circumflex branch (CX) runs along the mitral annulus
to the lateral and posterior parts of the LV. Side branches
perfuse the posterolateral, posterobasal, and not infrequently,
also the inferolateral part of the left ventricle. Also atrial
branches can branch off. This may lead to atrial infarction
in case of occlusion or to sinus node dysfunction, because
in 40% of cases, this structure is perfused by this branch.
Only in a minority (10%), does the CX perfuse the interven-
tricular and interatrial septum, including the AV node. The
rare occasion of AV conduction delay or block in the setting
of CX occlusion therefore identifies dominance of this
vessel.
The RCA runs opposite to the CX in the groove between
the right ventricle and atrium and perfuses the conus pul-
monalis; the right atrium, including the sinus node (in 60%
of cases); the right ventricle; the interventricular septum,
including the posteromedial papillary muscle; the interatrial
septum, including the AV node; the posterior wall; and some-
times also the posterolateral wall of the left ventricle. Occlu-
sion of the RCA, therefore, may lead to distinct clinical
61
V2
V3
V4
V5
V6
features, such as bradycardia because of sinus node and AV
node dysfunction (both also frequently aggravated by strong
vagal discharges occurring in this setting), atrial infarction,
right ventricular infarction, inferoposterior wall infarction
of the left ventricle, and mitral regurgitation. Recognizing
proximal RCA occlusion is therefore important so as to be
prepared for these possible complications.
ST Elevation in Acute Myocardial Infarction. Elec-
trodes facing the ischemic area record ST elevation in acute
transmural myocardial ischemia. This is considered to be the
consequence of differences in shape and height of the plateau
phase of endocardial and epicardial action potentials. In
anterior wall infarction ST elevation is observed in the pre-
cordial electrodes, at least in V2 and V3. In inferior wall in-
farction ST elevation occurs in at least leads II, III, and aVF.
Lateral infarction is apparent in leads I, aVL, V5, and V6. The
situation is more complex in posterior wall infarction because
no standard leads face this part of the LV. The precordial
leads record the reverse of ST elevation of the posterior wall,
that is, ST segment depression. In clinical trials and in clini-
cal practice, posterior wall infarction, mostly in the setting
of CX disease, is underdiagnosed and therefore undertreated,
resulting in increased morbidity and mortality.
CX
LAD
RCA
D1 OM
S1
PL
RV RDP
IA
FIGURE 3.35. Scheme of the coronary artery system. See text.
62 chapter 3

aVR aVL

V6
V5
V4
V1 V2 V3

III aVF II FIGURE 3.36. Proximal LAD occlusion in anterior wall

myocardial infarction. Directional changes in the frontal
and the transverse plane and the resulting changes in
the ST segment.

In the following subsection the ischemia vector is used
to explain the ECG changes in different forms of acute
STEMI and the resulting assessment of the area at risk.
Acute Anterior Wall Myocardial Infarction. The
LAD perfuses anterior, basal, apical, lateral, and frequently
inferior parts of the LV (Fig. 3.35). The resulting ECG during
obstruction depends on the involvement and size of these
respective segments. The more proximal the occlusion, the
more segments will be ischemic. By definition the anterior
wall will always take part, resulting in an anterior direction
of the ST vector in the transversal plane and thus in ST
segment elevation in leads V2 and V3. The ST segment behav-
ior in the other leads depends on the competing forces in the
basal versus the apical area and the medial versus the lateral
area. The apical part is smaller than the more basally located
segments. Involvement of the septum and the lateral areas
depends on the location of the obstructing lesion before a
dominant septal or diagonal branch, most frequently being
the proximal branches, perfusing the basal areas (Fig. 3.35).
Proximal Occlusion. An occlusion before the first
septal and diagonal branch will lead to dominance of the
basal part balanced between the septal and lateral segments.
In the frontal plane the result will be an ST vector in the
superior direction (Fig. 3.36). The ECG will show ST eleva-
tion in leads aVL and aVR and ST depression in the inferior
leads. It should be noted that ST negativity in leads II, III,
and aVF does not indicate absence of ischemia or subendo-
cardial ischemia, but is the result of more dominant forces
at the opposite site. In the transverse plane the vector will
point anteriorly and sometimes even anteromedially leading
to marked ST elevation in V1 and ST depression in V6 (Figs.
3.36 and 3.37A).
Distal Occlusion. In cases of a distal occlusion, below
the dominant diagonal and septal side branches, the apical
segments can be exposed leading to an inferior direction of
the ST vector in the frontal plane (Figs. 3.37B and 3.38). The
ECG now shows ST elevation or isoelectric ST segments in
the leads II, III, and aVF, and ST depression in lead aVR and
sometimes in aVL. The ST vector in the transversal plane is
oriented in a lateral direction, which leads to ST elevation
in lead V6 and sometimes to ST depression in lead V1
(Fig. 3.38).
Occlusion Behind the First Septal Branch. In cases
in which the septal tree is spared, ischemia in the lateral

A B
I V1 I V1

II V2 II V2

III V3 III V3
FIGURE 3.37. (A) Anterior wall myocardial
infarction due to proximal LAD occlusion.
Sinus rhythm, the ST segment vector is per-
aVR V4 aVR pendicular to lead I, resulting in the frontal
V4
plane in ST elevation in aVL and aVR, and ST
depression in the inferior leads. In the trans-
verse plane typically there is ST depression in
V5 V6. (B) Anterior wall myocardial infarction due
aVL aVL V5 to distal LAD occlusion. ST elevation is present
in the precordial leads indicating anterior wall
infarction. In the frontal plane the ST seg-
V6 ments in the inferior leads are isoelectric, indi-
aVF aVF V6 cating distal occlusion behind the major septal
and diagonal branches.
 elect roca r diogr a ph y 63

aVR aVL

V6
V5
V4
V1 V2 V3

FIGURE 3.38. Distal LAD occlusion in anterior wall

III aVF II
myocardial infarction. Directional changes in the frontal
and the transverse plane and the resulting changes in the
ST segment.

wall will dominate and the frontal ST vector will point later-
ally (Figs. 3.39 and 3.40A), frequently perpendicular to lead
II. This leads to ST depression in leads III and aVR, ST eleva-
tion in lead aVL, and an isoelectric ST segment in lead II. In
the transversal plane the ST behavior is similar to that in
distal occlusion.
Occlusion Behind the First Diagonal Branch. Oc-
casionally the first diagonal branch originates before the first
septal branch or there is an anterolateral (intermediate)
branch taking off between the LAD and CX. In these circum-
stances the occlusion can be located behind the first diagonal
and before the first septal perforator (Figs. 3.40B and 3.41).
The ST vector points medially in the frontal plane, leading
to ST elevation in leads III and aVR, and sometimes to ST
segment negativity in lead aVL. In the transverse plane
similar behavior will be observed as in a proximal occlusion
(see above).
The ECG findings as described have a high specificity,
but a limited sensitivity to predict the correlation with the
coronary anatomy. Most sensitive are ST depression in the
inferior leads and ST elevation in aVR to predict a proximal
occlusion, and absence of ST depression in the inferior leads
to predict a distal occlusion (Table 3.10).25
Occlusion of a Diagonal Branch. Occlusion of a
dominant mostly first diagonal branch or of an anterolateral
branch results in ST elevation restricted to the leads V2, V3,
I, and aVL. This picture should be differentiated from other
STEMIs with ST elevation in I and aVL, such as a dominant
marginal branch from the CX. In that case V2 and V3 will
depict ST depression. When this same picture is present but
also V1 and aVR are elevated, left main or three-vessel disease
have to be considered (see below).
Acute Non-Anterior Wall Myocardial Infarction.
Non-anterior wall infarction comprises involvement of the
posterior, inferior, and lateral parts and combinations. The
culprit vessel could be either the RCA or the CX or one of
its side branches.
The ECG gives information about which of both vessels
is occluded and whether the right ventricle is involved. The
latter points to a proximal RCA obstruction and identifies a
high-risk situation with early and late hemodynamic and
arrhythmic complications such as cardiogenic shock, sinus
and AV node conduction impairment (sinus arrest or brady-
cardia, AV block of different degrees), and ventricular
arrhythmias.
RCA Occlusion. In cases of RCA occlusion, the isch-
emia vector in the frontal plane will point in an inferomedial
direction, because the RCA perfuses the right ventricle and
the inferior part of the septum and of the left ventricle (Figs.
3.42 to 3.44). This leads to ST segment elevation in leads II,
III, and aVF, ST being higher in lead III than in lead II. Con-
sequently lead I will show ST depression. Usually also aVR
and aVL show ST segment depression. Rarely ST elevation in
aVR is observed. This identifies also more basally located
ischemia, due to either a dominant posterior descending
branch or to multivessel disease.

aVR aVL

V6
V5
V4
FIGURE 3.39. Anterior wall myocardial infarction with V1 V2 V3
involvement of the first diagonal, but not the first septal III II
branch. Directional changes in the frontal and the trans- aVF
verse plane and the resulting changes in the ST
segment.
64 chapter 3

A B

I V1 I V1

FIGURE 3.40. (A) Anterior wall myocardial

II V2 II V2
infarction with involvement of the first diago-
nal, but not the first septal branch. Because of
dominance ischemia of the lateral wall, the ST
III V3 III V3 segment vector points perpendicular to aVF in
lateral direction. Therefore, III, aVR, and aVF
show ST depression and in the transverse plane
also, VI has ST depression. (B) Anterior wall
aVR V4 aVR V4 myocardial infarction with involvement of the
first septal, but not the first diagonal branch.
Because of dominance ischemia of the septum,
aVL V5 aVL V5 the ST segment vector points perpendicular to
aVF in medial direction. Therefore, III, aVR,
and aVF show ST elevation and the ST segment
in aVL may be depressed. In the transverse
aVF V6 aVF V6 plane, V1 has ST elevation and V6 ST
depression.

aVR aVL

V6
V5
V4
V1 V2 V3
FIGURE 3.41. Anterior wall myocardial infarction with
III aVF II involvement of the first septal, but not the first diagonal
branch. Directional changes in the frontal and the trans-
verse plane and the resulting changes in the ST
segment.

TABLE 3.10. Criteria to identify the occlusion site in the LAD

Criterion Occlusion site Sens Spec PPA NPA

CRBBB Proximal to S1 14 100 100 62

ST↑V1 ≥2.5 mm Proximal to S1 12 100 100 61
ST↑aVR Proximal to S1 43 95 86 70
ST↓V5 Proximal to S1 17 98 88 62
Q aVL Proximal to D1 44 85 67 69
ST↓ II ≥1.0 mm Proximal to S1/D1 34 98 93 68
Q V5 Distal to S1 24 93 71 53
ST↓ aVL Distal to D1 22 95 87 46
No ST↓ III Distal to S1/D1 41 95 92 53

NPA, negative predictive accuracy; PPA, positive predictive accuracy; RBBB, right bundle branch block.

CX aVR aVL

I
V6
RCA
V5
V4r
V4
V1 V2 V3
FIGURE 3.42. Inferior wall infarction due to proximal
III aVF II
RCA occlusion. Directional changes in the frontal and
the transverse plane and the resulting changes in the ST
segment.
 elect roca r diogr a ph y
I V1
II
III
FIGURE 3.43. Inferior wall infarction due to
proximal RCA occlusion. Atrial fibrillation,
complete atrioventricular (AV) block, junc- aVR
tional escape rhythm with QRS configuration
similar to conducted beats, ST elevation in
leads II, III, and aVF, ST in III higher than in aVL
II, ST depression in lead I. In V2 to V3 ST
depression due to posterior wall infarction and
in the right precordial leads ST elevation as a
aVF
sign of right ventricular involvement.
CX Occlusion. In CX occlusion the ischemia vector in
the frontal plane points in an inferolateral direction, leading
also to ST elevation in leads II, III, and aVF, but now lead II
is equal to or higher than III. Consequently, in lead I the ST
segment will be isoelectric or elevated (Figs. 3.45 and 3.46).
CX Side Branch. Circumflex branch occlusion or one of
its side branches may also lead to posterolateral and even
pure posterior wall infarctions (Figs. 3.47 and 3.48). The ECG
will predominantly show ST depressions and may fail to
have two contiguous leads with ST elevation. The latter is a
guideline requirement to diagnose STEMI. This has led to
underrecruitment of CX infarctions in clinical trials and, as
stated previously, to underdiagnosis and undertreatment of
patients with CX infarctions.
The Value of V4R. The described ECG findings in the
frontal plane correlate well with the culprit vessel but depend
on the dominance of the vessel within the coronary system.
More specific, therefore, is the assessment of involvement of
the right ventricle, because this compartment is always per-
fused by the RCA. For this purpose, assessment of a right-
ward shift of the ischemia vector in the transverse plane is
very useful. To be able to record this feature the use of right
precordial leads V3R to V6R is needed. Lead V4R has been
found to be the most sensitive and specific lead. The direc-
tion of the ST vector in the transverse plane is determined
by the involvement of the posterior wall, the posterior
septum, and the right ventricular posterior and anterior wall.
In cases of CX occlusion, only the posterior wall is involved,
leading to an ischemia vector pointing in a posterior direc-
RCA
FIGURE 3.44. Inferior wall infarction due to distal RCA
occlusion. Directional changes in the frontal and the
transverse plane and the resulting changes in the ST
segment.
65
V2
V2 V1
V3 V3r
V4 V4r
V5 V5r
V6
V6r
tion, apparent in the precordial leads V1 to V4, but also in lead
V4R as ST depression. When the distal RCA is the culprit,
the posterior wall of the left ventricle and the posterior
septum, but not the right ventricle, is involved. This leads to
a slight rightward shift of the ST vector now coming more
perpendicular to V4R, resulting in an isoelectric ST segment.
When the RCA is occluded in the proximal part, the isch-
emic right ventricle will shift the ST vector more to the
right, and now the right precordial leads become positive.
Conduction Disturbances in STEMI. The conduc-
tion system is perfused by different coronary arteries (Fig.
3.49). All parts of the conduction system can be involved in
STEMI. Sinus node and AV node dysfunction is frequently a
feature of RCA or CX disease. Sinus bradycardia, sinoauricu-
lar block of different degrees, and sinus arrest may occur in
this setting. First-degree AV nodal conduction delay, or
Mobitz I (or Wenckebach block) or complete AV block may
occur. Reperfusion usually leads to fast recovery. The LAD
perfuses the His bundle and ischemia may induce prolonged
PR interval, Mobitz II block, and complete AV block. The
proximal part of the right bundle is perfused by the first
septal perforator of the LAD, and the RBBB in this setting
identifies a proximal LAD occlusion and a large area at risk.
The RBBB has the typical QR configuration in lead V1, due
to loss of the initial septal r wave. Additional fascicular
blocks may occur, anterior fascicular block more frequently
than posterior hemiblock (Fig. 3.50). Both situations indicate
increased risk of large infarctions, posterior more than ante-
rior block. This is likely due to the double blood supply of
CX aVR aVL
V6
V5
V4r
V4
V1 V2 V3
III aVF II
66 chapter 3

CX aVR aVL

I
V6
RCA
V5
V4r
V4
V1 V2 V3
FIGURE 3.45. Inferior wall infarction due to CX
III aVF II occlusion. Directional changes in the frontal and the
transverse plane and the resulting changes in the ST
segment.

I V1 V2

II V2 V1

III V3 V3r

aVR V4 V4r

aVL V5 V5r
FIGURE 3.46. Inferior wall infarction due to CX occlusion. Sinus
rhythm, ST elevation in the inferior leads, lead II equal to III, isoelec-
tric ST segment in I, ST depression in aVR and aVL; ST depression V2
aVF V6 V6r and V3 due to posterior wall infarction and ST elevation in V5 to V6
due to lateral infarction. The right precordial leads show ST depres-
sion indicative of CX occlusion.

CX aVR aVL

I
V6
RCA
V5
V4r
V4
V1 V2 V3
FIGURE 3.47. Occlusion of an obtuse postero-
III aVF II lateral branch of the CX. Directional changes
in the frontal and the transverse plane and the
resulting changes in the ST segment.

I V1 V2
AV node His RBB
LAD
II V2 V1

AF
III V3 V3R

aVR V4 V4R PF
RCA
aVL V5 V5R

RDP
aVF V6 V6R FIGURE 3.49. The AV conduction system and its blood supply. See
text. AF, anterior fascicle; LAD, left anterior descending branch;
FIGURE 3.48. Posterolateral infarction with predominantly ST His, bundle of His; PF, posterior fascicle; RBB, right bundle branch;
depression. RCA, right coronary artery; RDP, right descending posterior.
 elect roca r diogr a ph y 67
these situations. Serial comparison of ECGs recorded within
and without the ischemic episodes is helpful in identifying
I V1 additional ischemic changes (Figs. 3.51 and 3.52). Criteria
were developed in LBBB to help in diagnosing acute infarc-
tion.27 These criteria are highly specific but their sensitivity
II V2 is low (Table 3.11).
Isolated Right Ventricular Infarction. When only the
right ventricle is ischemic, no counteraction of the posterior
III V3 forces is present and this will lead to ST elevation in the
standard precordial leads. Because the right ventricle is an
inferior structure, some ST elevation in the inferior leads II,
III, and aVF also may be present (Fig. 3.53). Recognizing RV
aVR V4
infarction is important, because this condition may be con-
fused with an LAD infarction. Usually, however, no grade 3,
but rather grade 2 ischemia is present. Isolated right ventricu-
aVL V5 lar infarction is seen in three possible situations: (1) a non-
dominant RCA, (2) a collaterally perfused RCA, or (3) an
isolated occlusion of a right ventricular branch.
aVF V6 Atrial Infarction. A frequently unrecognized condition
is an atrial infarction. The ECG signs of atrial infarction are
elevation of the Ta segment, the repolarization phase of the
FIGURE 3.50. RBBB and posterior fascicular block in anteroseptal
atria, in leads I, II, III, V5, or V6, or a depression in the pre-
wall infarction. Sinus rhythm, right axis deviation, q wave in lead
III, absence of septal q in RBBB. cordial leads that may exceed 0.15 mV and 0.12 mV in leads
I, II, and III (Fig. 3.54). Recognizing infarction of the atria is
important because of its clinical implications. It can occur
both in RCA or CX occlusion and indicates a proximal loca-
the left bundle, that is, both from the LAD and from the
tion of the lesion. Atrial infarction is often complicated by
RCA. Complete LBBB is a rare complication in the setting of
atrial fibrillation and also by more serious conditions, such
STEMI, likely because of this double blood supply. This rare
as atrial thrombosis and even rupture of the atrial wall.
occasion, therefore, implies multivessel disease and an
extensive area at risk (Fig. 3.51).
ST R ECOVERY FOLLOWING R EPERFUSION
Acute Ischemia in Cases of a Widened QRS Persistent ST deviation is the hallmark of transmural isch-
Complex. Widened QRS complexes occur in conditions emia. In the preintervention era the ST segment gradually
such as BBB, ventricularly paced rhythms,26 and preexcita- returned to baseline within the first 24 hours, frequently
tion syndromes. Diagnosing acute infarction is complicated being accompanied by T-wave inversion and Q-wave forma-
by the primary repolarization abnormalities occurring in tion. Resolution of ST segment elevation and T-wave

A B

I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4

FIGURE 3.51. A. Ischemia-induced LBBB.

During chest pain LBBB is present with addi-
tional ischemic ST segment changes. (B) On aVL V5 aVL V5
relief of chest pain, QRS widening diminishes
indicating the ischemic nature of the conduc-
tion impairment. Rate-related LBBB as a mech-
anism is excluded because of the equal heart aVF aVF
V6 V6
rates in both situations. Case of left main ste-
nosis and multivessel disease.
68 chapter 3

A B
I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4

aVL V5 aVL V5

FIGURE 3.52. ST segment changes in ven-

aVF
aVF tricular paced rhythm. (A) Baseline. (B) During
V6 V6
ischemia. Note the marked ST segment depres-
sion in the precordial leads during ischemia.

TABLE 3.11. Criteria to diagnose acute MI in LBBB

Odds ratio (95% conficence
Criterion interval) Score

ST segment elevation ≥1 mm concordant with QRS complex 25.2 (11.6–54.7) 5

ST segment depression ≥1 mm in lead V1, V2, or V3 6.0 (1.9–19.3) 3
ST segment elevation ≥5 mm discordant with QRS complex 4.3 (1.8–10.6) 2
To obtain a sensitivity of 78% and a specificity of 90%, the minimal total score should be 3 (modified from Sgarbossa
et al.26)

I V1 V2

II V2 V1

I V1

III V3 V3r
II V2

aVR V4 V4r III V3

aVR V4
aVL V5 V5r

aVL V5

aVF V6 V6r
FIGURE 3.53. Isolated right ventricular infarction. ST elevation is
present in leads II, III, and aVF, the ST vector is directed to the right
+120 degrees (perpendicular to aVR). ST elevation is most pro-
nounced in leads V1 to V4 and in the right precordial leads, due to
the lack of counter forces from the posterior wall.
aVF V6
FIGURE 3.54. Atrial infarction. Inferoposterior wall infarction due
to RCA occlusion. Ta segment elevation and prolonged atrial con-
duction or repolarization time, leading to merging of the P wave
into the QRS complex.
 elect roca r diogr a ph y 69
inversion is accelerated when the occluded vessel is reopened,
either by thrombolytic therapy or percutaneous coronary I
intervention. T-wave inversion is frequently one of the
earliest signs of reperfusion, but is seen in only 60% of reper- II
fused cases. The speed and completeness of ST segment nor-
III
malization is a marker not only of reopening of the culprit
vessel, but also of the quality of reperfusion at the tissue
aVR
level. ST segment normalization of 30% or less is associated
with poor reperfusion, 31% to 70% with moderate reperfu-
aVL
sion, and 71% or more with good reperfusion. The amount
of ST segment resolution correlates with clinical outcomes,
aVF
such as heart failure and death, in the subacute and late
phase after MI. V1
In about half of the patients receiving thrombolytic
therapy and 10% of those with a PCI, the initial change is V2
an increase of ST segment elevation at the time of onset of
reperfusion, followed by ST segment normalization. Absence V3
of ST segment resolution following thrombolytic therapy,
especially in large infarctions, is an indication for PCI. V4
Continuous ST segment monitoring is the best way to
document reflow in the infarct related coronary artery. It V5
allows recognition of reopening, the quality of the reperfu-
sion, and eventual reocclusion. V6
The onset of reperfusion is frequently accompanied by
ventricular arrhythmias, the accelerated idioventricular FIGURE 3.55. Accelerated idioventricular rhythm in reperfused
rhythm (AIVR) being the most typical one (Fig. 3.55). These acute anterior wall myocardial infarction.
arrhythmias relate with worse quality of reperfusion at the
tissue level.28
formation, and (3) persistent or recurrent ST elevation
(Fig. 3.56).29
INTRAVENTRICULAR SEPTAL RUPTURE A FTER STEMI
Acute infarctions are not infrequently complicated by rupture L EFT VENTRICULAR A NEURYSM
of the free wall, the interventricular septum, or a papillary No or suboptimal reperfusion leads to persistent ischemia,
muscle. Free wall rupture leads in most cases to electrome- hibernation, and finally necrosis or apoptosis of the myocar-
chanical dissociation and sudden death. Rupture of a papil- dium with scar formation and not infrequently aneurysm
lary muscle leads to severe acute pulmonary edema, and formation. Electrocardiographically this leads to loss of QRS
interventricular septal rupture leads to cardiogenic shock. In voltage or Q formation and persistence of ST segment eleva-
surviving patients the ECG is characterized by (1) sinus tion. Serious ventricular arrhythmias often develop in these
tachycardia, (2) subacute infarction evident as Q wave situations.

A B

I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4

FIGURE 3.56. Interventricular septum rupture in aVL V5 aVL V5

inferior wall infarction. (A) Reperfused small inferior
wall infarction with Q-wave formation and normal-
ization of the ST segment, T-wave negativity in lead
III. (B) Recurrent complaints with sinus tachycardia aVF V6 aVF V6
and new ST elevation.
70 chapter
Acute Pericarditis
Acute pericarditis leads to epicardial injury and in this way
to generalized ST elevation, except for lead aVR (Fig. 3.57).
Also part of the picture is Ta depression, best seen in lead II
and V1. Pain, fever, or hemodynamic compromise leads to
sinus tachycardia, and atrial fibrillation may occur. When
pericardial effusion is present, it may lead to generalized loss
of voltage of the P-QRS-T complex. Alternation of the QRS
voltage is seen in hemodynamic compromising effusions,
frequently in the setting of malignancies. In the subacute
phase of pericarditis the ST segment normalizes and abnor-
mal T waves are seen, such as flat or inverted T waves, which
can remain for a prolonged period of time.
Non-STEMI
Non-STEMI comprises coronary syndromes with a seem-
ingly less severe acute course, such as shorter lasting or
spontaneously relieving chest pain, normalization of the
ECG, and less increase of cardiac plasma enzymes. There-
fore, the diagnostic and therapeutic strategies are frequently
less aggressive and invasive than in STEMI patients. However,
non-STEMI contains high-risk categories such as (1) left
main stenosis, proximal three-vessel disease, and graft occlu-
sion; (2) proximal LAD occlusion; and (3) as mentioned before,
acute pure posterior wall infarctions. Left main and three-
vessel disease frequently do not express as STEMI because
the ECG changes are the consequence of a complex interplay
due to subcritical stenoses at multiple sites, collateral circu-
lation, and frequently already-old infarction(s). This leads to
ST changes caused by endo- and epicardial ischemia in dif-
ferent sites in the heart.
Left Main and Three-Vessel Disease
One of the most critical conditions in clinical cardiology is
ischemia due to left main stem stenosis. Frequently no com-
plete obstruction is present, unless collateral circulation
from the RCA has developed. In most instances in left main
disease, multiple stenoses also are found in the other coro-
nary arteries. Also not rarely an old MI is seen in the stan-
dard ECG. Recognizing left main disease is important in
directing the patient without delay to the most optimal treat-
A B
I V1 I V1
II V2 II
III V3 III
aVR V4 aVR
V5
aVL aVL
aVF V6 aVF
3
ment strategy, most likely surgical coronary revasculariza-
tion. The ECG in left main disease is similar to that of
proximal three-vessel disease, and therefore they are dis-
cussed together.
The ischemia vector in left main disease in the frontal
plane typically points in the superior direction, not infre-
quently even the right superior (extreme axis) direction, indi-
cating involvement of the basal parts of the left ventricle.
This leads to ST segment elevation in leads aVR and some-
times in lead III, whereas the other frontal leads show ST
depression. In the precordial leads V1 usually is elevated,
whereas the other precordial leads show ST depression. Some
specific features of the ECG pattern include (1) ST depression
in eight leads or more in the 12-lead ECG30; (2) elevation in
aVR and V1; (3) being higher in aVR than in lead V131; (4) severe
down-sloping ST configuration in the precordial leads, typi-
cally in lead V4; and (5) ST elevation in lead III, not being
present in lead II (Fig. 3.58).
ST vector in the Frontal Plane to Identify
the High-Risk Patient
In the above discussion the usefulness of assessing the isch-
emia vector has been clarified. The ST vector can be used to
identify patients with a large area at risk (Fig. 3.59). Vectors
pointing inferiorly or laterally indicate lower risk than
vectors in a superior or extreme direction. In cases of a pos-
terior vector in the transversal plane inferomedial, the infe-
rior and inferolateral or lateral direction indicates RCA or
CX disease. When the vector is directed anteriorly, distal
LAD disease is diagnosed. In case of a superior or extreme
direction, the possibilities are high-risk situations such as
proximal LAD disease and left main or three-vessel
disease.
The T Wave
Ischemic T-Wave Behavior and Its
Clinical Significance
DURING ISCHEMIA
ST-segment elevation is a characteristic feature of acute
transmural ischemia of ventricular myocardium. Also more
discrete abnormalities due to ischemia may be observed
V2
V3
V4
V5
V6
FIGURE 3.57. Acute pericarditis.
 elect roca r diogr a ph y 71

–60∞
I V1

aVR aVL

II V2
high-risk
ischemia
vector
I
III V3

aVR V4

+120∞ II
aVL V5
aVF
FIGURE 3.59. High-risk ST vector. ST segment vectors between
−60 and 120 degrees, leading to ST elevation in aVR suggesting
V6 high-risk situations such as proximal LAD occlusion, left main
aVF
and/or three-vessel disease.

FIGURE 3.58. Left main and/or three-vessel disease. ST depression

is present in most leads and is typically down sloping. Lead aVR
shows more ST elevation than V1.

during the repolarization phase of the ventricles: (1) Early,
probably subendocardial, ischemia may present predomi-
nantly as shortening of the QT interval. It is observed in
subtotal stenosis of the culprit artery or in complete obstruc-
tion in the presence of collateral circulation. (2) Peaked T
waves are another early feature of acute ischemia and are
classified as grade 1 ischemia32 (Fig. 3.60). Pronounced ST-
segment elevation leads to incorporation of the T wave in the
ST segment. Severe ischemia with marked ST-segment eleva-
tion is sometimes accompanied by alternation of the ST
segment and the T wave.41–43
A FTER ISCHEMIA
After an episode of chest pain, relieving spontaneously or by
an intervention, negative T waves are commonly observed,
both in unstable angina and in acute MI. Starting with nega-
tivity of only the terminal portion of the T wave, this is fol-
lowed within hours or days by total negativity. In patients
admitted with a normal ECG after an episode of chest pain,
it is therefore helpful to repeat ECG recordings, because the
possible rapid onset of T-wave negativity unmasks the isch-
emic nature of the chest complaints.
SITE OF T-WAVE A BNORMALITY IN R ELATION TO
CORONARY A NATOMY
Generally, negative T waves are observed in the leads showing
ST-segment elevation during chest pain. These changes may
also be seen in other leads, suggesting a larger area of isch-
emia than suggested during the chest pain episode. Negative
T waves in leads II, III, and AVF are related to inferior wall

A B

I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4

FIGURE 3.60. Peaked T waves during the aVL

acute phase of ischemia. The T-wave abnor- V5 aVL V5
malities are localized in the precordial leads,
indicating a critical stenosis in the LAD. After
relief of ischemia, terminal T-wave negativity aVF V6 aVF V6
is seen.
72 chapter
ischemia with either right coronary artery or circumflex
branch occlusion and in the precordial leads to the anterior
wall, being perfused by the left anterior descending branch.
A diagnostic problem is presented by an ischemic event in
the posterior wall. Here the postischemic changes are present
as increased positivity of the T waves in the precordial
leads.
T HE HIGH LAD SYNDROME
The development of negative T waves in the precordial leads
from at least V2 to V4 after an episode of ischemia has been
found to be useful to identify a subgroup of patients with
increased risk of subsequent anterior wall STEMI or sudden
cardiac death33,34 (Fig. 3.60). Coronary angiographic correla-
tions revealed invariably severe stenosis in the left anterior
descending branch or total occlusion in the presence of col-
lateral circulation. As the dominant vessel of the coronary
artery system, recurrence of the obstruction will lead to
extensive MI of the anterior wall.
T-WAVE CHANGES FOLLOWING R EPERFUSION IN STEMI
As pointed out above, the occurrence of terminal T-wave
negativity is also very helpful in assessing reperfusion during
thrombolytic therapy in acute MI. It has been shown to be
one of the earliest noninvasive signs that the infarct vessel
is reopening 28,35 (Figs. 3.60B and 3.61A). Sensitivity, specific-
ity, and the likelihood ratio in this study of terminal T-wave
negativity to predict reperfusion were 63%, 94%, and 10.6%,
respectively. Close ECG monitoring of this finding and other
noninvasive signs of reperfusion, such as disappearance of
chest pain, decrease of ST-segment elevation, the occurrence
of ventricular premature beats with long coupling interval,
and accelerated idioventricular rhythms during this phase,
are useful to diagnose reperfusion.
GIANT T WAVES AND QT PROLONGATION
After an ischemic event the QT interval may increase con-
siderably. QT prolongation is sometimes combined with
A B
I V1 I V1
II
II V2
III V3 III
V4
aVR
aVR
V5 aVL
aVL
aVF V6
aVF
3
giant T-wave negativity (Fig. 3.61B). This latter phenomenon
has been described to predict a good prognosis, as evidenced
by recovery of R waves and preservation of left ventricular
function.35
T HE TAKO -TSUBO SYNDROME
This novel syndrome (transient left ventricular apical bal-
looning syndrome and stress-induced cardiomyopathy) is
another cause of temporary (giant) T-wave inversions, QT
prolongation, and Q waves, most of these features resolving
within days to weeks.36,37 This syndrome of chest pain or
heart failure is caused by severe sudden stress, occurs most
frequently in women, and induces severe temporary apical
dyskinesia in the setting of a normal coronary
angiogram.38
R ECOVERY OF T-WAVE A BNORMALITIES
FOLLOWING ISCHEMIA
In patients with non-STEMI because of proximal LAD ste-
nosis who have survived at least 6 months after the ischemic
event, normalization occurs within 6 weeks in half of this
population and in 80% within 6 months. Similar findings
are seen after balloon angioplasty, revealing normalization
of the T wave in 90% of patients after 28 weeks.39,40 Persis-
tence of T-wave inversion is reportedly related to worse
outcome in comparison with those with recovery of their T
wave.
Other Causes of ST-T Wave Changes
CARDIAC M EMORY
Cardiac memory refers to persistent T-wave changes that
follow resumption of sinus rhythm after a period of altered
activation sequence.39 Prolonged alteration of activation
sequence has a variety of causes including ventricular pacing,
intermittent LBBB, ventricular tachycardia, ventricular
extrasystoles, and ventricular preexcitation. T-wave changes
are more prominent and have slower regression dependent on
the duration and extent of abnormal activation.40
V2
V3
V4
V5
FIGURE 3.61. Postischemic T-wave changes
and giant T waves. (A) ECG taken after relief
of ischemic chest pain. Note terminal T-wave
inversion. (B) One day later, giant negative T
V6 waves have developed.
 elect roca r diogr a ph y
The T-wave polarity during normalization of the QRS
width is dependent on the QRS polarity during QRS widen-
ing: Negative QRS complexes during abnormal depolariza-
tion lead to negative T waves during normal activation and
vice versa (Fig. 3.27).
E ARLY R EPOLARIZATION
Early repolarization has elevated, upward, concave ST seg-
ments, located commonly in precordial leads, with recipro-
cal depression in aVR; tall, peaked, and slightly asymmetrical
T waves with notch; and slur on the R wave.44 The other
accompanying features in the ECG are vertical axis, shorter
and depressed P-R interval, abrupt transition, counterclock-
wise rotation, presence of U waves, and sinus bradycardia.
Males dominate and patients are often younger than 50 years
of age. The incidence of 1% to 2% is found equally common
in all races. Degree and incidence of ST elevation decrease
as age advances. Exercise or isoproterenol administration
may normalize the ST segment. Early repolarization is a
benign condition. If the ECG conforms to a classic pattern
of this syndrome on serial ECGs, it would exclude the unnec-
essary hazards of present-day revascularization therapy for
MI such as primary angioplasty or thrombolytic therapy, or
aggressive management of acute pericarditis.
HYPOTHERMIA
Hypothermia slows both conduction and repolarization, in
this way prolonging all measured ECG intervals.45–49 Also AV
nodal block may be part of the picture. The presence of
Osborn waves in hypothermic patients appears to be a func-
tion of temperature rather than the electrolyte or acid–base
status (Fig. 3.62).43 Below a temperature of 30°C, the J waves
are detectable in 80% of patients. Ventricular fibrillation is
a major risk at core body temperatures below 27°C.
The electrophysiologic mechanism of Osborn waves is
suggested to be related to an epicardial–endocardial voltage
gradient associated with the localized spike and dome morphol-
ogy of Ito-mediated action potential in ventricular epicar-
dium but not endocardium.40
Osborn waves are most commonly observed in hypother-
mia. Also other conditions reportedly may cause J waves,
I V1
II
III
aVR
aVL
aVF
FIGURE 3.63. The long QT syndrome. Alter-
nation of the T waves.
73
I V1
II V2
III V3
V4
aVR
V5
aVL
V6
aVF
FIGURE 3.62. Hypothermia. Sinus bradycardia, late positive deflec-
tions in the QRS complex, known as Osborn waves, mild ST-segment
elevation, most prominent in the anterolateral leads.
such as hypercalcemia, brain damage, cardiac arrest, Chagas’
disease, ischemic heart disease, and the Brugada syndrome.
T HE LONG QT SYNDROME
The long QT syndrome is characterized by a prolonged QT
interval and torsades de pointes ventricular arrhythmias,
leading to collapse and sudden death. Hereditary and acquired
forms exist, and recently the genetic aspects of the former
and the pharmacologic aspects of the latter conditions have
gained much attention. Characteristics of the ST-T interval
have been described in relation to the genetic form of
LQTS.50,51 The ECG during sinus rhythm shows, besides the
prolonged QT interval, a dynamic behavior of the T wave,
such as T-wave alternation and bifid T waves, depending on
the rate and regularity of the preceding rhythm and the state
of the autonomic nervous system (Fig. 3.63).
V2
V3
V4
V5
V6
74 chapter 3

A B C D E F
I I

II II

III III

aVR aVR

aVL aVL

aVF aVF

V1 V1

V2 V2

V3 V3

V4 V4

V5
V5

V6 V6
KALIUM KALIUM
(mmol/L) (mmol/L) NaHCO3
FIGURE 3.64. Hyperkalemia. Six panels showing increasing levels pearance of P wave, widening of the QRS complex, and occurrence
of serum potassium (A–D) and abrupt normalization on sodium of peaked and negative T wave. On treatment rapid normalization
bicarbonate infusion (E,F). Note the gradual flattening and disap- is seen.

Recently also a short QT syndrome was described as a

familial cause of sudden cardiac death.52

ELECTROLYTE A BNORMALITIES 53
Changes in Serum Potassium Concentration. The
changes in the surface ECG are frequently correlated with
endo
the serum potassium level. However, no constant relation-
ships between the potassium level and the ECG abnormali-
ties exist. The more acute and severe the abnormalities, epi
the better the correlation. Probably the ECG changes are the
result of the extra-intracellular myocardial potassium gradi-
70 mV
ent. This gradient is decreased in hyperkalemia and increased
90 mV
in hypokalemia.
R
Hyperkalemia. Hyperkalemia, frequently occurring in
renal failure, extensive tissue damage, or adrenal dysfunc- J
T
tion, may lead to profound changes in the ECG. Depending
on the level of serum potassium, the cardiac action potential
shows diminished diastolic polarization, slowing of phase 0, Q
S
slowed conduction, and shortening of the action potential
duration (Figs. 3.64 and 3.65). Above serum levels of 5.8 mmol/
L the T wave become peaked and small, and with increasing FIGURE 3.65. Hyperkalemia. Scheme of underlying mechanism.
levels ST segment depression and disappearance of the U See text.
 elect roca r diogr a ph y
I V1
II
III
aVR
aVL
FIGURE 3.66. Hypokalemia. (A) Hypokale-
mia, as shown by the bifid T waves merging
with U waves. (B) Normalization of repolariza-
tion waves after restoration of potassium aVF
concentration.
waves is seen. Above 6.k mmol/L atrial, atrioventricular and
ventricular conduction impairment is seen. This leads to a
decrease in and broadening of the P waves, a prolonged PR
interval, and widening of the QRS complex and T-wave nega-
tivity. At higher levels no P waves are visible anymore and
the widened QRS fuses with the T wave. This ECG picture
may be confused with slow ventricular tachycardia. Indeed,
lethal ventricular arrhythmias may occur in this setting.
The ECG changes in hyperkalemia are more prominent
in cases of concomitant hyponatremia, acidosis, or
hypocalcemia.
Hypokalemia. Hypokalemia, a frequent complication
of the use of diuretics, leads to decreasing potassium levels
and to flattening of the T waves, ST depression, and increase
of the U wave (Fig. 3.66). This further leads to increasing
fusion of the T and U waves until both waves are not to be
distinguished anymore. In this setting torsades de pointes
arrhythmias may occur. Also digitalis-induced arrhythmias
occur more frequently in hypokalemic states. The picture is
enforced by concomitant hypercalcemia.
Changes in Serum Calcium Concentration. Cal-
cium influences the duration of the plateau phase of the
monophasic action potential. The ECG picture is dependent
on the ionized calcium concentration rather than on the
amount of protein bound calcium. The correlation between
serum calcium levels and the ECG is better than in distur-
bances of the potassium metabolism. In hypocalcemia the
repolarization phase is prolonged, especially at the expense
of lengthening of the ST segment, whereas the QRS and T
wave duration remain the same. In hypercalcemia QT short-
ening is seen, due to shortening of the ST segment, and in
severe cases the T wave follows the QRS complex directly.
Summary
Electrocardiography is the graphic one-dimensional repre-
sentation of the electrical activity of the heart as recorded
from the body surface. The basic principle is the vectorial
75
A B
I V1
V2 II V2
V3 III V3
V4 aVR V4
V5 aVL V5
V6 aVF V6
400 msec
nature of the ECG, the deflections in the respective leads
being the consequence of timing, direction, and strength of
the electrical instantaneous forces. Standard recordings are
derived from six leads in the frontal plane and six leads in
the transversal plane. Additional (mostly right precordial)
leads are used mainly for the purpose of diagnosing RV
infarction. The ECG is especially helpful not only in diag-
nosing structural and functional aspects of cardiac disease
but also in monitoring its natural history, in assessing its
severity, in identifying the patient at risk, and in evaluating
the effect of treatment. Structural changes of the four cardiac
compartments are recognized, such as left and right atrial
and ventricular hypertrophy, infarction, and cardiomyopa-
thy. Also conduction disturbances in atria and ventricles can
be diagnosed, leading to specific widening of the P wave and
QRS complex. In the left and right bundle branch block,
sequential activation of the ventricles is present, allowing
more accurate assessment of each ventricle separately.
Changes from the typical configuration of the right and left
bundle branch block give information about additional
disease affecting the heart.
The ECG has proven to be especially useful in diagnosing
acute ischemia. ST elevation and non-ST elevation acute
coronary syndromes are recognized, enabling the stratifica-
tion of patients to different diagnostic and treatment strate-
gies. Assessment of the acuteness and severity of the
ischemia, the area at risk, and the coronary vessel involved
can be derived from the surface ECG. For the latter purpose,
the directional change of the ST segment, as depicted by the
ST vector, was found to be very useful. ST vectors pointing
in a rightward direction, leading to ST elevation in aVR,
identify high-risk patients both in STEMI, such as in proxi-
mal LAD occlusion, and in non-STEMI, such as in main
stem or three-vessel disease. In inferoposterior infarction,
high-risk situations are recognized by diagnosing right ven-
tricular involvement and atrial infarction. Recognizing con-
duction abnormalities in ischemic syndromes is also of help
in identifying the high-risk patient.
The analysis of T-wave changes has been found to be
important in acute, subacute, and chronic coronary syn-
76 chapter
dromes, and in a number of other important disorders, such
as early repolarization, hypothermia, the long and short QT
syndrome, and electrolyte abnormalities.
Acknowledgments
The artwork of Adri van den Dool and Geert-Jan van
Zonneveld is greatly acknowledged.
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34. Watanabe E, Kodama I, Ohono M, Hishida H. Electrocardio-
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2003;89:231–237.
35. Doevendans PA, Gorgels APM, van der Zee R, Partouns J, Bär
FWHM, Wellens HJJ. Electrocardiographic diagnosis of reper-
fusion during thrombolytic therapy in acute myocardial infarc-
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tive T-wave in acute anterior wall infarction predicts R-wave
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1996;75:229–234.
37. Tsuchihashi K, Ueshima K, Uchida T, et al., Angina Pectoris-
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38. Wittstein IS, Thiemann DR, Lima JA, et al. Neurohumoral
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 4 Chest X-Ray
Mary Ella Round
Principles of Chest Radiography. . . . . . . . . . . . . . . . . . . . . 80
Pathophysiologic Principles Pertaining to the
Radiographic Signs of Cardiovascular Disease . . . . . . 86
Key Points
• Chest x-ray is perhaps the simplest radiologic test, and
yet it is highly valuable, as it can be used to diagnose and
assess the severity of cardiovascular diseases and the
response to therapy.
• Optimal image acquisition is essential for the proper
interpretation of the findings on a chest x-ray.
• To reduce oversights, a consistent approach to film inter-
pretation should be followed for each observation.
• A “good” inspiratory effort is indicated by the right hemi-
diaphragm being inferior to the eighth posterior right rib.
If an image is obtained during expiration, the cardiac
silhouette appears larger and the pulmonary markings
are more prominent.
• The interpretation of the cardiac size, silhouette, and
pulmonary parenchymal markings depends on the posi-
tioning and projection of the patient.
• An increased or “splayed” angle of carina suggests eleva-
tion of the left mainstem bronchus secondary to left
atrial enlargement as seen in cardiomyopathy or mitral
stenosis.
• Visualizing the edge of the lung is necessary for diagnos-
ing a pneumothorax.
• Pulmonary vascular markings are normally distinct.
Indistinct markings, fissural thickening, and septal lines
suggest vascular congestion and radiographic diagnosis of
congestive heart failure.
• The cardiac diameter divided by the widest chest diame-
ter should be less than 60%. The average value is 45% in
a 70-kg man.
• The volume of the left ventricle must increase by approx-
imately 66% in order to produce an abnormal cardiotho-
racic ratio.
• A dilated right ventricle will not affect the cardiothoracic
ratio.
• In the lateral view on a chest x-ray, a line drawn from the
junction of the sternum and diaphragm to the carina will
Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
pass through the aortic valve, while the mitral valve and
its annulus lie posterior and inferior to that diagonal.
• Aortic dissection is not a plain chest film diagnosis.
• Pulmonary venous pressure greater than 10 to 12 mm Hg
results in redistribution or “cephalization” of blood from
the lung bases into the upper lobe vessels, while peribron-
chial “cuffing” and fluid accumulation in the interlobu-
lar septa, referred to as Kerley B lines, suggest a
pulmonary venous pressure between 20 and 30 mm Hg.
Elevated pulmonary venous pressure greater than
30 mm Hg demonstrates symmetric small parenchymal
densities in addition to the above findings.
• Pulmonary arterial hypertension is manifested by
decreased caliber of the lower lobe segmental arteries
(pruning) and dilatation of the central or main pulmo-
nary arteries.
• Radiographic signs do not correlate well with pulmonary
embolic disease, and further testing is required, if clini-
cally suspicious.
• Fewer than 10% of the patients with pulmonary embo-
lism show the classic signs referred to as the Hampton’s
hump, the Westermark sign, and the Fleischner sign.
• Radiographic findings on a chest x-ray are similar in car-
diomegaly and pericardial effusion.
Conventional chest radiography remains one of the most
frequently ordered radiologic examinations in clinical cardi-
ology. Chest radiographs are universally available, relatively
inexpensive, and cost-effective. The exam can be used to
assess patient response to therapy or to monitor the status of
cardiovascular disease.
This chapter is limited in its scope. A brief summary of
radiographic technique is provided. Radiographic findings in
the normal patient population and the critically ill are
addressed. A sample algorithm for evaluating the chest radio-
graph is presented. Finally, radiographic interpretation
specifically as it pertains to cardiovascular disease is
reviewed.
79
80
Principles of Chest Radiography
Principles of Radiologic Technique
An x-ray is a bundle of electromagnetic energy called a
photon. The average energy of an x-ray photon is 30 kiloelec-
tron volts (keV). Radiographic image production entails the
x-ray photons passing through tissue and interacting with an
image receptor. The image receptor can be a radiographic
film. In computed radiology or digital imaging, the image
receptor is a computer chip that can store and display the
radiographic image on a digital screen. The quantity and
quality of the x-ray beam affects the interaction within
various tissues in the body. Conversely, the composition of
the anatomic tissues affects the x-ray beam interaction. The
radiation that exits the patient will have varying energies,
which can translate to different shades of gray on the image
receptor.1
To create an image the x-rays must be absorbed at differ-
ent levels. The interaction of the x-ray with matter may be
one of three interactions—the x-ray may be absorbed, scat-
tered, or transmitted. X-rays can pass through the lung paren-
chyma unimpeded, but they cannot pass through the
vertebral body. The image receptor then detects the differen-
FIGURE 4.1. The cardiac silhouette, pulmonary vasculature, pul-
monary parenchyma, diaphragmatic surfaces, and costophrenic
angles should all be clearly visible without the use of a “bright” light
in both the posteroanterior (PA) (A) and the lateral (B) projections.
chapter 4
tial absorption and the image documents a contrast between
the lung parenchyma and the vertebral body.
The purpose of the conventional chest radiograph is to
visualize clearly the thoracic anatomy on the posterior ante-
rior (PA) and lateral radiographs. Optimal chest x-ray images
are the product of appropriate utilization of peak kilovoltage,
amperage, and time expressed as milliampere-seconds2 (Fig.
4.1). The kilovoltage peak (kVp) determines the maximum
energy of the emitted photons from the x-ray tube. The mil-
liampere-seconds (mAs) measures the tube current and expo-
sure time in seconds. This parameter determines the number
of photons emitted. Typically chest radiographs are per-
formed at 120 kVp and 5 mAs. Equally important factors
include characteristics of the x-ray generator, the target film
distance (72 inches), compatible film–screen combinations,
and the appropriate use of a grid. Depending on the clinical
question, these factors can be altered to best visualize the
anatomy in question. For example, the technical exposure
factors can be altered to visualize the ribs or lungs. Overex-
posure of the chest x-ray is appropriate in patients sustaining
blunt trauma in which it is critical to visualize the medias-
tinal soft tissue structures and the pulmonary parenchyma
behind the heart (Fig. 4.2). A higher mA, however, also could
lead to secondary or scattered Compton radiation, which is
The technical factors used to obtain this PA radiograph (A)
were 110 kVp and 1.6 mAs and, for the lateral (B), 110 kVp and
6.5 mAs.
 c h e s t x- r a y 81

FIGURE 4.2. “Overpenetrated” PA (A) and lateral (B) chest x-rays at the expense of “burning out” the lungs, including the pulmonary
of the patient as in Figure 4.1 obtained with 120 kVp and 3.0 mAs. vasculature.
This technique demonstrates the thoracic spine through the heart

often referred to as “fog” as it can obscure the pulmonary cessed, the image is permanent and further adjustments
interstitium, bronchi, and pulmonary vessels (Fig. 4.3). cannot be made. This can sometimes result in repeating the
Conventional film–screen radiography is limited by these image to answer clinical questions. Digital imaging
technical parameters. Once a conventional image is pro- can record a wider range of tissues with one exposure. This

FIGURE 4.3. Effect of secondary (Compton) radiation “fog” on the pulmonary parenchyma and vasculature are clearly demon-
“image clarity” in the same patient as in Figure 4.1: 110 kVp and strated. (B) Radiation “fog” diminishes image clarity, particularly
1.6 mAs (A); 110 kVp and 6.9 mAs (B). (A) The image is “sharp” and as it relates to the lungs and the pulmonary vasculature.
82
information provides quantitative data on the attenuation
characteristics of the tissues to visualize the thorax with or
without overlying structures. Radiographic images can now
be obtained, interpreted, processed, stored and retrieved
more quickly.3 Computed radiography (CR) or digital radiog-
raphy has largely replaced conventional screen–film combi-
nation techniques. A common technique in CR uses a
photostimulable phosphor plate within a cassette to store
transmitted x-rays. An exposed cassette is scanned with a
low-energy laser beam to encode the digital image. Newer
technologies include using a photoconductor such as amor-
phous selenium to convert x-rays directly into electrical
charges. This technique is used in digital radiography
(DR).3
Principles Regarding the Chest X-Ray
The routine chest radiograph includes the posteroanterior
(PA) and lateral projections. Each is obtained with the patient
erect and in deep inspiration if the patient is able. Ideally,
patients are imaged without overlying radiopaque foreign
bodies or artifacts. Chest radiographs are obtained usually
with a high kilovoltage and milliamperage to decrease expo-
sure time and cardiac motion.
Posteroanterior (PA) refers to the direction of the x-ray
beam through the chest. The patient is positioned with the
anterior chest wall closest to the film. The lateral chest x-ray
is obtained with the patient’s left side closest to the film.
This positioning coupled with the x-ray source 72 inches
from the detector results in the most radiographically accu-
rate representation of the cardiac size.
Patients who are unable to be imaged in the radiology
department may require portable chest radiography exami-
nations. The cassette is placed behind the patient and the
FIGURE 4.4. Effect of inspiration (A) and expiration (B) of the same patient as in Figure 4.1 obtained within minutes of each other. (B) In
expiration, both the superior mediastinum and the cardiac silhouette increased in transverse diameter.
chapter 4
projection is anterior to posterior or anteroposterior (AP).
Obtaining radiographs at maximum inspiration is limited in
this setting. Since the patient is supine or semierect, the
blood flow is redistributed to the upper lobe pulmonary veins
and the heart is magnified.4
Inspiratory effort is evaluated by the diaphragmatic
excursion. A “good” inspiratory effort is indicated by the
right hemidiaphragm being inferior to the eighth posterior
right rib (Fig. 4.4). When evaluating patients with more com-
pliant lungs, the 11th rib may be visualized. Frequently
patients with chronic obstructive pulmonary disease will
also demonstrate an increased inspiratory lung volume. The
right hemidiaphragm is usually higher than the left. If an
image is obtained during expiration, the cardiac silhouette
appears larger and the pulmonary markings are more
prominent.
Normal Chest X-Ray
The normal anatomic landmarks of the mediastinum visual-
ized on the PA radiograph include the aorta, the lateral
margin of the left subclavian artery, the aorticopulmonary
clear space or “window,” the main pulmonary artery, the
lateral margin of the left auricular appendage, the lateral
margin of the left ventricle, and, on the right, the brachioce-
phalic artery, the superior vena cava, and the lateral margin
of the right atrium (Figs. 4.5 to 4.7).
The right hilum is typically higher than the left. The
hilar densities are composed mainly of right and left main
pulmonary arteries and their primary divisions. The azygous
vein is seen at the junction of the trachea and the right main-
stem bronchus.
The carina and the bronchi are best visualized on the PA
radiograph. Usually the carina angle is acute. If the angle is
 c h e s t x- r a y 83

FIGURE 4.5. Normal PA chest x-ray shows, along the left side of
the cardiac silhouette, from superior to inferior, the lateral margin
of the left subclavian artery (straight black arrow), the aortic arch
(asterisk) the aorticopulmonary window (arrowhead), the main pul-
monary artery (p), the left auricular appendage (open black arrow),
and the lateral wall of the left ventricle (large white arrow). On the
right, the superior vena cava (curved black arrow), the azygos vein
(small white arrow), and the wall of the right atrium (curved open
arrow) are visible.

increased or “splayed,” then the elevation of the left main-

stem bronchus may be secondary to left atrial enlargement
as seen in cardiomyopathy or mitral stenosis.
On the lateral chest x-ray, normal anatomic landmarks
include the anterior wall of the right atrium, the posterior
segment of the aortic arch and the proximal descending
aorta, the posterior left atrium, the posterior left ventricle,
and the inferior vena cava. The retrosternal clear space is a
radiolucent area posterior to the sternum and anterior to the
ascending aorta. Right ventricular enlargement may encroach
upon the retrosternal clear space. Left ventricular enlarge-
ment is noted on the lateral exam when the left ventricle
border projects greater than 2 cm behind the inferior vena
cava (Fig. 4.7B).
The lobar pulmonary arteries arise from the main pul-
monary arteries.5–7 The lobar arteries accompany the lobar
and segmental bronchi branching out from each hilum. In
the upper lobes, the pulmonary arteries extend superolater- FIGURE 4.6. Normal chest x-ray. (A) PA. (B) Lateral. Major land-
ally from the superior portion of the hilum. The arterial marks on cardiac silhouette are marked. RA, right atrium; LV, left
margins are normally sharply defined. The arteries branch ventricle.
and gradually diminish in caliber. The upper lobe veins are
less numerous than the pulmonary arteries. Normally, the
84 chapter 4

FIGURE 4.7. Relationship of the posterior wall of the left ventricle

to the inferior vena cava on a lateral chest x-ray as an estimate of
cardiac size. (A) On the erect PA chest x-ray, the heart appears
enlarged with left ventricular preponderance. (B) However, on the
lateral chest x-ray, the distance between the inferior vena cava
(arrowheads) and the posterior wall of the left ventricle (arrows) is
less than 2 cm (double-ended arrow), indicating that the heart is not
enlarged.

pulmonary arteries, bronchi, veins, and accompanying inter-
stitial tissue are visible up to 2 cm from the visceral pleural
surface over the convexity of the lung (Fig. 4.8).
The lower lobe arteries and veins extend inferiorly and
laterally from the inferior aspect of the hila.6 There is a dif-
ference in the size of the pulmonary vessels in the upper lung
zones compared with the lower, as a result of pressure varia-
tion in the blood flow from the apex to base. A similar
volume of lung at the base of the lung has a four to eight
times increased blood flow as a similar volume at the apex.8
These findings are not so apparent on the supine
radiograph.
Principles for Assessing the
Radiographic Examination
A consistent approach to film interpretation should be fol-
lowed for each observation. Some clinicians interpret images
from the center radiating outward or vice versa. The
approach is not as important as a consistent algorithm. This
provides the observer with a system to evaluate areas of
secondary interest that might otherwise be forgotten. This
suggested approach or checklist may help in evaluating car-
diovascular disorders while starting with areas of secondary
interest.
 c h e s t x- r a y 85

FIGURE 4.8. Normal left upper lobe pulmonary vasculature as

seen on an erect PA chest x-ray. The pulmonary arteries (a) extend
upward from the superior aspect of the hilum in an arborizing
pattern as they leave the hilum, the arteries are 3 to 4 mm in width
with sharply defined margins. The arteries branch, taper, and gradu-
ally disappear as they approach the periphery of the lung. A left
upper lobe vein (v) is visible in the second anterior interspace lateral
to the arteries. It extends obliquely downward toward the left atrium
in a course that is inconsistent with its arising from the pulmonary
artery.

Assessing the chest radiograph should begin with assess-

ing the patient identification parameters and date, including
the year. Appropriate comparison x-rays or complementary
studies should be available for possible correlation. Briefly
the positioning of the patient and the projection of the radio-
graph should be noted. Posterior and lateral imaging is not
always possible in the acutely ill patient. The interpretation
of the cardiac size, silhouette, and pulmonary parenchymal
markings depends on the positioning and projection of the
patient (Fig. 4.9). In the critically ill patient evaluation may
start with overlying or indwelling lines and tubes.9 A list of
possible lines and tubes that one may find in a critically ill
patient is shown in Table 4.1.
Considering chest x-ray findings outside the thorax first
may be helpful to identify secondary findings. The soft
FIGURE 4.9. Effect of erect (A) and supine (B) posture on the PA
tissues may give clues of trauma or prior surgeries. Cardiac chest x-ray of the same patient obtained within minutes of each
surgery, thyroid procedures, and breast surgeries are other. (A) The erect PA chest x-ray was obtained with a target film
frequently noted by surgical clips or wires. Next, evaluation distance (TFD) of 72 inches and in deep inspiration. (B) The supine
of the abdomen can exclude intraperitoneal gas or spleno- chest x-ray was obtained at a TFD of 46 inches and in deep inspira-
tion. Recumbency produces positional redistribution of blood
megaly. Visualizing the bowel gas pattern is also important. throughout the cardiovascular system, resulting in increased trans-
Evaluating the bony thorax for subtle cough fractures may verse diameter of the superior mediastinum and the cardiac silhou-
also explain chest pain in the cardiology patient. Back pain ette as well as increased width of the upper lobe vessels.
86 chapter
from a thoracic aortic aneurysm may be suggested clinically;
however, careful evaluation of the thoracic vertebral bodies
may document a compression wedge fracture. The pleura
should be evaluated for a pneumothorax or pleural effusion.
Visualizing the edge of the lung is necessary for diagnosing
a pneumothorax. In the supine patient the air migrates
anteromedially and can outline the heart. The upright exam
may show a pneumothorax at the apex of the lung. A pleural
effusion can be diagnosed as a crescent or meniscus in the
lateral or posterior costophrenic sulcus. Evaluating the lungs
for an infectious or neoplastic abnormality may be the most
natural evaluation of the chest x-ray. Evaluating the lungs in
the middle of the algorithm ensures that secondary findings
will not be missed. The pulmonary vascular markings should
be evaluated for three separate findings. Pulmonary vascular
markings are normally distinct. If the markings appear
indistinct, vascular congestion should be considered. Fis-
sural thickening and septal lines are two other radiographic
signs to include in the imaging diagnosis of congestive heart
failure. Classically, the redistribution of pulmonary blood
flow is used to make the diagnosis of heart failure. Patients
in congestive heart failure may not be able to stand or gener-
ate a deep inspiratory effort to demonstrate these findings on
the supine or semierect anterior posterior portable chest
radiograph.
Finally, the evaluation of the cardiac and mediastinal
silhouettes can proceed. Checking the width of the medias-
tinum and the contour can help the diagnosis of tumors,
aneurysms, or lymphadenopathy. Many factors contribute to
the mediastinal contour including patient positioning as
well as the projection of the radiograph (Fig. 4.9). With aging,
the mediastinum may widen from vascular tortuosity. Even
the depth of inspiration affects the contour (Fig. 4.4). Subtle
abnormalities may be missed on chest radiographs and
further evaluation with other cross-sectional modalities
such as computed tomography (CT) may be necessary.
The size and shape of the heart are determined by both
the pericardium and the heart. A pericardial effusion and
TABLE 4.1. Lines, tubes, and devices in a critically ill patient
Percutaneous indwelling central catheter
Central venous catheter
Pulmonary artery catheter
Intraaortic balloon pump
Pacemaker
Cardiac defibrillator
Left ventricular assist device
Endotracheal tube
Tracheostomy tube
Intratracheal oxygen catheter
Stents
Feeding tube
Nasogastric tube
Intraesophageal monitor
Temperature probe
pH probe
Chest tube
4
TABLE 4.2. Chest x-ray evaluation
Check identifying parameters and date of exam
Recognize the positioning of the patient, inspiratory effort, and
projection
Lines, tubes, and cardiac devices
Soft tissues
Thyroid, breast, and cardiac procedures
Upper abdomen
Bowel gas pattern, free intraperitoneal air, splenomegaly
Bones
Cough fractures, surgeries, compression fractures, metastasis
Pleura
Pleural effusion, pneumothorax
Lungs
Neoplasm, inflammatory process
Pulmonary vascular markings
Indistinctness, septal lines, fissural thickening
Mediastinum (may best be evaluated by CT)
Tumor, lymphadenopathy, aortic pathology
Cardiac pericardial silhouettes (may best be evaluated by
echocardiography)
Cardiomegaly, pericardial effusion
Pathophysiologic principles pertaining to the radiographic signs of
cardiovascular disease
cardiomegaly can look the same on a chest x-ray. It is impor-
tant to evaluate the cardiothoracic ratio. A false-positive
diagnosis of cardiomegaly is possible in the supine AP exam
at poor inspiratory effort. When there is a question of cardiac
size or a pericardial effusion, echocardiography would best
evaluate the heart. A useful list for assessing a chest x-ray is
shown in Table 4.2.
Pathophysiologic Principles Pertaining
to the Radiographic Signs of
Cardiovascular Disease
Heart
The cardiac silhouette should be evaluated for size and con-
figuration, signs of chamber preponderance (the chest x-ray
does not distinguish between chamber dilatation and hyper-
trophy), cardiovascular disease, coronary calcification, and
left ventricular aneurysm.
A normal cardiac silhouette size may be determined by
the cardiothoracic ratio. The PA view should be used. The
cardiac diameter divided by the widest chest diameter should
be less than 60%.10 The average value is 45% in a 70-kg
man.10 The volume of the left ventricle must increase approx-
imately 66% in order to produce an abnormal cardiothoracic
ratio.11 Since the right ventricle does not contribute to the
cardiac silhouette, a dilated right ventricle will not affect the
cardiothoracic ratio. An accurate chest x-ray assessment of
cardiac size is obtained from the inferior vena cava to the
left ventricular wall distance.
 c h e s t x- r a y
Valves
Cardiac valves are not visualized on a chest x-ray unless they
are calcified, typically at the annulus. Annular calcification
usually involves the aortic and mitral valves and is relatively
common in the elderly. Aortic valve calcification, on a chest
x-ray, is best located by following the ascending aorta down-
ward to its origin at the valve in the PA view. In the lateral
view on a chest x-ray, a line drawn from the junction of the
sternum and diaphragm to the carina will pass through the
aortic valve, while the mitral valve and its annulus lie pos-
terior and inferior to that diagonal (Fig. 4.10).
Calcification of the mitral annulus is typically broad,
irregular and most commonly appears in a reversed C or J
configuration to the left of the spine and caudal to the atrial
appendage on the PA view of a chest x-ray.
Aorta
The diagnosis of acute aortic dissection must be considered
in any patient with the appropriate clinical symptoms and
aortic ectasia or laminar aortic calcification.12–14 However,
aortic dissection is not a plain chest film diagnosis. The
diagnosis can be established or excluded with an intravenous
contrast–enhanced helical CT. Other methods used to make
FIGURE 4.10. Cardiac valve sites. (A) On the lateral chest x-ray, the
aortic valve (arrow) lies on or above a diagonal line connecting the
junction of the sternum and the diaphragm with the carina. (B) On
the frontal chest x-ray, the location of the mitral valve is indicated
87
the diagnosis of aortic dissection include aortography, trans-
esophageal echocardiography, and magnetic resonance
imaging (MRI).
Aortic aneurysms can present as a mass immediately
adjacent to or indistinguishable from the aortic contour.
Leaking aneurysms may widen the mediastinum and are
associated with a hemothorax.
Pulmonary Vasculature
Pulmonary vasculature alterations do reflect altered pulmo-
nary hemodynamics.15–17
Pulmonary Venous Hypertension
Elevated pulmonary venous pressure is associated with car-
diomegaly. Occasionally pleural fluid collections develop.
Pulmonary venous pressure greater than 10 to 12 mm Hg
results in redistribution or “cephalization” of blood from the
lung bases into the upper lobe vessels. Redistribution is man-
ifested on the erect PA chest x-ray by an increase in the
number and caliber of upper lobe vessels. The upper lobe
vessels extend further toward the pleura. The upper lobe
vessels remain sharply demarcated (Fig. 4.11).
by its prosthesis (arrow), and the location of the tricuspid is shown
by the upward arc (arrowhead) in the cable of the right ventricular
electrode.
88 chapter 4

FIGURE 4.11. Elevated pulmonary venous pressure without pulmo-

nary edema. This 18-year-old patient has a ventricular septal defect,
as reflected by the cardiac configuration. The intrinsic pulmonary
hypervolemia results in increased caliber of the upper lobe vessels,
whose margins remain distinct. There is no peribronchial cuffing.

Pulmonary venous pressure between 20 to 30 mm Hg

results in peribronchial “cuffing” (Fig. 4.12). The pulmonary
vessels are indistinct. Fluid accumulation in the interlobular
septa is evidenced by Kerley B lines. These are 1.0-cm, linear,
pleura-based densities visible on the lateral chest wall on the
PA chest x-ray and retrosternally on the lateral radiograph.
Elevated pulmonary venous pressure greater than
30 mm Hg demonstrates symmetric small parenchymal den-
sities in addition to the findings described at lesser pressures.
Kerley A lines are 2 to 3 cm long irregular linear densities
1 mm in width. These course obliquely from the lung to the
hilum and represent lymphatic channels (Fig. 4.13). These
findings may be manifest in other conditions. For example,
thickening of the interlobular septa or fissures may be seen
in anthracosis, hemosiderosis, occupational exposure, viral
pneumonia, or lymphangitic spread of carcinoma.

FIGURE 4.12. Interstitial pulmonary edema. (A) The normal radio- in the number and caliber of right upper lobe vessels whose margins
graphic appearance of this patient’s right lung. Note, particularly, are now indistinct (arrows, compare with A) and peribronchial
the medial right upper lobe artery (arrows) and the wall of the bron- “cuffing” (arrowheads), all representative of elevated pulmonary
chus (arrowhead). (B) Signs of interstitial edema include an increase venous pressure with interstitial pulmonary edema.
 c h e s t x- r a y
FIGURE 4.13. Alveolar pulmonary edema. (A) On the PA chest x-
ray, pulmonary vasculature is almost completely obscured by the
bilateral symmetric alveolar pattern parenchymal densities. Peri-
bronchial “cuffing” (arrowhead) is marked. (B) The lateral chest x-
ray shows the “rosette” character of the alveolar fluid, unsharpness
of the interlobar fissures (arrows) representative of subpleural edema,
and a small pleural effusion (arrowhead).
89
Abrupt or severe cardiac decompensation secondary to a
massive myocardial infarction or ruptured valvular leaflets
may result in a central symmetric consolidation.7
Pulmonary Arterial Hypertension
On the PA chest x-ray pulmonary arterial hypertension is
manifested by decreased caliber of the lower lobe segmental
arteries and dilatation of the central or main pulmonary
arteries (Fig. 4.14). In chronic obstructive pulmonary disease,
precapillary hypertension results in spasm of precapillary
arterioles. Persistent arterial hypertension causes the spasm
to move progressively proximally to involve the small arter-
ies. Persistent spasm results in hypertrophy and hyperplasia
of the muscular layer or media of the arteries that further
elevates pulmonary artery pressure. Classically, the radio-
graphic appearance of pulmonary artery hypertension is
referred to as “pruning” of the pulmonary arteries. The
pathophysiology demonstrates the distal vessels to appear
normal with hypertrophy of the central pulmonary arteries
and early divisions.
Pulmonary Embolism
The chest x-ray is usually the first imaging study performed
when pulmonary embolic disease is suspected and it is
usually nonspecific. One large study concluded the chest
radiograph to be normal in 12% of patients with pulmonary
emboli.18,19 Radiographic signs do not correlate well with
pulmonary embolic disease, and further testing is required
if clinically suspicious.18 Nonetheless, it is important to use
chest radiographs to exclude other causes of disease, such as
FIGURE 4.14. Pulmonary arterial hypertension, seen in a PA chest
x-ray of this patient with chronic obstructive pulmonary disease, is
manifest by dilation of the main pulmonary arteries (arrowheads).
It is important to be aware that the basilar segmental arteries are
not “pruned,” but rather have a string-like appearance.
90 chapter
A B
FIGURE 4.15. PA (A) and lateral (B) chest x-ray in a patient with pericardial effusion.
pneumonia, pneumothorax, rib fractures, aortic dissection,
pleural effusions, pericardial effusion, tumor, and hiatal
hernia.
Nonspecific radiograph findings in pulmonary embolic
disease include an elevated hemidiaphragm, pleural effusion,
and atelectasis.
Although most pulmonary emboli occur without chest
x-ray findings, three classic radiographic signs have been
described for pulmonary embolic disease. These signs occur
in fewer than 10% of patients with pulmonary emboli.18,19
The Hampton’s hump is a wedge-shaped pleural-based density
representing a lung infarction secondary to an embolus. The
Westermark sign is proximal pulmonary arterial dilatation
and peripheral oligemia. The Fleischner sign is a large central
pulmonary artery due to central thrombus with abrupt taper-
ing. Helical CT is most accurate in detecting pulmonary
emboli.
Septic pulmonary emboli manifest as multiple ill-defined
wedge-shaped or round peripheral nodules on chest radio-
graphs. These can be associated with infected central venous
catheters, tricuspid valve endocarditis, or peripheral septic
thrombophlebitis.
Pericardial Diseases
It is difficult to distinguish between cardiomegaly resulting
from chamber dilatation and pericardial effusion on a chest
x-ray, as the findings are practically similar. An acute increase
4
in cardiac size on serial chest x-ray, a flask-shaped heart, and
relatively clear lung fields would favor the diagnosis of peri-
cardial effusion (Fig. 4.15). The presence of calcification, par-
ticularly ring-shaped calcification, best visualized on the
lateral view of a chest x-ray, would suggest the diagnosis of
constrictive pericarditis. Epicardial fat and pericardial cysts
could alter the cardiac silhouette by obscuring the diaphrag-
matic angles.
Summary
Chest x-ray remains one of the oldest and most commonly
used radiographic techniques. It can be used to diagnose
cardiovascular conditions and assess the response to treat-
ment. Appropriate image acquisition in conjunction with a
systematic approach is essential for proper interpretation of
a chest x-ray. A good inspiratory effort and an erect position
are important determinants of a good-quality chest x-ray.
Typically, the cardiac silhouette occupies about 45% of the
widest chest diameter. An increase beyond 60% indicates
left ventricular enlargement, at least by 66%. Enlargement
of the right ventricle does not significantly affect the cardio-
thoracic ratio. Left atrial enlargement may be evident as
widening or splaying the angle of carina as well as fullness
and straightening of the left heart border. Chest x-ray find-
ings of cardiomegaly due to chamber enlargement and peri-
cardial effusion are largely similar and not sufficiently
helpful in differentiating these two conditions.
 c h e s t x- r a y
A chest x-ray is not sufficiently sensitive or specific for
the diagnosis of aortic dissection, which could be easily
diagnosed by spiral CT. Chest x-ray is quite useful in the
diagnosis of pulmonary congestion and could provide some
evidence of left atrial pressure. An increased pulmonary
artery pressure is diagnosed by pruning of the middle and
distal pulmonary arteries and dilatation of the main
pulmonary artery. A chest x-ray has a poor sensitivity
and specificity for the diagnosis of pulmonary embolism,
a condition readily diagnosed by spiral CT pulmonary
angiography.
References
1. Fauber TL. Radiographic Imaging and Exposure. St. Louis:
Mosby, 2004:46.
2. Curry TS III, Dowdy JE, Murry RC Jr. Christensen’s Physics of
Diagnostic Radiology, 4th ed. Philadelphia: Lea & Febiger,
1990:196–218.
3. Fauber TL. Radiographic Imaging and Exposure. St. Louis:
Mosby 2004:291.
4. Chen MYM, Pope TL, Ott DJ. Basic Radiology. New York:
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5. Muller NL, Fraser RS, Colman NC, Pare PD. Radiologic Diag-
nosis of Diseases of the Chest. Philadelphia: WB Saunders,
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6. Harris JH. The pulmonary arteries and veins: their radio-
graphic identification. Med Radiograph Photogr 1963;39:
52–53.
7. Milne ENC, Pistolesi M. Reading the Chest Radiograph. St.
Louis: Mosby-Year Book, 1993:9–79.
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8. Glazier JB, DeNardo GL. Pulmonary function studied with the
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10. Danzer CS. The cardio-thoracic ratio: an index of cardiac
enlargement. Am J Med Sci 1919;157:513–521.
11. Miller SW. Cardiac Radiography. The Requisites. St. Louis:
Mosby, 1996:6.
12. Razavi M. Acute dissection of the aorta: options for diagnostic
imaging. Cleve Clin J Med 1995;62:360–365.
13. Dowd SB, Wilson BG, Hall JD, et al. Review of techniques used
to image aortic dissection. Radiol Technol 1996;67:223–230.
14. Petasnick JP. Radiologic evaluation of aortic dissection. Radiol-
ogy 1991;180:297–305.
15. Simon M, Potchen EJ, Le May M. The radiographic assessment
of pulmonary hemodynamics. In: Simon M, Potchen EF, Le Nay
M, eds. Frontiers of Pulmonary Radiology. New York: Grune &
Stratton, 1969:205–221.
16. Healy RF, Dow JW, Sosman MC, Dexter L. The relationships
of the roentgenographic appearance of the pulmonary artery to
pulmonary hemodynamics. AJR 1949;62:777–787.
17. Palla A, Petruzzelli S, Donnemaria V, et al. Radiographic assess-
ment of perfusion impairment in pulmonary embolism. Eur J
Radiol 1985;5:252–255.
18. The Prospective Investigation of Pulmonary Embolism Diag-
nosis (PIOPED) Investigators. Value of the ventilation/perfu-
sion scan in acute pulmonary embolism. Results of the
prospective investigation of pulmonary embolism diagnosis
(PIOPED). JAMA 1990;263:2753–2759.
19. Torassi GD, Floyd CE, Coleman RE. Improved noninvasive
diagnosis of acute pulmonary embolism with optimally
selected clinical and chest radiographic findings. Acad Radiol
1996;3:1012–1018.
 5 Introduction to
Echocardiography
Raymond F. Stainback
Historical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Indications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Two-Dimensional Imaging . . . . . . . . . . . . . . . . . . . . . . . . . 97
Doppler Examination and Hemodynamics . . . . . . . . . . . 114
Key Points
• Echocardiography is a safe, noninvasive, and widely
available method that often provides a definitive ana-
tomic and hemodynamic diagnosis and guides medical
management.
• Although long viewed as clinically “mature,” echo-
cardiography has undergone further “revolutionary”
advances during the past 10 years, including not only
technologic breakthroughs but also new clinical applica-
tions for older techniques.
• The recent explosion of potential “add-on” techniques
presents echocardiographers with challenging questions
about what constitutes real clinical progress and what
techniques should be incorporated into the standard
examination protocol. By becoming familiar with their
clinical indications, echocardiographers can use these
techniques selectively, on an “as-needed” basis, and thus
streamline patient care.
• Because of increased availability and clinical utility,
echocardiography’s usage has greatly expanded in recent
years. However, echocardiography demands a major com-
mitment in terms of time, personnel, ongoing training,
and technology.
• An understanding of the physics of ultrasound is essen-
tial for performing echocardiography examinations and
interpreting their results.
• A comprehensive transthoracic echocardiography exami-
nation includes systematic acquisition of a set of two-
dimensional and M-mode views, along with spectral
Doppler and color Doppler evaluation of the intrathoracic
cardiovascular structures (e.g., the myocardium, cardiac
valves, pericardium, and great vessels).
• Transthoracic and transesophageal echocardiography are
frequently used as complementary imaging techniques.
Accordingly, the advantages and disadvantages of these
two methods should be understood.
• Newer imaging modalities that are being introduced into
the standard examination include contrast echocardiog-
Parametric Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
Methods for Improving Two-Dimensional Imaging. . . . 125
Three-Dimensional Echocardiography. . . . . . . . . . . . . . . 128
Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
raphy, harmonic imaging modalities, parametric imaging
modes, and selected three-dimensional techniques.
• Echocardiography examinations using standardized and
novel imaging modes are frequently applied to a wide
range of new clinical treatments, including assessment
of left ventricular assist devices.
• In this growing field, important quality assurance mea-
sures have evolved along with imaging techniques to
improve the quality of delivered care.
Echocardiography is a safe, noninvasive, and widely available
method that often provides a definitive anatomic and hemo-
dynamic diagnosis and guides medical management. The
modern echocardiography machine is a highly sophisticated,
multimodal device that is an integral part of any cardiovas-
cular care center. Ultimately, however, echocardiography
remains operator-dependent and subject to the physical prin-
ciples of ultrasound. Efficient usage of this technology
depends on basic training1–4 in imaging techniques, machine
settings, new technology, continuing education, quality
assurance, data storage and retrieval,5 and reporting stan-
dards.6–9 Accordingly, this chapter discusses the fundamen-
tal physical principles of cardiovascular ultrasonography,
with an emphasis on classic two-dimensional (2D) and
Doppler methods for transthoracic (TTE) and transesopha-
geal (TEE) echocardiography. This discussion will help echo-
cardiographers design protocols for performing TTE or TEE
2D and Doppler examinations and will provide a basis for
understanding the more advanced imaging techniques. For
certain echocardiography-derived measurements of cardiac
mass, volume, area, and dimensions, interested readers
should refer to other echocardiography chapters in this book
or to a comprehensive echocardiography textbook.
Historical Perspective
The first clinical cardiac ultrasound examination was per-
formed in 1953 by two Swedish researchers, Inge Edler, a
physician, and Hellmuth Hertz, an engineer, who used an
93
94 chapter
“ultrasonic reflectoscope” obtained from a shipyard and
designed to detect structural defects in boats.10,11 The first
images consisted of A-mode signals that were hard to inter-
pret and often misleading. However, the clinical impact of
these images and their subsequent refinements was so sig-
nificant that, in 1970, Elder and Hertz received the Lasker
Prize in Medicine. By that time, the clinical aspects of their
technique were based primarily on M-mode examination.12
During the 1970s, cardiology was revolutionized by further
advances in surface planar imaging techniques (oscillating
mechanical sector scanners,13 linear array transducers,14 and
phased array transducers15,16) which provided recognizable,
moving, cross-sectional images of the cardiac anatomy for
the first time. M-mode17 and then “real-time” moving-image
capability18 was quickly adapted to TEE probes17,18 providing
new higher-resolution esophageal imaging windows on the
heart and aorta. Clinical spectral Doppler echocardiography
techniques were introduced in the early 1980s.19,20 By 1986,
the concept of an integrated M-mode, 2D, and spectral
Doppler examination for use in clinical practice had fully
taken shape.21 This breakthrough was soon followed by the
addition of color-flow Doppler,22–26 biplane TEE,27–29 and then
multiplane TEE imaging techniques.30,31
Clinical Applications
Throughout the 1980s and 1990s, the important role of 2D
and Doppler echocardiography in the diagnosis and manage-
ment of many cardiovascular conditions became clearly
established, to the point of essentially replacing interven-
tional hemodynamic testing in many cases. (The echocar-
diography indications are listed in Table 5.1.) From the late
1980s32 through the 1990s, a large number of clinical studies
established echocardiography as a viable noninvasive means
of identifying “diastolic dysfunction” by analyzing several
routinely acquired blood-flow spectral Doppler,33–36 color M-
mode,37 and tissue Doppler imaging (TDI) parameters. This
led to a widespread realization that echocardiography can
readily identify a large, previously unrecognized subset of
patients with congestive heart failure resulting from dia-
stolic dysfunction despite a normal or near-normal left ven-
tricular ejection fraction.38 The comprehensive Doppler
examination can frequently help distinguish between certain
forms of diastolic dysfunction (e.g., constrictive,35 restric-
tive,39–41 hypertrophic,42 and ischemic43 cardiomyopathies)
and can estimate the left atrial pressure,44–46 assess disease
prognosis,40,47–53 and follow up the response to therapy.54–56
Ongoing refinements include the use of increasingly sensi-
tive and specific anatomic and physiologic parameters to
assess not only diastolic heart failure but also ventricular
mass,57 systolic function,58 and valvular heart disease.
Technologic Breakthroughs and Evolving
Clinical Applications
Although long viewed as clinically “mature,” echocardiog-
raphy has undergone further “revolutionary” advances during
the past 10 years, including not only technologic break-
throughs but also new clinical applications for older tech-
niques.59 The hemodynamic assessment of left ventricular
assist devices (LVADs) is just one example of an emerging
5
TABLE 5.1. Echocardiography indications: general categories
Patients with signs or symptoms of cardiovascular disease
Valvular heart disease (potentially pathologic murmurs)
Endocarditis
Ischemic heart disease
Chest pain syndromes (suspected to be cardiopulmonary in origin)
Congestive heart failure (systolic or diastolic)
Cardiomyopathies
Pericardial disease
Hypertension/hypertensive heart disease
Atrial fibrillation/flutter
Cardioembolic disease
Disease of the aorta
Suspected cardiac neoplasm
Congenital heart disease
Hemodynamic instability/critically ill patients
Suspected device malfunction (prosthetic valve, pacemaker lead,
ventricular assist device)
Invasive procedures (procedure monitoring, postprocedure
assessment)
Cardiovascular surgery (intraoperative)
Pericardiocentesis
Cardiac biopsy
Percutaneous ASD closure (TEE/ICE)
Electrophysiology, selected (TEE/ICE, lead extraction, RFA)
Percutaneous valve procedures
Screening echocardiography
Marfan syndrome (asymptomatic family members)
Hypertrophic cardiomyopathy (asymptomatic family members)
Familial dilated cardiomyopathy (asymptomatic family members)
Cardiotoxic chemotherapy exposure (pre- and posttreatment)
ASD, atrial septal defect; ICE, intracardiac echocardiography; RFA, radio-
frequency ablation; TEE, transesophageal echocardiography.
clinical focus that uses echocardiography for research and
patient management.60–64
In the 1990s, exercise and pharmacologic stress echocar-
diography came into widespread clinical use for the assess-
ment of myocardial ischemia, myocardial viability,65–72 and
valvular heart disease.73–77 The accuracy of stress echocar-
diography continues to undergo refinement with the incor-
poration of newer imaging and Doppler techniques (see the
sections on Tissue-Doppler Imaging, Contrast Harmonics,
and Three-Dimensional Echocardiography, below).
With the development of intravascular and intracardiac
ultrasonography, the boundary between noninvasive and
invasive imaging techniques became blurred. Intravascular
ultrasonography (IVUS),78 uses a shallow, high-resolution
radial image display (Fig. 5.1) that is ideal for assessing vas-
cular structures.78–82 Ongoing technologic refinements
include commercially available real-time, three-dimensional
(3D) echocardiography83–87 (Figs. 5.10C, 5.45, 5.48, and 5.49),*
miniature handheld ultrasonic devices (Fig. 5.2),88–92 and
intracardiac echocardiography (ICE).93–102 The latter
* To preserve the sequence of a typical TTE or TEE examination,
the figures in this chapter are not always numbered sequentially,
according to their order of appearance in the text.
 i n t roduct ion to echoc a r diogr a ph y 95
Echocardiography contrast agents (intravenously deliv-
ered, highly echoic microbubbles) and harmonic imaging
modalities (see below) have greatly improved the diagnostic
accuracy of left ventricular functional assessment during
routine and stress echocardiography. Microbubbles improve
endomyocardial detection by “opacifying” the blood pool.
Currently, two different echocardiography contrast agents
(microbubbles) are approved by the United States Food and
Drug Administration (FDA) for this indication. Left ventric-
ular opacification is possible only when microbubbles persist
within the imaging field during imaging. Conversely, another
application of microbubbles, myocardial contrast echocar-
diography (MCE) uses ultrasound energy to burst microbub-
bles within an area of interest. Intermittent observations
regarding the rate of myocardial microbubble replenishment
allow myocardial perfusion characteristics to be determined.
Although FDA approval is still pending, recent clinical
research suggests that MCE is a potentially important emerg-
ing clinical modality.123–126 Experimental studies have also
shown that acoustically active intravenous microbubbles
with surface ligands may permit “targeted” pathology-
specific ultrasound imaging.127,128 Additionally, microbubbles
may eventually also become vehicles for the localized deliv-
FIGURE 5.1. Intravascular ultrasound image from within a right ery of pharmacologic or gene therapy.129
coronary artery after deployment of a stent. Luminal dimensions The recent explosion of potential “add-on” techniques
are in millimeters. Submillimeter structures include a bright plaque presents echocardiographers with challenging questions
calcification (arrowhead) and a coronary stent wire in cross section about what constitutes real clinical progress and what
(arrow).
techniques should be incorporated into the standard exami-
nation protocol. By becoming familiar with their clinical
indications, echocardiographers can use these techniques
selectively, on an “as-needed” basis, and thus streamline
technology uses a phased array transducer and a planar patient care.
imaging-sector display analogous to a small intravascular
TEE probe that is inserted into the circulation percutane-
ously. This small ultrasound catheter has, in fact, been
employed as a TEE probe experimentally in tiny subjects.103
New clinical indications for ICE include guidance of electro-
physiologic radiofrequency ablation procedures,104 deploy-
ment of percutaneous atrial septal occluders101 (Fig. 5.3), and
monitoring of other interventional procedures.102 Because
IVUS and ICE are invasive techniques, they will not be dis-
cussed further in this chapter.
Novel parametric imaging modes enable rapid depiction
and quantitation of intramyocardial functional heterogene-
ity. Real-time, color-coded TDI105 (Figs. 5.41–5.45) and derived
strain (Fig. 5.46) and strain-rate image data (Fig. 5.47)106–109 are
now commercially available because of increased processing
speeds. These new Doppler methods for analyzing myocar-
dial motion produce familiar anatomic images with super-
imposed physiologic data (a color-encoded “parametric”
display). The combined anatomic and physiologic data are
stored digitally for either real-time or retrospective off-line
analysis. The clinical utility of parametric imaging tech-
niques (myocardial Doppler imaging) will increase as more
reference values110–112 and validation studies become available
for the assessment of cardiomyopathies, coronary artery
disease,113,114 ventricular dyssynchrony115,116 and other pathol-
ogies. Tissue-Doppler-imaging–derived “outcome indices”
are being developed117 to improve candidate selection for
cardiac resynchronization therapy (CRT)115,118–121 (Fig. 5.44) or FIGURE 5.2. Small handheld echocardiography device (arrow)
CRT refinement.117,122 being used at the bedside.
96 chapter
A
FIGURE 5.3. (A) Fluoroscopic image of an intracardiac echocardiog-
raphy (ICE) device in the right atrium (arrow) just before release of
an atrial septal occluder (arrowhead) from its deployment catheter.
Indications
The indications for echocardiography are increasingly promi-
nent in evidenced-based clinical practice guidelines.130–139
Although these indications are too extensive to review here,
Table 5.1 summarizes their general categories. Indeed, echo-
cardiography indications are so numerous that one might
more appropriately ask when this method should not be used.
Because of increased availability and clinical utility, echo-
cardiography’s usage has greatly expanded in recent years.
However, echocardiography demands a major commitment
in terms of time, personnel, ongoing training, and technol-
ogy. It is a valuable resource that must be deployed appropri-
ately. Echocardiography is not indicated for situations in
which it would not influence patient care; nor is it indicated
for asymptomatic patients in whom detection of mild sub-
clinical lesions or misleading imaging artifacts could cause
harm or increase cost because of a need for subsequent con-
firmatory procedures. No randomized clinical trials assess-
ing the outcome of diagnostic imaging tests are available,132
so expert opinion is based on summaries of clinical obser-
vational studies.132,136–139 Consensus opinion regarding the
inclusion of additional new imaging modalities (e.g., con-
trast, 3D, tissue harmonics, TDI) is not addressed in recent
echocardiography guideline statements. However, clinical
guidelines do address the frequency with which indicated
examinations should be repeated. Clinical research fre-
quently relies on quantitative echocardiography methods140
that may go beyond the scope of routine clinical protocols.
Echocardiography as a Screening Tool
Echocardiography is not generally recommended as a screen-
ing tool for asymptomatic patients who lack signs (on physi-
5
(B) ICE ultrasound image obtained in the same patient. LA, left
atrium; RA, right atrium; RAA, right atrial appendage.
cal examination, chest roentgenography, electrocardiography,
or other imaging procedures) or symptoms of cardiovascular
disease. Important exceptions include screening of patients
with a family history of genetically transmitted cardiovas-
cular disease. Examples include asymptomatic first-degree
relatives of patients with Marfan syndrome, other familial
aortic aneurysms, hypertrophic cardiomyopathy, or sus-
pected familial dilated cardiomyopathy. In addition, echocar-
diography may be used for baseline and follow-up evaluation
of left ventricular function in asymptomatic patients who
are to receive potentially cardiotoxic chemotherapeutic
agents.132,136–139
Transthoracic Versus Transesophageal
Echocardiography
Because almost all the imaging modalities available for TTE
are also applicable to TEE, some confusion may exist regarding
the relative merits of these two methods. In fact, they are
complementary approaches, whose advantages and disadvan-
tages vary depending on the diagnosis and imaging conditions.
Because TEE is semi-invasive and typically requires conscious
sedation, it is usually preceded and “guided” by TTE. Because
of numerous possible imaging windows, TTE often provides a
superior and more comprehensive Doppler examination. It can
also provide a superior analysis of ventricular wall motion,
particularly when echocardiography contrast agents are used.
Occasionally, a comprehensive surface echocardiogram will
obviate the need for TEE. However, even in the best of hands,
a surface examination may be technically inadequate or it may
raise clinical suspicion concerning an underlying pathologic
condition that requires further evaluation by TEE. The trans-
esophageal approach permits superior anatomic evaluation of
the posterior cardiac structures in most cases and optimal
Doppler evaluation under special circumstances (e.g., assess-
 i n t roduct ion to echoc a r diogr a ph y
ment of periprosthetic mitral regurgitation, left atrial append-
age assessment, congenital heart disease; or for aortic valve
planimetry).
In the intensive care unit (ICU), TEE may be useful when
surface echocardiography is not logistically possible (e.g., in
an intubated patient whose condition is unstable). Because
TEE does not invade the operative field, it has largely sup-
planted intraoperative epicardial imaging and is widely used
for hemodynamic monitoring during cardiovascular surgery.
At the end of cardiopulmonary bypass, TEE may be used to
assess congenital cardiac repairs, complex heart valve proce-
dures, left ventricular myomectomies, tumor removals,
LVAD implants, and aortic dissections involving the aortic
root. Accordingly, a separate field of perioperative (intraop-
erative) TEE has emerged, as practiced by dedicated cardiolo-
gists, specially trained cardiovascular anesthesiologists,141,142
and some cardiovascular surgeons.
Two-Dimensional Imaging
The Physics of Ultrasound
An understanding of the physics of ultrasound is essential
for performing echocardiography examinations and inter-
preting their results. Sound comprises the directional (lon-
gitudinal) propagation of compressions and rarefactions of
an acoustic medium (air, tissues, fluids). The frequency
(number per unit time) of these compressions and rarefac-
tions is reported in cycles per second or hertz (Hz) (1 Hz =
1 cycle/s). The spectrum of sounds audible by the human ear
ranges from 20 to 20,000 Hz. The term ultrasound denotes
sounds that are higher (>20 kHz) than the human audible
range.
A B
FIGURE 5.4. (A) Broadband combined imaging and Doppler transducer with imaging gel and index mark (arrow). (B) Nonimaging “Pedoff”
transducer for dedicated continuous-wave Doppler examination.
97
The propagation time (in seconds) required for sound
energy to complete 1 cycle of compression and rarefaction
is called a period. In diagnostic ultrasonography, a typical
period ranges from 0.1 to 0.5 μs, depending on the sound fre-
quency. Period and frequency are inversely related (period =
1/frequency). The wavelength is the propagation length,
within a medium, of one complete cycle. Frequency and
wavelength are also inversely related.
An “echograph machine” works by electrically stimulat-
ing a piezoelectric element, called a “crystal” or ceramic,
that is housed within a transducer (Fig. 5.4). Mechanical
deformation of the crystal produces ultrasound waves that
are transmitted into the patient’s body, where they are scat-
tered, are reflected, or eventually fade (attenuate). The energy
from reflected ultrasound (echoes) deforms the transducer’s
piezoelectric crystal, creating a faint electrical impulse that
is amplified, processed, recorded, and displayed in the famil-
iar formats seen throughout this chapter.
Echocardiographic image resolution (clarity, or the degree
to which adjacent points in an image may be distinguished
as separate) is linked to ultrasound frequency. To clearly
show thin structures such as the endocardium, the valve
apparatus, and small mass lesions, basic surface echocardio-
grams require an axial and lateral spatial resolution of 1 to
2 mm. An ultrasound wavelength of <1 mm is necessary to
achieve that resolution.
At all frequencies, the speed of ultrasound (propagation
velocity) in soft tissue is approximately 1,540 ms (1.54 mm/
μs). At a frequency of 1 MHz (1 million cycles per second),
sound has a wavelength of 1.54 mm in soft tissue. Because
wavelength and frequency are inversely related, the wave-
length of a 2-MHz signal is half that of a 1-MHz signal
(1.54 mm/2 = 0.77 mm). This wavelength is less than the
necessary spatial resolution, which is why a minimum
98 chapter
frequency of 2 MHz is required for surface echocardiography.
Higher ultrasound frequencies (20–40 MHz) produce even
finer degrees of spatial resolution, allowing even ultrastruc-
tural vascular layers to be measured with IVUS (Fig. 5.1).
Reflected soundwaves may produce a wide variety of
imaging artifacts that can either be recognized as such or
can lead to erroneous interpretation. One reason for these
artifacts is that the sound energy gradually attenuates as it
becomes more distant from its source. This attenuation
eventually makes it impossible for the operator to distin-
guish reflected ultrasound signals from random background
“noise” at a limiting depth of interrogation. However, signal
attenuation is directly related to soundwave frequency, so it
is more common at higher frequencies. High-frequency
(high-resolution) imaging is possible only at shallower
imaging depths (low tissue penetration). This interplay
between ultrasound wavelengths, image resolution, and
signal attenuation explains why medically useful ultraso-
nography is constrained to a frequency range of 2 to 40 MHz
and to certain imaging depths. Transthoracic echocardiogra-
phy operates at one end of an imaging depth range of approxi-
mately 2 to 24 cm, and IVUS (Fig. 5.1) operates at the other
end (<1 cm). Transesophageal echocardiography (Fig. 5.26)
and ICE (Fig. 5.3) operate in the middle range (Table 5.2).
Two-dimensional images are created from pulses of ultra-
sound. The pulse repetition frequency (in kHz) is inversely
related to imaging depth. Along with the wavelength, the
pulse duration and pulse length also affect image resolution.
Axial resolution (in which resolving points are aligned or in
parallel with the ultrasound beam) is superior to lateral reso-
lution (in which resolving points are perpendicular to the
ultrasound beam).
Echocardiography machines produced in the 1980s oper-
ated with single-frequency transducers (2.5, 4, and 7 MHz)
that had to be manually changed, depending on imaging-
depth requirements (deep vs. shallow, in an adult vs. a pedi-
atric patient). Modern transducers are “broadband,” or
“multifrequency,” and can better balance near- and far-field
imaging by sending and receiving multiple frequencies
simultaneously.
Differences in acoustic impedances related to density
and stiffness between adjacent media (e.g., tissue planes)
determine the extent to which soundwaves are either
reflected or transmitted. Blood, myocytes, collagen, and
adipose tissue differ only slightly with respect to acoustic
impedance, and this fact forms the basis for echocardio-
TABLE 5.2. Cardiovascular ultrasound modalities
Practical image Axial resolution
Modality f (MHz) depth (cm) (mm)
TTE 2.5–5 25 1–2
TEE 4–7 20 0.5
ICE 5–10 10–15 0.2
IVUS 20–40 0.5–1.0 0.05
Depth, maximum imaging depth; ICE, intracardiac ultrasound; IVUS, intra-
vascular ultrasound; TEE, transesophageal echocardiography; TTE, transtho-
racic echocardiography; f = ultrasound frequency.
Note: axial resolution is also affected by emitted pulse length and pulse
duration. Indicated depth and resolution values are estimates; lateral resolu-
tion (not shown) is poorer than axial resolution.
5
graphic imaging based on subtle reflections at tissue inter-
faces. However, the heart is surrounded by two strong
ultrasound attenuators—lung and bone—both of which tend
to variably reflect, scatter (lung), or absorb (bone) ultrasound
energy. This set of circumstances poses a major (and in some
patients insurmountable) problem for cardiac ultrasound
imaging. The key to optimal imaging is the sonographer’s
degree of experience and the machine’s technologic ability
to extract maximal usable information even from highly
attenuated signals (see Contrast Harmonics, below). As dis-
cussed above, TEE can be used adjunctively when surface
echocardiography attenuation artifacts prevent adequate
examination.
For further details about ultrasound physics, a number of
excellent references are available.143–147
Transthoracic Echocardiography
Ordering an Echocardiogram
A comprehensive TTE examination includes systematic
acquisition of a set of 2D and M-mode views, along with
spectral Doppler and color Doppler evaluation of the intra-
thoracic cardiovascular structures (e.g., the myocardium,
cardiac valves, pericardium, and great vessels). For ease of
communication, ordering a comprehensive examination is
sometimes casually called “getting an echo.” The word
“echo” is potentially confusing for order-entry personnel and
sonographers, however, because the necessary extent of the
examination may be unclear. An initial comprehensive
examination, including 2D imaging and Doppler evaluation,
is required for most patients. A limited 2D (anatomic-only)
exam is reserved for following up certain previously diag-
nosed pathologic conditions. To ensure that the clinical ques-
tion is addressed, all orders for an echocardiogram should
include the exact indication for the study, pertinent details
of the patient’s cardiovascular medical and surgical history,
and pertinent physical findings when available. The patient’s
age, sex, height, weight, and blood pressure at the time of the
examination should also be recorded. If possible, previous
echocardiography exams should be reviewed.5
Scanning Techniques
Without proper scanning procedures and machine settings,
even the most advanced imaging devices may prove inade-
quate. Appropriate patient positioning is an important
element of good sonography. In the echocardiography labora-
tory, optimal results are generally obtained with the subject
lying comfortably in the left lateral decubitus position, but
this position is not always attainable by intubated, wounded,
or otherwise ill patients. As in cardiac auscultation, the left
lateral decubitus position allows gravity to decrease the dis-
tance from the myocardium to the listening device (trans-
ducer) by reducing the amount of interposed lung. To enable
full access to apical windows and avoid apical foreshortening
of views, one should use a special echocardiography bed with
a pull-away section (Fig. 5.5). Extension of the patient’s left
arm, combined with gentle gravity-induced left lateral tho-
racic extension, causes the ribs to spread slightly, minimiz-
ing acoustic shadowing. Depending on the body habitus,
 i n t roduct ion to echoc a r diogr a ph y
FIGURE 5.5. Sonographer obtaining apical views, using a special
echocardiography bed with a pull-away section (bracket), which
facilitates proper positioning of the transducer.
however, other positions (e.g., supine, semiupright, and right
lateral decubitus) may be used to optimize certain views.
Because the typical examination lasts for 30 to 45 minutes
(not including the setup time), the sonographer should be
seated comfortably and ergonometrically, typically on the
patient’s left side (Fig. 5.5). Alternatively, scanning from the
patient’s right side has some advantages, but it requires
the sonographer to reach around the patient’s thorax, and this
may be problematic. A coupling medium (ultrasonographic
gel) (Fig. 5.4A) is used to maximize ultrasound transmission
between the transducer and the patient’s body, in part by
eliminating air interfaces. Breathing instructions are often
crucial. For example, “breathe out and hold” can transiently
eliminate lung attenuation, bringing the heart into full view.
“Small breath in and hold” can elevate the diaphragm and
perhaps raise a rib-shadowed inferior left ventricular wall
into view (apical two-chamber view). During normal breath-
ing, the heart moves phasically across the otherwise station-
ary imaging plane. This translational motion causes
endocardial segments (and other structures) recorded during
systole to be from a different anatomic location than those
recorded during diastole, leading to erroneous analyses of
segmental wall motion and anatomic volume measurements.
The sonographer can often “coach” a patient to stop breath-
ing at an ideal point in the respiratory cycle. When data are
then acquired during a brief breath-hold, the respiratory com-
ponent of cardiac translation, a common pitfall of real-time
planar imaging, can be eliminated.
The Planar Image Display
The planar image is sector-shaped. Ultrasound emanates
from the smallest portion of the displayed sector, which
appears at the top of the screen in echocardiograms of adults.
The broader, more distant portion of the image, derived from
diverging echoes, appears at the bottom of the screen. Because
the transducer position varies greatly throughout an exami-
nation, spatial orientation entails a distinct learning curve
related to poorly visualized adjacent thoracic anatomic land-
marks. In predominantly long-axis views, caudal structures
appear to the left of the screen, and cephalad structures are
99
displayed on the right. In predominantly short-axis or cross-
sectional views, left-sided structures appear to the right of
the screen, and right-sided structures appear to the left, as if
the viewer were standing at the foot of a supine patient,
looking toward the head. Because the heart lies obliquely in
the chest, this is only a rough comparison, but it is consistent
with display standards for other types of axial imaging (i.e.,
computed tomography and magnetic resonance imaging). A
small icon (index mark), which varies depending on the man-
ufacturer, should appear to the right of the image sector (Fig.
5.6). This icon corresponds to a ridge or groove (Fig. 5.4A)
placed on one side of the otherwise symmetric imaging
transducer. In TTE, anterior structures appear at the top of
the screen, and more posterior structures appear toward the
bottom (Fig. 5.6).
Transthoracic (Surface) Echocardiography Views
PARASTERNAL LONG -A XIS (PSLAX) VIEW
Left Ventricular Inflow and Outflow Tracts. The
surface examination begins with a parasternal long-axis
view of the left ventricular inflow and outflow tracts and
the aortic root. The transducer is usually placed adjacent to
the sternum in the left third or fourth intercostal space,
although optimal patient-imaging “window” positions may
vary greatly from one patient to another. An initial high-
depth setting is selected to include anatomic features pos-
terior to the left ventricular chamber (Fig. 5.6). Subsequent
shallower, “optimized” views are focused on the left
ventricular myocardium and the valves (Figs. 5.7 to 5.9).
Important measurements (e.g., left ventricular end-diastolic
septal- and posterior-wall thickness; left ventricular end-
diastolic and end-systolic internal chamber diameters) are
obtained from a carefully selected midline imaging plane
that bisects both the aortic and the mitral valve annuli
during diastole (Fig. 5.7A) and systole (Fig. 5.7B). A common
pitfall is acquisition and measurement of “off-axis” para-
sternal views that yield erroneously small ventricular
FIGURE 5.6. Parasternal long-axis view at increased depth. An
index mark (arrowhead) always appears to the right of the image
sector. *, posterior pericardial effusion; **, pleural effusion; aAo,
ascending aorta; dAo, descending thoracic aorta; LA, left atrium; LV,
left ventricle; RVOT, right ventricular outflow tract; Vb, vertebral
body.
10 0 chapter
A B
FIGURE 5.7. Parasternal long-axis view at a shallower, “optimized”
depth. (A) Diastolic image with the mitral valve (double arrows)
open and the aortic valve (single arrow) closed. Ao, aortic root; dAo,
descending thoracic aorta; LA, left atrium; LV, left ventricle; RVOT,
right ventricular outflow tract. (B) Systolic image with the mitral
valve closed and the aortic valve open. *, left ventricular outflow
diameters and erroneously large myocardial thicknesses.
In addition to obtaining a “midline” image, the sonographer
should also scan incrementally toward both the medial and
lateral aspects of the aortic and mitral valves to exclude
pathology along the extent of each valve’s leaflet coaptation
zone. Generally, measurements of parasternal diameters
should be obtained from 2D views (as opposed to M-mode).
Although M-mode measurements have certain advantages
(fast sample rates and improved temporal resolution), their
use can be limited by oblique cut planes imposed by patient
imaging-window constraints. The ascending aorta should
FIGURE 5.8. Parasternal long-axis view at the level of the aortic
root and ascending aorta. The double arrows indicate the mitral
valve anterior leaflet. Measurements of the proximal aorta are
obtained during diastole (with the aortic valve closed). a, Aortic root
diameter, sinus of Valsalva level; b, sinotubular junction diameter;
c, ascending aortic diameter.
5
tract; single arrow, mitral valve chordae tendineae; double-headed
arrow, left ventricular outflow-tract dimension/diameter for calcu-
lating left ventricular outflow-tract flow. Line a indicates the orthog-
onal image plane shown in Figure 5.10A. Line b indicates the
orthogonal image plane shown in Figure 5.10B. Line c indicates the
orthogonal image plane shown in Figure 5.11A.
be imaged and measured if possible. This may require a
separate parasternal long-axis view at a more cephalad
transducer position (Fig. 5.8). Note that aortic measure-
ments distal to the aortic valve leaflets are obtained during
diastole.
Right Ventricular Inflow Tract (Fig. 5.9). With the
transducer in an optimized left-sided, parasternal long-axis
position, a subtle leftward and anterior tilting motion often
easily produces the right ventricular inflow tract view, which
includes the tricuspid valve and right atrium.
FIGURE 5.9. Parasternal long-axis view of the right ventricular
inflow tract and tricuspid valve. Arrow, coronary sinus. A, tricuspid
valve anterior leaflet; I, inferior vena caval ostium; P, tricuspid valve
posterior leaflet; RA, right atrium; RV, right ventricle. (Note: With
more “septal” angulation, the tricuspid valve anterior and septal
leaflets may be seen in this view.)
 i n t roduct ion to echoc a r diogr a ph y
PARASTERNAL SHORT -A XIS VIEW
Left Ventricle (Fig. 5.10). With the transducer in
an optimized left-sided parasternal long-axis position, a
90-degree clockwise transducer rotation will produce left
ventricular short-axis views. These “breadloaf” slices
should be obtained in the region of the apex (not shown),
at the midpapillary muscle level (Fig. 5.10A), and through
the basal segments at the chordal and mitral valve leaflet
level (Fig. 5.10B). This approach will show the basal, middle,
and apical coronary artery distributions that correspond
to the standard 17-segment model.6 The left ventricular
short-axis view should be perpendicular to the left ventri-
cular long axis. Ideal parasternal left ventricular
short-axis views are not obtainable when the left ventricle’s
major axis within the chest is located in an extreme
anterior-to-posterior position (“horizontal” heart); in
such patients, only limited “oblique” or oval-shaped short-
axis views are possible, and these may be difficult to
interpret.
A B
C
FIGURE 5.10. (A) Parasternal short-axis view of the left ventricle
at the papillary muscle level. AL, anterolateral papillary muscle;
PM, posterolateral papillary muscle. Line a indicates the orthogonal
image plane shown in Figure 5.13A (apical four-chamber view). Line
b indicates the orthogonal image plane shown in Figures 5.7 and
5.13E (parasternal long-axis views and apical three-chamber). Line
c indicates the orthogonal image plane shown in Figure 5.13D
(apical two-chamber view). (B) Parasternal short-axis view, mitral
valve level. A1, anterior segment of the mitral anterior leaflet; A 2,
middle segment of the mitral anterior leaflet; A 3, posterior segment
101
Aortic, Tricuspid, and Pulmonary Valve Level (Fig.
5.11). Further cephalad positioning of the imaging plane
above the left ventricular level reveals the aortic valve in the
short-axis view. With that valve centered in the imaging
sector, subtle transducer adjustments will show the three
aortic cusps in perfect symmetry during diastolic closure.
Color Doppler examination at this level (not shown) will
detect aortic regurgitation. Slightly cephalad, when imaging
conditions are ideal (in pediatric cases and frequently in
adults), the left and right coronary ostial locations within
the aortic root can be recorded. The adjacent tricuspid valve,
atria, interatrial septum, and right ventricular outflow tract
are also visualized in this view. The pulmonary valve’s long
axis (perpendicular to the aortic valve) is often not optimized
at the aortic leaflet level and is best seen in a separate,
slightly more cephalad imaging plane just above the aortic
valve cusps. Branching of the left and right pulmonary arter-
ies should be documented if possible (Fig. 5.11B). This view
is important for Doppler evaulation of the right ventricular
out flow tract (Fig. 5.12).
of the mitral anterior leaflet; AL, anterolateral commissure; P1,
anterior scallop of mitral valve posterior leaflet; P2, middle scallop
of the mitral valve posterior leaflet; P3, posterior scallop of the mitral
valve posterior leaflet; PM, posteromedial commissure; RVOT, right
ventricular outflow tract. (C) Three-dimensional surface-rendering
mode from the cut plane shown in Figure 5.10A, looking toward the
mitral valve. The arrow labels are the same as in B. AL, anterolateral
commissure; PM, posteromedial commissure; RVOT, right ventric-
ular outflow tract; *, left ventricular outflow tract.
 10 2 chapter
A aortic valve.
B gous to the parasternal long-axis view, the apical three-
FIGURE 5.11. (A) Parasternal short-axis view, aortic valve level.
Arrowhead, interatrial septum; single arrow, pulmonary valve;
double arrows, tricuspid valve. L, left coronary cusp of the aortic
valve; LA, left atrium; N, noncoronary cusp of the aortic valve; R,
right coronary cusp of the aortic valve; PA, pulmonary artery; RA,
right atrium. (B) Parasternal short-axis view, pulmonary artery (PA)
level. Double-headed arrow, pulmonary annulus dimension for right
ventricular outflow-tract flow assessment. Ao, ascending aorta; L,
left PA at the pulmonary bifurcation; R, right PA at the pulmonary
bifurcation; RVOT, right ventricular outflow tract. Note: The right
PA is directly posterior to the ascending aorta.
Apical Views (Fig. 5.13)
With the patient carefully positioned, placing the transducer
over the palpated point of the left ventricular apical impulse
is often a good way to start looking for apical windows. If
the transducer is not placed exactly over the cardiac apex and
properly aligned with the left ventricular major axis, apical
“foreshortening” will occur. Because this condition impairs
ventricular segmental wall-motion analysis and volume
assessment, avoidance of apical foreshortening is a crucial
aspect of accurate scanning.
5
A PICAL FOUR-CHAMBER VIEW (Fig. 5.13A)
This view is a good starting point from which one can easily
attain the other apical views by simply rotating the trans-
ducer. The cardiac apex and left ventricular major axis should
be centered within the imaging sector. The interventricular
septum appears on the left side of the sector, with the oppos-
ing lateral wall on the right side. The other apical views are
obtained by rotating the transducer counter clockwise around
the central axis. This view is used for Doppler evaluation of
the mitral valve (Fig. 5.14), the pulmonary veins (Fig. 5.15),
myocardial tissue Doppler (Fig. 5.16), and trisuspid valve (Fig.
5.17).
A PICAL FIVE-CHAMBER VIEW (Fig. 5.13B)
Angling the transducer slightly anteriorly from the four-
chamber view position produces the apical five-chamber
view, which shows the anterior interventricular septum, the
left ventricular outflow tract, and an oblique cut across the
A PICAL FOUR-CHAMBER VIEW: CORONARY SINUS L EVEL
(Fig. 5. 13C)
A slight inferior angulation of the imaging plane from the
apical four-chamber view will show the coronary sinus and
the inferior interventricular septum.
A PICAL T WO -CHAMBER VIEW (Fig. 5.13D)
By rotating the transducer 90 degrees counterclockwise from
the apical four-chamber view, one can see the left ventricular
anterior and inferior walls in opposition, as well as the mitral
valve and left atrium (two chambers).
A PICAL T HREE-CHAMBER (LONG -A XIS) VIEW (Fig. 5.13E)
An additional transducer rotation, approximately 30 degrees
counterclockwise past the apical two-chamber view, will
bring the right ventricular outflow tract, left ventricular
outflow tract, and aortic valve (long axis) into view. Analo-
chamber view shows similar anatomic features but focuses
on the left ventricular endocardium. This view (along with
the apical five-chamber view) is important for spectral
Doppler evaluation of the left ventricular outflow tract (Fig.
5.18).
Contrast echocardiography for improved endocardial
definition (Fig. 5.19) is performed in apical views.
Subcostal Views (Figs. 5.20 and 5.21)
While the patient lies supine with relaxed abdominal muscles
(the knees may be slightly flexed), the flat side of the trans-
ducer is placed on the abdomen. The transducer surface is
placed in the immediate right subcostal or mid-subxiphoid
region, pointing toward the right shoulder. Gentle downward
pressure produces the subcostal four-chamber view (Fig.
5.20A). Clockwise transducer rotation produces the subcos-
tal short-axis views (Fig. 5.20B). The subcostal view is impor-
tant for evaluating right ventricular function, left ventricular
segmental wall motion (of the septum and lateral wall), the
interatrial septum, and pericardial effusion. This view may
be excellent in patients with obstructive lung disease (hyper-
expanded lungs) and can salvage an otherwise technically
 i n t roduct ion to echoc a r diogr a ph y
A B
C D
FIGURE 5.12. (A) Color-flow Doppler image of the right ventricular
outflow tract and pulmonary valve: yellow (aliased) color is seen at
the pulmonary valve (arrow). (B) Color-flow Doppler image of the
pulmonary trunk, showing a normal pulmonary artery bifurcation.
This is an important view for excluding a patent ductus arteriosus
or proximal pulmonary artery stenosis (not present in this normal
example). L, left pulmonary artery; R, right pulmonary artery. (C)
Pulsed Doppler view of right ventricular outflow at the level of the
difficult exam because multiple subcostal views can fre-
quently be attained. The inferior vena cava should be imaged
along its long axis as it crosses the diaphragm and enters the
right atrium (Fig. 5.21A). Dynamic motion of the inferior
vena cava during normal respiration and while the patient
gently sniffs is used to assess the right atrial pressure (Fig.
5.21B; Table 5.3). The hepatic vein is also imaged along its
long axis for coaxial pulsed Doppler interrogation (Fig. 5.21C).
The upper abdominal aorta, lying alongside the inferior vena
cava, can be imaged in the short- and long-axis orientations
(Fig. 5.22). From this position, pulsed Doppler examination
of the descending thoracic aorta is used to assess the severity
of aortic regurgitation. The subcostal four-chamber view is
used for analyzing feasibility and the needle angle and depth
required for percutaneous pericardiocentesis procedures.
(Note: Real-time echocardiography guidance of percutaneous
pericardiocentesis is from the apical four-chamber view,
remote from the sterile needle site.)
Suprasternal Notch
In most (but not all) patients, the aortic arch may be visual-
ized along its short (not shown) and long axes (Fig. 5.23).
10 3
pulmonary valve annulus. Note the valve-closure artifact (arrow)
and absence of an opening artifact, indicating a good sample-volume
position. Note the automated time-velocity integral (TVI = 0.141 m
or 14.1 cm, arrowhead) from electronic outlining of the spectral
Doppler envelope (dotted curve). (D) Continuous-wave Doppler
image, right ventricular outflow tract (pulmonary valve). Note the
typical small pulmonary valve opening (left arrow) and closing
(right arrow) artifacts.
Although a patient’s body habitus may cause considerable
variation in image quality, this view should be attempted. It
can be used to detect an aortic arch aneurysm or dissection.
Pulsed Doppler interrogation in the region of the proximal
descending aorta is used to assess the severity of aortic insuf-
ficiency. Color Doppler and continuous-wave (CW) Doppler
in the same region (ligamentum arteriosum) can detect
coarctation of the aorta and patent ductus arteriosus, which
are important potential incidental diagnoses.
Modified Views
Sonographers should be familiar with certain “modified”
views (not shown) that are obtained with the patient supine
or in the right lateral decubitus position. Such views include
the superior right parasternal window (for visualizing the
superior vena cava and for CW Doppler evaluation of aortic
valve stenosis) and a modified right apical four-chamber view
(for accurate assessment of tricuspid regurgitation and for
ventricular visualization when apical windows are poor). A
posterior thoracic window may be useful for visualizing the
descending thoracic aorta when a pleural effusion is present
as an acoustic medium.
10 4 chapter 5

A B

C D

E
FIGURE 5.13. Apical views. (A) Apical four-chamber view. Arrow-
head, apical segment; single arrow, mid-septum; double arrows,
lateral wall. (B) Apical five-chamber view. Arrowhead, left ventricu-
lar outflow tract; double arrows, anterior septum. (C) Apical four-
chamber view, coronary sinus level. Single arrow, coronary sinus
entering the right atrium; double arrow, inferior portion of the
septum. (D) Apical two-chamber view. *, coronary sinus in short
axis; single arrow, anterior wall; double arrows, inferior wall. Line
a indicates the orthogonal image plane shown in Figure 5.13A (apical
four-chamber view). Line b indicates the orthogonal image plane
shown in Figure 5.13B (apical five-chamber view). Line c indicates
the orthogonal image plane shown in Figure 5.13C (apical four-
chamber, coronary sinus level). (E) Apical three-chamber (apical
long-axis) view. Arrowhead, left ventricular outflow tract; single
arrow, anterior septum; double arrows, inferolateral wall. RVOT,
right ventricular outflow tract.
 i n t roduct ion to echoc a r diogr a ph y 10 5

A B

C D
FIGURE 5.14. Mitral valve Doppler interrogation, apical four-
chamber view. (A) Mid-diastole. Small double lines at the open
mitral-leaflet tips indicate the proper pulsed Doppler sample-volume
position for obtaining mitral E and A velocities (B) and the mitral
deceleration time (double-headed arrow, view B). The double-headed
arrow (A) indicates the proper position for measuring the mitral
annulus diameter and the appropriate level for pulsed Doppler
sample-volume placement when obtaining mitral annulus velocities
(C) used for calculating mitral valve forward flow. (B) Pulsed Doppler
image obtained at the mitral valve-leaflet tips. Double-headed arrow,
mitral deceleration time. E, E-wave; A, A-wave. (C) Pulsed Doppler
image, at the mitral annulus level, showing an automated mitral
inflow–time-velocity integral (TVI = 0.144 m) used for determining
mitral valve flow. Although the same patient is shown in views B
and C, the aliased, high-velocity, systolic mitral regurgitation signal
(MR, black arrows) appears in view C but not view B because the
pulsed-Doppler sample volume is appropriately placed on the atrial
side of the mitral-leaflet closure line in view C. (D) Continuous-wave
Doppler examination across the mitral valve detects, in this case, a
trivial/mild high-velocity mitral regurgitation lesion (arrow).

Standard M-Mode Views
M-mode recordings from the parasternal long-axis view (at
the aortic valve, mitral valve, and left ventricular levels) and
from the short-axis view (at the pulmonary valve level) are a
feature of the standard examination (Fig. 5.24). The M-mode
display shows data reflected from a single, linear interrogat-
ing beam, displayed over time. M mode provides a rapid
sample rate [1800 frames per second (fps) versus <100 fps for
2D imaging] and superior axial resolution. This enables
detection of small, thin, fast-moving structures (e.g., heart
valves, small masses, and endocardial surfaces) and accurate
timing of their motion, particularly in the setting of tachy-
cardia. M mode is useful for detecting partial right ventricu-
lar free-wall diastolic collapse in pericardial tamponade, as
well as ventricular contractile dyssynchrony,148 paradoxical
septal motion, and the independent motion of tiny vegeta-
tions. If M mode is to be used for parasternal measurements,
the operator and interpreter must ensure that the M-mode
beam is exactly tangential to the long axis of the measured
structure. Because this goal is not always technically possi-
ble, assessment of ventricular and aortic dimensions fre-
quently relies on the 2D image (Fig. 5.7). Classic M-mode
patterns can indicate obstructive lesions of the left ventricu-
lar outflow tract and a variety of pathologic valve conditions
(see Chapter 21). The mitral anterior leaflet’s E-point septal
separation distance (Fig. 5.24B) can be an important clue to
left ventricular dilatation and systolic dysfunction. Because
of its superior sample rate, M mode, combined with color
Doppler (color M mode), can assist in the timing of color-flow
Doppler phenomena, especially during tachycardia (see
Chapter 21).
10 6 chapter
A B
FIGURE 5.15. Color Doppler (A) and pulsed Doppler (B) examina-
tion of the right superior pulmonary vein from the apical window.
The pulsed sample volume is placed approximately 1 cm into the
pulmonary vein (arrow, image A). (B) Normal systolic (S) and dia-
Transesophageal Echocardiography
Technical Aspects
In size and design, the semiflexible TEE probe is similar to
a gastroscope. Because the TEE probe does not incorporate a
fiberoptic visualization system, however, it must be “blindly”
passed into the esophagus. An uncommon but potentially
life-threatening complication is esophageal perforation.
FIGURE 5.16. Apical four-chamber myocardial tissue Doppler
image, with the sample volume placed in the basal lateral wall near
the mitral valve annulus. The myocardial velocity is normal, going
toward the transducer during systole (S) and away from the trans-
ducer in early (E′) and late (A′) diastole.
5
stolic (D) pulmonary vein forward flow and late diastolic reverse
flow during atrial contraction (A). The orange area indicates flow
toward the transducer. LV, left ventricle; RA, right atrium; RV, right
ventricle.
Training and experience with safe probe passage and with
conscious sedation are important elements of the examina-
tion. Because imaging windows are available only from the
esophagus or stomach, TEE offers less freedom to obtain
coaxial Doppler flow signals than does TTE, potentially lim-
iting the amount of hemodynamic data available in certain
cases. The desired TEE views are produced by combinations
of the following maneuvers: (1) probe-tip deflection in the
medial, lateral, antegrade, and retrograde directions by means
of hand-operated controls; (2) electronic rotation of the
imaging crystal (which is stationary within the probe tip)
throughout 180 degrees; (3) advancement and withdrawal of
the probe within the esophagus; and (4) clockwise and coun-
terclockwise rotation of the probe within the esophagus (Fig.
5.25). In different patients, available TEE images may vary
considerably, depending on the orientation of the heart
within the chest and the heart’s relationship to the esopha-
gus. Usually, the left atrium lies directly anterior to the
esophagus, and that structure’s blood pool provides an
extremely good acoustic window on the posterior cardiac
structures. The left atrium and the mitral valve are generally
seen with exceptional resolution, as are the pulmonary veins,
interatrial septum, descending thoracic aorta, proximal
superior vena cava, and proximal pulmonary veins. Struc-
tures positioned more anteriorly (the tricuspid or pulmonary
valve) or apically (the left ventricular apex) in the “far field”
may variably suffer from image attenuation or shadowing
related to calcifications or prosthetic valves.
Image Display
The TEE image display can differ from one laboratory
to another. Most operators display the small “sound-
emanating” portion of the TEE image sector at the top of the
screen (Fig. 5.26). Because the transducer is positioned within
a posterior structure (the esophagus), this situation creates a
unique display in which the posterior anatomy appears at the
top of the screen with the anterior structures toward the
 i n t roduct ion to echoc a r diogr a ph y 10 7

A B
FIGURE 5.17. Tricuspid valve interrogation by continuous-wave tricuspid-valve regurgitation velocity (VEL) and derived peak-
Doppler in the four-chamber view, using a combined imaging and systolic right ventricular pressure gradient (PG) were obtained by
Doppler transducer for color Doppler guidance (A) and a dedicated placing an electronic caliper on the spectral Doppler peak-velocity
nonimaging transducer (B) in the same patient. Note the improved position (+).
clarity of the spectral Doppler envelope in image B. The automated

A B

C D
FIGURE 5.18. Selected left ventricular outflow-tract Doppler inter-
rogations from the apical window. (A) Color-flow Doppler image,
apical five-chamber view. Note that the color in the left ventricular
outflow tract changes from blue to orange (arrow) when the velocity
exceeds the Nyquist limit of 53 cm/s, as indicated on the color scale
(arrowhead). (B) Color-flow Doppler image of the left ventricular
outflow tract (LVOT) (arrow) in the apical three-chamber view. (C)
Pulsed Doppler image of the LVOT, obtained with the sample
volume immediately proximal to the aortic annulus. The aortic-
leaflet closure artifact (arrow) and the lack of an opening artifact
indicate a good sample-volume position. Note the automated time-
velocity integral measurement (TVI, arrowhead) from outlining of
the spectral Doppler envelope (dotted curve). (D) Continuous-wave
Doppler image across the LVOT and aortic valve. Note the normal,
automatically derived low peak-flow velocity (Vmax), peak gradient
(Pk Grad), and mean gradient (Mn Grad), as well as the aortic valve
(AoV) TVI obtained by outlining the continuous-wave spectral
Doppler envelope (dotted curve).
10 8 chapter 5

A B

C
FIGURE 5.19. Apical four-chamber view in fundamental frequency (A), tissue harmonic (B), and contrast harmonic (C) imaging modes, in
the same technically difficult case, with increasingly apparent left ventricular endocardial border delineation. LV, left ventricle.

A B
FIGURE 5.20. Subcostal four-chamber view (A) and subcostal left ventricular short-axis view (B). *, liver; double arrows, inferior wall or
diaphragmatic wall; single arrow, anterior wall; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
 i n t roduct ion to echoc a r diogr a ph y 10 9

A B

FIGURE 5.21. Subcostal view of the inferior vena cava (arrow) entering
the right atrium during normal respiration (A) and with normal “collapse”
during an inspiratory “sniff” (B) indicating normal (low) right atrial pres-
sure. (C) Normal pulsed Doppler image of the hepatic vein, via the sub-
costal window, with predominant antegrade inflow (below baseline)
during systole (S) and diastole (D). A normal small flow reversal occurs
after atrial contraction (A). Arrowhead, normal augmentation of antegrade
inflow velocities during inspiration. x = x-descent; y = y-descent. V, sys-
tolic V wave; *, liver. C

bottom of the screen [see Fig. 5.11A (TTE) vs. 5.28A (TEE) and
Fig. 5.13A (TTE) vs. 5.26B (TEE)]. The caudal anatomy remains
displayed on the left and cephalad structures on the right.
Accordingly, by convention, there is a potentially confusing
“up-down” inversion of the anatomy in the TEE image rela-
tive to the surface image. All commercial echocardiography
machines have an up-down image-inversion mode. Some
practitioners intentionally invert the TEE image in up-down
fashion (placing the small part of the sector at the bottom) to
make the anterior-posterior image display consistent on both
surface and TEE images. This inversion is not incorrect, and
the choice of TEE display is up to the individual laboratory

TABLE 5.3. Estimated right atrial pressure

IVC, response to Estimated RAP
IVC, baseline inspiration (mm Hg)

Small or slit-like Complete collapse 0–4

Normal (1.5–2.0 cm) ≥50% decrease 5–10
Normal <50% decrease 10–15
Dilated <50% 15–20
Dilated No change >20
IVC, inferior vena cava; RAP, right atrial pressure. Inferior vena cava observed FIGURE 5.22. Color-flow Doppler image of the suprarenal abdomi-
in the subcostal view during normal respiration or while the patient “sniffs” nal aorta in the long-axis view, from the subcostal window, in an
gently to decrease intrathoracic pressure. imaging plane adjacent to that seen in Figure 5.21.
110 chapter
A B
C
FIGURE 5.23. The aortic arch in a long-axis, small suprasternal-
notch view (A). 䉱, right pulmonary artery, short axis; arrowhead,
left brachiocephalic (innominate) vein; single arrow, left common
carotid artery; double arrow, left subclavian artery; aAo, ascending
aorta; dAo, descending aorta. (B) Color-flow Doppler image showing
an aliasing phenomenon (aliasing velocity >81 cm/s, white arrows)
in the ascending (left black arrow) and descending (right black
arrow) thoracic aorta, with complete absence of a color signal when
or clinician. In all cases, the index mark remains to the right
of the sector apex (Fig. 5.26B), as in TTE.
Sequence of Standard Views
Laboratory protocols for TTE (surface) examination should
establish a consistent sequence of required views. Although
TEE examination protocols should also define all of the
required views or images, the order of image acquisition may
vary. For instance, TEE examinations may follow a “pathol-
ogy-directed” sequence of views designed to answer the
clinical question in a timely fashion in case the patient
cannot tolerate the probe or becomes hemodynamically
unstable before the exam is completed. After the chief indi-
cation for the examination has been addressed, further views
are obtained to complete the study. Obtaining a comprehen-
sive/complete TEE exam (in which all views and appropriate
Doppler evaluations are present) is particularly important
when evaluating diseases that potentially involve multiple
cardiac sites (e.g., rheumatic heart disease, endocarditis, an
atypical myxoma with multiple foci, and the cardiovascular
source of an embolus). In fact, completeness of examination
is important whenever possible because of the high likeli-
5
the blood-flow vector is tangential to the interrogating ultrasound
vector (black stripe, arrowhead). Solid orange indicates laminar flow
toward the transducer; solid blue indicates laminar flow away from
the transducer. (C) Pulsed Doppler image of the distal aortic arch,
showing normal systolic antegrade flow below the baseline (single
arrow) and normal lesser retrograde early diastolic flow (above the
baseline, double arrows) related to coronary artery and aortic-arch
vessel runoff.
hood that TEE will detect unexpected findings that could
alter patient care.
Transesophageal Views
PERICARDIUM AND VENTRICLES (Fig. 5.26)
The examination should include a sequence of images
obtained at an adequate depth to visualize all ventricular
epicardial (pericardial) and endocardial segments, including
the cardiac apex. Frequently, a stable imaging window can be
found (usually on gentle probe-tip retroflection followed by
slight probe withdrawal and rotation) so that the left ventri-
cle’s major axis lies in the center of the imaging sector in all
of the orthogonal planes. In this case, the transesophageal
four-chamber view (near 0 to 30 degrees of transducer rota-
tion), bicommissural view (near 60 degrees), two-chamber
view (near 90 degrees), and apical three-chamber view (long-
axis view, usually near 120 degrees but up to 160 degrees in
older patients) (Fig. 5.26) can all be obtained by electronically
adjusting the imaging angle of the transducer. In some patients
with relatively “vertical” hearts (in which the ventricular
long axis is relatively parallel to the esophagus), views of the
cardiac apex can be difficult or impossible to achieve.
 i n t roduct ion to echoc a r diogr a ph y 111

A B

C
FIGURE 5.24. (A) Aortic valve M-mode tracing with normal, wide
systolic cusp separation (double arrows) and a central diastolic
closure line (single arrow). LA, left atrium; RVOT, right ventricular
outflow tract. (B) Mitral valve, M mode. Single arrow, posterior
mitral leaflet; double arrows, anterior mitral leaflet. E, mitral leaflet
early diastolic position; A, mitral “A-wave” position; C, mitral
closure line; EPSS, E-point septal separation; LV, left ventricle; RV,
right ventricle. (C) M-mode tracing of the left ventricle at the papil-
lary muscle level. EDD, left ventricular end-diastolic dimension;
ESD, left ventricular end-systolic dimension; LV, left ventricle; RV,
right ventricle.

T RANSESOPHAGEAL VIEWS AT A DECREASED “OPTIMIZED”

DEPTH (Figs. 5.27 to 5.33)
After viewing the “big picture,” as described above, the
examiner may decrease or “optimize” the depth to view
near-field structures in greater detail and at improved
(increased) frame rates. The cardiac structures should be
viewed in the long-axis, short-axis, and (in many cases) inter-
mediate, oblique imaging planes. Because of patient varia-
tion, standard anatomic views do not always occur at specific
transducer angles. Figures 5.26 through 5.33 show the basic
TEE views. Additional or modified views may be obtained
as appropriate. Doppler interrogations should mirror those
performed during TTE examinations. Transverse or horizon-
tal views lie close to a transducer angle of 0 to 30 degrees.
Intermediate views (30 to 60 degrees) allow assessment of
the aortic valve along its short axis (Fig. 5.28), the left atrial
appendage [which is imaged in multiple views (Figs. 5.32B
and 5.33)], the mitral bicommissural region (Fig. 5.27), and
proper alignment of the pulmonary veins (Fig. 5.32) and pul-
monary valve. Vertical or “long-axis” views of the left ven-
tricle, aortic root, mitral valve, superior vena cava (bicaval
view, Fig. 5.31), and descending thoracic aorta are generally
obtained from 90- to 120-degree angles. A patent foramen
ovale may be documented in the TEE bicaval view by using FIGURE 5.25. Schematic diagram of a transesophageal probe,
intravenous agitated normal saline (Fig. 5.31). Various showing left and right lateral flexion, anteflexion, retroflexion, and
strategies may be needed to systematically obtain all the rotation of the imaging plane through 180 degrees.
112 chapter 5

A B

C D

E
 i n t roduct ion to echoc a r diogr a ph y
FIGURE 5.26. Transesophageal views of the left ventricle (at the
mid-esophagus level) showing the entire ventricular myocardium
and pericardium (at increased depth). Note: The indicated trans-
ducer angles may vary considerably among patients. (A) Five-
chamber view (transducer angle approximately 0 degrees in the
horizontal plane). Compare with transthoracic echocardiography
(TTE) image, Figure 5.13B. Arrowhead, left ventricular outflow
tract; LA, left atrium; LV, left ventricle; RA, right atrium; RV, left
ventricle. (B) Four-chamber view (transducer angle approximately 30
degrees). Compare with TTE image, Figure 5.13A. Arrow, index
mark; arrowhead, left ventricular apex. (C) Bicommissural view
(transducer angle approximately 60 degrees) showing the three pos-
necessary views. It is important to maintain both a station-
ary probe and a stationary transducer angle position while
recording complete individual cardiac cycles, so that the
same anatomic features can be visualized throughout systole
and diastole. The probe can then be manipulated systemati-
cally in a logical, incremental fashion to acquire subsequent
images according to the examination protocol or in a pathol-
ogy-directed sequence that reflects the indication for the
exam.
Transgastric Views
This additional imaging window is obtained by advancing
the TEE probe into the stomach. During this advancement,
one can usually obtain a low transesophageal (gastroesopha-
geal-junction) view (Fig. 5.34), which shows the posteriorly
located coronary sinus along its long axis and the lower
portion of the tricuspid valve. Though sometimes ignored,
this view can be important for detailed tricuspid valve assess-
ment, for guiding coronary sinus catheter placement in the
operating room, or for visualizing other pathologic condi-
tions of the coronary sinus. Further probe advancement into
the stomach yields a short-axis view of the left ventricle, at
the papillary muscle level (Figs. 5.35 and 5.36), which appears
inverted relative to the analogous TTE view (Fig. 5.10A).
A B
FIGURE 5.27. Transesophageal bicommissural view at decreased
depth during systole (A) and diastole (B), showing the mitral valve’s
posteromedial commissure (left arrowhead) and anterolateral com-
113
terior leaflet scallops of the mitral valve—the anterior (P1), middle
(P2), and posterior (P3) scallops—in the systolic (closed) position.
This view is important for localizing posterior-leaflet prolapse or
chordal-rupture lesions. Left arrowhead, posteromedial papillary
muscle tip; right arrowhead, anteromedial papillary muscle tip. (D)
Two-chamber view (transducer angle approximately 90 degrees in
the vertical plane). Compare with TTE image, Figure 5.13D. Arrow-
head, apex; single arrow, anterior wall; double arrows, inferior wall.
(E) Three-chamber view (transducer angle approximately 120 to 160
degrees). Compare with TTE image, Figure 5.13E. Single arrow,
anterior septum; double arrows, inferolateral wall; Ao, aortic root;
LA, left atrium; RVOT, right ventricular outflow tract.
Ninety-degree transducer advancement from the left ven-
tricular short-axis position will produce the gastric left ven-
tricular long-axis view (Fig. 5.37A). Clockwise probe rotation
from the left ventricular long-axis view will produce the
right ventricular and tricuspid valve long-axis view (Fig.
5.37B). Even if the tricuspid valve was obscured in trans-
esophageal windows, it can often be seen clearly in this view.
In most but not all cases, the left ventricular outflow tract
can be visualized and evaluated for obstruction or insuffi-
ciency with Doppler methods from a horizontal-plane, “deep-
gastric” view, obtained by further advancing the probe to the
cardiac apex (Fig. 5.38A,B), or from a more proximal modified
left ventricular long-axis view (Fig. 5.38C). Gradual probe
withdrawal from the gastric LV short axis view produces the
mitral valve short-axis view (Fig. 5.39) just below the gastro-
esophageal junction. As in surface imaging (compare with
Fig. 5.10B), this view can be important for determining indi-
vidual scallop involvement in mitral valve dysfunction.
Transesophageal Views: Descending Thoracic
Aorta (Fig. 5.40)
Because of its generally excellent imaging windows, TEE is
an important modality for detecting pathologic conditions of
missure (right arrowhead). Three posterior mitral valve scallop
regions (P1 to P3) are present.
114 chapter 5

A B
FIGURE 5.28. Transesophageal short-axis view of the aortic valve atrium; RVOT, right ventricular outflow tract. For analogous trans-
in diastole (A) and systole (B). *, left atrial appendage; arrowhead, thoracic echocardiography view (inverted), see Figure 5.11A. Note:
interatrial septum; single arrow, pulmonary valve; double arrows, The appropriate transducer angle varies from 30 to 90 degrees
tricuspid valve; L, left coronary cusp; LA, left atrium; N, noncoro- depending on the patient’s age and the left ventricle-aortic root
nary cusp; PA, pulmonary artery; R, right coronary cusp; RA, right angle.

the aorta, for example, dissection (Fig. 5.30), atheroma (Fig.

40B,D), and intramural hematoma. The aortic root and
ascending aorta should be visualized in the other transesoph-
ageal views noted above (Figs. 5.26A,E and 5.28 to 5.30). The
rest of the thoracic aorta, from the midtransverse arch to the
level of the diaphragm, is visualized by rotating the probe
leftward, away from the heart, toward the left paravertebral
region (transducer position = 0 degrees). The aorta should be
centered within the imaging sector. Representative short- and
long-axis aortic views are sequentially acquired at 5-cm
intervals or whenever important pathology is encountered.
The descending thoracic aorta (diaphragm level) is usually
seen in the short-axis view when the teeth (incisors) are even
with the probe’s 35- to 40-cm depth mark, depending on
patient size. The curvilinear distal arch is visualized in the
short-axis view by using intermediate (30 to 60 degrees) trans-
ducer angles as the probe is gradually withdrawn so that the
incisors are at approximately the probe’s 25-cm depth mark
(Fig. 5.40C). The mid-arch is visualized in the short-axis view
at a transducer angle of approximately 90 degrees. The distal FIGURE 5.29. Transesophageal echocardiogram of the great vessels,
ascending aorta and proximal aortic arch frequently lie in a in the short-axis view (horizontal plane), at the level of the ascend-
ing aorta and right pulmonary artery (RPA), showing typical side-
TEE “blind spot” because of interposed airways.
by-side short-axis “circles” of the ascending aorta (aAo), superior
vena cava (SVC), and right superior pulmonary vein (arrowhead).
This view is important for excluding anomalous right superior pul-
Doppler Examination and Hemodynamics monary venous drainage into the superior vena cava and for viewing
the proximal great vessels. Line a indicates the orthogonal image
planes shown in Figures 5.26E and 5.30A. Line b indicates the
When sound is reflected from a stationary target, the return- orthogonal image plane shown in Figure 5.31A. Line c indicates the
ing reflected frequency is the same as the original transmit- orthogonal image plane shown in Figure 5.32A. PA, pulmonary
ted frequency. When sound returns from a moving target, artery.
however, the reflected frequency is higher than the transmit-
ted frequency if the target is moving toward the receiver. In
medical ultrasound, the transducer is both the sound emitter
and sound receiver. The reflected sound has a lower fre-
quency if the target is moving away from the receiver. Known
as the Doppler shift,
 i n t roduct ion to echoc a r diogr a ph y 115

A B
FIGURE 5.30. (A) Long-axis view of the aortic root and ascending right ventricular outflow-tract collapse indicating associated peri-
aorta in a patient with Type A aortic dissection (arrow). The intimal cardial tamponade; black arrowhead, left coronary artery ostium;
flap extends proximally to the right coronary artery ostium (black single arrow, dissection flap within the right coronary sinus of Val-
arrowhead). Double arrows, pericardial effusion; LA, left atrium; salva; double arrows, right atrial compression; FL, false lumen; LA,
RA, right atrium. (B) Short-axis view of the aortic root. *, partial left atrium; TL, true lumen.

A B

FIGURE 5.31. Transesophageal “bicaval” views. (A,B) Similar anatomy,

but view A optimizes tricuspid-valve visualization (downward arrowhead)
and is useful for Doppler interrogation. IVC, inferior vena cava; LA, left
atrium; RAA, “broad-based” right atrial appendage; SVC, superior vena
cava. View B shows the thin fossa ovalis (single arrow) which, in this case,
is patent. Arrowhead, eustachian valve of the IVC; bracket, patent fossa
ovalis (PFO) tunnel. (C) Intravenous agitated saline contrast bubbles
transit from the right atrium (RA) to the left atrium (double arrows) via
the PFO on relaxation of a Valsalva maneuver. The RA and superior vena
cava (SVC) are completely “opacified” by intravenous injection of saline
contrast. C
116 chapter
A B
FIGURE 5.32. Transesophageal view of the superior pulmonary
veins. (A) The right superior pulmonary vein (arrow) with the pulsed
Doppler sample volume approximately 1 cm inside the os; adjacent
is the right-sided superior vena cava (SVC). LA, left atrium; RA,
Doppler shift (Hz) = Reflected frequency − Transmitted
frequency,
this physical principle explains why a stationary listener
notices an abrupt fall in the pitch of an approaching train’s
whistle just after the train passes and begins to move away.
The velocity of a moving insonated target (e.g., blood cells or
the myocardium in motion) can be calculated by using the
Doppler equation to analyze the returning sound frequency
initially emitted from the transducer:
Sound propagation speed × Doppler shift
Velocity =
2 × Transmitted frequency × cos ∅
If blood is moving parallel (coaxial) to the interrogating
sound beam, the complete Doppler shift is measured and an
A B
FIGURE 5.33. Transesophageal view of the left atrial appendage
(LAA). The “narrow-based” LAA is imaged in both the horizontal
(A) and the vertical (B) plane. A normal prominent “reflection” of
5
right atrium. (B) The left superior pulmonary vein (arrow) lies
immediately posterior to the left atrial appendage (LAA). LA, left
atrium; LV, left ventricle.
accurate velocity reported (since cos 0 degrees = 1). When the
path of a moving insonated target is not parallel to the inter-
rogating sound beam, the reported velocity will be lower
than the true velocity, proportional to cos ∅ of the intercept
angle between the ultrasound beam and the true direction
of blood movement:
Measured velocity = True velocity × cos ∅
Because cos 20 degrees = 0.94, Doppler alignment errors of
<20 degrees will result in a velocity measurement error of
<6%, which is acceptable without correction in most clinical
situations. Note that because cos 60 degrees = 0.5, an inter-
cept angle of 60 degrees will yield only half of the true veloc-
ity, and an intercept angle of 90 degrees (cos 90 degrees = 0)
will produce no measurable blood-flow velocity (Fig. 5.23B).
left atrial tissue (*) is seen between the LAA and the left upper pul-
monary vein (LUPV). Ao, aortic root; LA, left atrium; LV, left
ventricle.
 i n t roduct ion to echoc a r diogr a ph y 117

FIGURE 5.34. Transesophageal view at the gastroesophageal junc- FIGURE 5.35. Transgastric image of the left ventricle in the short-
tion. Arrowhead, coronary sinus in long axis, showing entry into axis view at the papillary muscle level. AL, anterolateral papillary
the right atrium (RA). Compare with TTE image, Figure 5.13C. LV, muscle; LV, left ventricle; PM, posteromedial papillary muscle; RV,
left ventricle; RV, right ventricle. right ventricle.

A B
FIGURE 5.36. Transgastric image of the left ventricle in the short- endocardial definition improved. Upper arrowhead, inferior wall;
axis view at the papillary muscle level. (A) Fundamental frequency lower arrowhead, anterior wall. Line a indicates the orthogonal
imaging mode: the result is technically poor, with an attenuated image plane shown in Figure 5.37A. Line b indicates the orthogonal
image and a low signal-to-noise ratio. (B) Tissue harmonic imaging image plane shown in Figure 5.37B. LV, left ventricle; RV, right
mode in the same patient. Intracavitary “noise” is decreased and ventricle.

A B
FIGURE 5.37. Transgastric long-axis views of the left and right Right ventricle: normal tricuspid valve chordae tendineae arise from
ventricles. (A) Left ventricle (LV): normal mitral valve chordae ten- the right ventricle (RV) anterior papillary muscle (*). RA, right
dineae arise from the posteromedial (*) and anterolateral (arrow) atrium.
papillary muscles. LA, left atrium; LAA, left atrial appendage. (B)
 118 chapter 5

A B

FIGURE 5.38. (A) Deep gastric view of the left ventricle (transducer angle
approximately 0 degrees). This view enables coaxial Doppler evaluation
of the left ventricular outflow tract by means of transesophageal echocar-
diography. See Figure 5.13B for the analogous surface echocardiography
view. Ao, aorta; LV, left ventricle; RVOT, right ventricular outflow tract.
(B) Color Doppler image of the left ventricular outflow tract with an
appropriately placed pulsed-Doppler sample volume (arrow). (C) A modi-
fied transgastric long-axis view of the left ventricle (LV), often at a trans-
ducer angle of >90 degrees, frequently enables Doppler evaluation of the
left ventricular outflow tract (arrow) when the deep gastric view is not
C possible. Ao, aortic root; LV, left ventricle.

A B
FIGURE 5.39. Transgastric image of the left ventricle, in the short- the orthogonal TEE imaging plane shown in Figures 5.26C and
axis view, at the mitral valve level. (A) Mitral valve posterior leaflet: 5.27A (bicommissural view). AL, anterolateral commissure; PM,
anterior (P1), middle (P2), and posterior (P3) scallops; mitral valve posteromedial commissure; RV, right ventricle. (B) Obtaining a
anterior leaflet: anterior (A1), middle (A 2), and posterior (A 3) seg- color-Doppler image at this level is important. In this same patient,
ments. This view is important for localizing mitral regurgitation it shows significant functional regurgitation along the entire zone
lesions. Compare with TTE image, Figure 5.10B. Line a indicates of mitral leaflet coaptation.
 i n t roduct ion to echoc a r diogr a ph y 119

A B

C D
FIGURE 5.40. Transesophageal views of the descending thoracic pleural effusion. (C) Normal left subclavian artery (arrow) at the level
aorta. (A) Normal aorta. (B) Grade II calcified atheroma (arrowhead) of the aortic isthmus. (D) Descending thoracic aorta in long axis, with
in the mid-descending thoracic aorta. *, atelectatic lung; **, large left complex atheroma and mobile atherosclerotic “debris” (arrow).

Because the exact path of the blood flow cannot be precisely
determined, even with anatomic guidance, velocity mea-
surements are determined from several different imaging
locations so that the highest values can be used.
Spectral Doppler
Spectral Doppler imaging comprises two modalities: con-
tinuous wave (CW) and pulsed wave (PW). On the spectral
Doppler display, Doppler shift–derived velocities moving
toward the transducer appear as positive deflections above
the baseline (see Fig. 5.14B). Flow velocities moving away
from the transducer are displayed below the baseline (see Fig.
5.18C).
Continuous-Wave Doppler
Basic Concepts. Continuous-wave Doppler uses a dedi-
cated crystal to continuously transmit signals while an adja-
cent crystal continuously receives the reflected signals. This
modality has the advantage of being able to measure the
high-frequency shifts and corresponding high-velocities
(>7 m/s) created by obstructive or regurgitant orifices. Con-
tinuous-wave Doppler examination has the disadvantage of
range ambiguity, because velocities anywhere along the
interrogating beam are displayed. Range ambiguity can be
problematic when serial obstructive lesions occur along the
line of interrogation [e.g., in combined dynamic left ventricu-
lar outflow-tract (LVOT) obstruction and aortic valve steno-
sis]. Barring the presence of serial stenoses, the highest
recorded velocities may be assumed to arise from the obstruc-
tive orifice in question. The CW Doppler modality is inte-
grated along with pulsed-wave Doppler in an imaging
transducer. This may be useful for positioning the interrogat-
ing beam with anatomic and color Doppler guidance.
However, the true direction of a jet lesion within the ana-
tomic orifice may be difficult to judge with either anatomic
or color Doppler guidance. Superior CW spectral Doppler
envelopes are recorded with a dedicated nonimaging trans-
ducer (Fig. 5.4B), which has a smaller footprint that is more
easily brought into coaxial alignment with jet lesions, using
a variety of surface windows.
12 0 chapter
Continuous-Wave Doppler and the Pressure-
Velocity Relationship. When blood crosses a small,
restricted orifice (e.g., stenotic valve, incompetent valve, or
ventricular septal defect), its velocity increases relative to
the pressure difference between the two chambers. The peak
instantaneous pressure drop across a narrow orifice is calcu-
lated with the simplified Bernoulli equation:
ΔP = 4V 2
where the peak velocity (V) is derived from the CW spectral
Doppler display (Fig. 5.17B). Mean pressure gradients are
determined by calculating the instantaneous pressure gradi-
ent (4V 2) at multiple time intervals during the flow period
and by averaging the results. Echocardiography machines
and off-line analysis programs automatically calculate peak
instantaneous and mean pressure gradients in millimeters
of mercury (mm Hg) when the CW Doppler spectral envelope
is manually outlined with a tracker ball (Fig. 5.18D). With
CW Doppler, the spectral display has a characteristically
“filled-in” appearance because of turbulent blood flow; a
large number of velocities occur at all points below the peak
instantaneous velocities represented by the envelope’s outer
edge (Figs. 5.12D and 5.18D). Table 5.4 lists the sites routinely
used for CW Doppler interrogation. The CW Doppler pres-
sure-velocity relationship is used to measure pressure gradi-
ents across obstructed valve orifices, ventricular septal
defects, and dynamic left and right ventricular outflow
obstructive lesions, as well as to identify and qualitatively
assess severity of valve regurgitation lesions.
Pulmonary Artery Pressure Calculation. The peak
right ventricular systolic pressure (RVSP) is routinely calcu-
lated with the simplified Bernoulli equation, as this approach
yields highly useful information, and up to 80% of individu-
als have at least trivial tricuspid regurgitation (TR), the
velocity of which (VTR) may be measured by CW Doppler. In
the absence of right ventricular outflow obstruction, the
peak systolic pulmonary artery pressure (SPAP) is the sum
of the RVSP and the estimated right atrial pressure
(RAP)149:
RVSP = 4VTR2
SPAP = 4VTR2 + RAP
The RAP can be determined by measuring the degree of
inferior vena cava (IVC) collapse approximately 2 cm from
the IVC–right atrium (RA) junction (subcostal view) during
normal inspiration or a “sniff” (Fig. 5.21; Table 5.3).150 During
positive-pressure mechanical ventilation, a small, collapsing
IVC indicates a low RAP, although an enlarged and noncol-
lapsing IVC does not necessarily indicate an elevated RAP
under this circumstance.151 When the TR velocity is faint, its
spectral Doppler envelope can be enhanced by intravenous
injection of agitated saline solution during interrogation.152
The peak CW Doppler-derived gradient of the pulmonary
valve insufficiency (PI) jet (4V PI2), also measurable in most
patients, has been shown to approximate the mean pulmo-
nary artery pressure153:
Mean PAP = 4(VPI)2
5
TABLE 5.4. Routine sites for continuous-wave Doppler
examination
Parasternal long axis, RV inflow tract TV
Parasternal short axis (at AoV and RVOT TV, PV
level)
Apical four-chamber TV, MV
Apical five-chamber LVOT
Apical three-chamber LVOT, MV
Subcostal* AoV (if AS*)
Sternal notch Descending Aorta,
AoV* (if AS)
Right parasternal* AoV* (if AS)
Modified apical* TV if difficult TR
velocity*
* Add if a pathologic condition is detected. It is desirable to repeat the evalu-
ation with a nonimaging probe for accurate V TR and for left-sided valve
obstructive lesions (i.e. AS, MS).
AoV, aortic valve; AS, aortic stenosis; LVOT, left ventricular outflow tract;
MV, mitral valve; PV, pulmonary valve; RV, right ventricular; RVOT, right
ventricular outflow tract; TR, tricuspid regurgitation; TV, tricuspid valve.
Pulsed Doppler
Basic Concepts. In pulsed Doppler mode, the piezoelec-
tric crystal alternates between sending and receiving at a
defined pulse repetition frequency. After sending out an
ultrasonic pulse, the machine “knows” when to listen for
the returning signal by calculating the send and receive time
of flight to the desired depth at which the Doppler frequency
shift is to be measured. The sonographer chooses the Doppler
depth by placing a sample volume in a desired location, using
the image sector for anatomic guidance (Figs. 5.12C, 5.14B,C,
5.15A,B,C, and 5.18A). Range discrimination is an inherent
property of pulsed Doppler mode because the blood velocity
is measured at a known distance from the transducer. The
maximum blood speed that can be measured with pulsed
Doppler at a given depth is called the Nyquist limit, which
is half the pulse repetition frequency. When blood velocities
exceed the Nyquist limit, the spectral Doppler display erro-
neously indicates that blood is moving in the wrong direc-
tion. This phenomenon is called aliasing (see Fig. 5.14C for
pulsed Doppler aliasing and Figs. 5.12A and 5.18A,B for color
Doppler aliasing). For practical purposes, pulsed Doppler
mode can unambiguously measure blood flow velocities of
up to about 2 m/s at normal imaging depths. With normal
laminar flow, the typical pulsed Doppler spectral envelope
has bright edges and a dark center (Fig. 5.18C). This is because
all the blood cells within the sample volume are moving in
the same direction and at roughly the same velocity, as rep-
resented by bright spectral envelope edges. The principal
applications for pulsed Doppler mode are assessing cardiac
output, regurgitant volumes, shunts, and diastolic function.
Table 5.5 indicates standard sites for pulsed Doppler
evaluation.
Stroke Volume and Cardiac Output. Where laminar
flow is present, the instantaneous flow rate is the product of
the cross-sectional area (CSA) and the instantaneous flow
velocity (cm/s) at the same site. Integrating the area under a
pulsed Doppler flow-velocity curve yields the time-velocity
integral (TVI) distance, reported in centimeters. The TVI
 i n t roduct ion to echoc a r diogr a ph y
TABLE 5.5. Routine sites for pulsed Doppler examination
Parasternal short axis, RVOT RVOT/PV annulus
level
Apical four-chamber MV leaflet tips and MV
annulus, right superior
pulmonary vein
Apical five-chamber LVOT
Apical three-chamber LVOT
Subcostal Hepatic vein, aorta* (if AI)
Sternal notch Descending aorta at isthmus
* Add if a pathologic condition is detected.
AI, aortic insufficiency; LVOT, left ventricular outflow tract; MV, mitral
valve; PV, pulmonary valve; RVOT, right ventricular outflow tract.
indicates the distance a volume of blood would travel during
the flow period within a conduit that has a certain CSA. The
flow during a cardiac cycle (stroke volume) can be calculated
by multiplying the CSA of a conduit by the integrated flow-
velocity curve (TVI) distance.
Left Ventricular Outflow Tract. Integrating the
area under the LVOT pulsed-Doppler velocity curve yields
the LVOT TVI in centimeters (Fig. 5.18C). It is valid to assume
that the normal LVOT is circular (CSA = π r 2 = D 2 × π/4 = D 2
× 0.785) (r = radius). The LVOT diameter (D) is measured in
the parasternal long-axis view (Fig. 5.7B). The LVOT area,
stroke volume (SV), and cardiac output (CO) can be calcu-
lated as follows:
CSA = D 2 × 0.785
SV (cm3) = CSA (cm2) × TVI (cm)
CO = SV × HR
Right Ventricular Outflow Tract. The right ven-
tricular outflow tract (RVOT) stroke volume and cardiac
output are obtained in analogous fashion, using the equa-
tions shown above (see Fig. 5.11B for the RVOT diameter and
Fig. 5.12C for the RVOT TVI). The RVOT diameter measure-
ment, obtained in the parasternal short-axis view (Fig. 5.11B)
may be less reliable than the LVOT diameter measurement
because of a somewhat retrosternal RVOT location that can
cause lateral RVOT image “dropout” from sternal or rib
shadowing.
Mitral Annulus. The mitral annulus stroke volume
and cardiac output are obtained in analogous fashion (see Fig.
5.14A for mitral annulus diameter and Fig. 5.14C for mitral
annulus TVI). The mitral annulus diameter (Fig. 5.14A) may
be difficult to measure if annular calcification or some other
leaflet deformity impairs leaflet motion. Although the mitral
annulus is elliptical and not circular, the four-chamber view
places the annulus dimension between the major and minor
mitral axes of the valve’s ellipse. This may explain why
assuming a circular mitral annulus has proved valid when
using the four-chamber annulus diameter. Note that pulsed
Doppler readings obtained at the mitral leaflet tips cannot
be used for calculating mitral valve flow because the leaflet-
tip orifice area (which is smaller than the annular orifice
area) cannot be reliably measured.
121
Technical Notes. In sinus rhythm, stroke volumes are
ideally calculated from 3 to 5 averaged TVIs. In irregular
rhythms (atrial fibrillation), stroke-volume calculations
should be derived from 5 to 10 averaged TVI measurements.
Premature ventricular contraction (PVC) and post-PVC cycles
should be excluded. Precise diameter measurements are
essential because this linear variable is squared during flow
calculations, so any error is compounded. Ideally, three
diameter values are obtained from different cycles to ensure
reproducibility. With satisfactory data, comparison of the
LVOT and RVOT stroke volumes can be used to calculate
right-to-left shunts (QP = pulmonary flow, QS = systemic
flow). The CO can be measured at rest or during exercise or
pharmacologic interventions. The outflow tract CSA and
TVI measurements are essential components of valve-area
calculations using the continuity equation. In addition, the
LVOT or RVOT stroke volume (in the absence of reference
valve-insufficiency lesions) may be subtracted from the
mitral annular stroke volume to calculate the mitral regur-
gitant volume. An aortic valve regurgitation volume may be
calculated in analogous fashion using the RVOT or mitral
annulus forward stroke volume as a reference value (in the
absence of significant reference-valve regurgitation).
Color-Flow Doppler
Color-flow Doppler is a multigated pulsed Doppler technique
that is valuable for visualizing overall flow patterns within
the heart and great vessels. Instead of measuring the direc-
tion and velocity of flow at a specific location (as with spec-
tral Doppler), this method assigns colors to the pixels
throughout an anatomic region of interest, depending on the
measured flow direction and velocity. Color-flow informa-
tion is superimposed on the anatomic gray-scale image so
that flow patterns can be correlated with the anatomy. Cal-
culating the velocity shift at numerous sites in “real time”
requires considerable computing speed. With older machines,
the color-flow sample rate can be unacceptably slow (i.e.,
<12 fps) when color sectors are too large. With parallel pro-
cessing, newer machines largely eliminate this concern. A
color map (Figs. 5.12B and 5.23B, upper right of images) is
shown alongside the anatomic image, indicating the direc-
tion of flow. Typically, blue (at the bottom of the map) indi-
cates flow away from the transducer, and orange/red (at the
top of the map) indicates flow toward the transducer (“BART”
= blue away, red toward). The number at either end of the
color map indicates the color-Doppler Nyquist limit, which
is typically below 1 m/s and generally set in the range of 50
to 60 cm/s for detecting and analyzing regurgitant lesions.
Color-Doppler aliasing is extremely common, because
normal intracardiac blood velocities often exceed 60 cm/s.
When this happens, the color abruptly changes to the hue
assigned to flow moving in the opposite direction. This color
“wraparound” effect clearly delineates flow-velocity bound-
aries, thereby identifying zones of mild acceleration (e.g., at
a valve annulus) (Figs. 5.12A and 5.18A,B) and proximal flow-
convergence zones associated with regurgitant lesions (see
Chapter 21). When blood flow is exactly tangential to the
direction of the interrogating beam, no color (black) is dis-
played (Fig. 5.23B). Color-Doppler mode is highly sensitive in
detecting (if not quantitating) regurgitant jet lesions, because
12 2 chapter
turbulent high-velocity flow is labeled with an easily recog-
nizable speckled or mosaic color pattern (Fig. 5.39B). Color-
Doppler gain and Nyquist-limit settings are easily adjustable;
they can markedly affect color-Doppler results and their
interpretation. Color-Doppler mode is beset by numerous
potential artifacts, which cannot be reviewed here. Addition-
ally, its appearance varies, depending on the equipment
manufacturer.
Tissue Doppler
Tissue-Doppler is analogous to pulsed Doppler assessment
of blood flow velocity. Instead of being placed in the blood
pool, however, the tissue Doppler sample volume is placed
in a myocardial segment (Figs. 5.16 and 5.41C). Appropriate
filters are applied so that only the high-amplitude but rela-
tively low velocities inherent in myocardial motion are
included. Tissue-Doppler studies are usually performed in
the apical views because longitudinal myocardial motion is
coaxial to the interrogating beam in this situation. Longi-
tudinal descent of the cardiac base is an important indica-
tor of systolic function. A growing body of literature has
shown that even localized myocardial tissue Doppler can
provide important information about diastolic function.
Moreover, this information is less affected by loading condi-
tions than are blood flow pulsed Doppler filling patterns.
Tissue Doppler can be used to assess left ventricular fill-
ing pressures, to detect overt and subclinical cardiomy-
opathy, and to distinguish constrictive from restrictive
cardiomyopathy.39,45,46,56
Parametric Imaging
Tissue Doppler Imaging
New ultrasound technology allows extremely high-frequency
imaging and measurement of myocardial tissue velocities of
>100 fps within the imaging sector. The pixels that represent
the anatomic myocardium are color coded to depict the myo-
cardial direction and velocity throughout the cardiac cycle
(Figs. 5.41 to 5.44). This type of moving anatomic and func-
tional display (TDI) is a parametric imaging modality.105
Changing color patterns within the anatomic image can
indicate regions of myocardial dysfunction with a sensitivity
potentially surpassing that of traditional gray-scale myocar-
dial wall-motion analysis. When one or more sample volumes
(Figs. 5.42 and 5.44C) are placed within the myocardium,
relatively high-fidelity curvilinear graphs of the average lon-
gitudinal myocardial velocity can be generated. Comparison
of the time-to-peak longitudinal velocities measured in
opposing myocardial segments may be an adequate proxy for
identifying dyssynchronous mechanical systole that may be
improved by cardiac resynchronization therapy (CRT) in
heart failure patients (Fig. 5.44).117–122
Curved Anatomic M-Mode Display
Curved anatomic M mode is a newer myocardial Doppler
imaging format that can show the timing of myocardial
motion (velocity) throughout a selected “length” of myocar-
dium (Fig. 5.43). Other forms of myocardial physiologic data
5
(e.g., strain, strain rate) can be displayed in anatomic M-mode
format so that physiologic conditions within different myo-
cardial segments can be displayed simultaneously (Figs. 5.45,
5.46, and 5.47).
Tissue Synchronization Imaging
Tissue synchronization imaging (TSI) is a relatively new
term for images produced by color coding myocardial pixels
with time-to-peak velocity values derived from TDI data.
Color values for delayed time-to-peak velocity values are
somewhat arbitrarily determined, but this method calls
attention to myocardial segments that contract late because
of conduction abnormalities or “dyssynchrony” (Figs. 5.44D
and 5.45).
Myocardial segments that do not contract or thicken
(i.e., scarred or hibernating myocardium) may exhibit con-
siderable translational motion because of tethering by adja-
cent contracting segments. Thus, one possible pitfall is that
TDI will encode tethered nonviable (scarred) segments or non-
contracting but viable segments (hibernating myocardium)
with velocity information. In this case, TDI erroneously
gives nonviable segments the appearance of contractility
where there is none. Another TDI-based modality that may
address this contractility problem is strain-rate imaging.
Strain, Strain Rate, and Strain-Rate Imaging
Derived from Doppler106–111
These additional imaging modes are derived from the myo-
cardial TDI velocity information discussed above. The con-
cepts of strain and strain rate are not new. However, the
recent commercial availability of their ultrafast derivation
and myocardial parametric display could produce a number
of clinically useful applications.
Strain is another word for deformation. Strain can be
calculated as the change in length (L) between two points
within a myocardial segment (L − L o) divided by the original
length (L o).
Strain = (L − Lo)/Lo
In normal myocardium, L (systolic length) is shorter than the
“original” diastolic length (L o). Therefore, normal myocar-
dium has negative systolic strain (because of segmental
shortening) and positive diastolic strain (because of segmen-
tal lengthening) (Fig. 5.46). When regional myocardial defor-
mation does not occur (L = L o), strain is zero, indicating an
absence of contractility regardless of whether the segment
is moving through space because of tethering. Strain is
expressed as a percentage of L o.
The strain rate is the speed at which regional myocardial
shortening or lengthening occurs. The strain rate is calcu-
lated from the myocardial tissue Doppler velocities (V)
obtained from two nearby points (V1 and V2) separated by a
distance L.
Strain rate = (V2 − V1)/L
The strain rate is also called the instantaneous spatial
velocity gradient, which is the rate at which two points are
approaching each other because of myocardial thickening
(during contraction) or moving further apart because of myo-
 i n t roduct ion to echoc a r diogr a ph y
A B
C
FIGURE 5.41. Normal tissue Doppler image in the apical four-
chamber view. (A) Normal, synchronous systolic longitudinal myo-
cardial motion toward the transducer produces a uniform orange-red
appearance. Upper right: the upward arrow next to the color scale
indicates myocardial motion toward the transducer. Lower left: The
upward arrow shows late systolic timing of the acquired image. (B)
Normal, synchronous diastolic longitudinal myocardial motion
away from the transducer produces a uniform blue appearance.
cardial lengthening. Strain is the time integral of the strain
rate (much as TVI is the time-velocity integral of the Doppler
flow-velocity curve over time). Because strain is produced by
shortening of the myocardial fibers, strain and strain rate
may be better indicators of myocardial contractility than is
the tissue-velocity information from which these parameters
are derived.
One pitfall of Doppler-derived strain measurements of
myocardial tissue is that this method can effectively describe
only longitudinal strain of the basal and midventricular seg-
ments from the apical views. This is because (as explained
above) pulsed Doppler imaging is accurate only in a direction
coaxial to the interrogating ultrasound signal. Ventricular
longitudinal shortening is only one of the three vectors that
describe myocardial motion. Inward myocardial motion
(radial thickening) and left ventricular torsional motion (cir-
cumferential shortening, which is prominent in the apex)
may also be described by radial and circumferential strain,
12 3
(Upper right) The downward arrowhead next to the color scale indi-
cates myocardial motion away from the transducer. (Lower left) The
downward arrowhead shows early diastolic timing of the acquired
image. (C) Tissue Doppler sample volume located in the basal lateral
wall (arrowhead), with corresponding tissue spectral Doppler
tracing. The arrow and arrowhead depict the direction and timing
of the images shown in views A and B.
respectively, so Doppler-derived longitudinal strain imaging
can show only part of the picture.
Strain and Strain-Rate Imaging by Means of
Speckle Tracking
Speckle tracking is a new modality that is still undergoing
clinical experimental validation. Discrete, brightly echoic
intramyocardial pixels can be “recognized” by the echocar-
diography device and tracked during the cardiac cycle. The
distance through which nearby speckles approach each
other (strain) and the rate at which this is accomplished
during the cardiac cycle (strain rate) may be derived from
the longitudinal, circumferential (torsional motion), or
radial inward motion of myocardial speckles (Fig. 5.48).
Though still in the early stages of clinical development, this
new modality may become an important tool for evaluating
myocardial health.
12 4 chapter
FIGURE 5.42. Tissue Doppler image of “opposing” segments of the
septal wall (yellow circle) and the lateral wall (green circle) in a
normal patient. Systolic myocardial motion inward, toward the
transducer, appears orange (upward arrow), and diastolic motion
outward, away from the transducer, appears blue (downward arrow-
head), as in Figure 5.41. The graph at right indicates the average
FIGURE 5.43. Tissue Doppler image in curved anatomic M-mode
format in the same (normal) patient shown in Figures 5.41 and 5.42.
This format shows simultaneous myocardial velocity readings, as
defined by the color scale along a defined line of myocardium from
5
spectral Doppler velocity pixel intensity displayed over time. Simul-
taneous display of the septal wall (yellow line) and lateral wall
(green line) average velocity curves, which show near-synchronous
achievement of peak velocity values (upward arrow) by the opposing
segments, as well as a synchronous negative directional peak veloc-
ity (downward arrowhead).
the basal to the middle and apical septum. Three cardiac cycles are
shown. Uniform timing of the red-to-blue color change from systole
(S) to diastole (D) indicates a synchronous myocardial velocity
change along the entire septum.
 i n t roduct ion to echoc a r diogr a ph y
A B
C D
FIGURE 5.44. Myocardial dyssynchrony, as shown by tissue
Doppler imaging (apical four-chamber view) in a patient with left
bundle-branch block. (A) Early systolic septal motion toward the
transducer (red), with simultaneous lateral wall motion away from
the transducer (blue). (B) Late systole in the same cardiac cycle,
showing septal motion away from the transducer and simultaneous
delayed lateral wall motion toward the transducer (red). (C) Simul-
taneous time plots of the mean tissue velocities within septal
(yellow circle) and lateral-wall (green circle) sample volumes confirm
an early septal time-to-peak velocity (left arrow, yellow curve) and
Methods for Improving Two-Dimensional
Imaging
Tissue Harmonics
Fundamental frequency imaging involves creating an image
by processing reflections that have the same frequency as the
originally transmitted frequency. Until the late 1990s, this
modality was the only 2D option that was commercially
available. Sound frequencies that are multiples of the funda-
mental frequency are known as harmonic frequencies. If the
fundamental transmitted frequency is 2.5 MHz, the second
harmonic frequency is 5 MHz (2 × 2.5 MHz). Because sound-
waves behave nonlinearly as they pass through tissues, the
waves produce harmonic frequencies that, until recently,
were not “listened for” by ultrasound machines. Although
this sound energy is minute, it undergoes less distortion than
the fundamental frequencies, so it is used to great effect for
distinguishing tissue signals from noise. The tissue-har-
12 5
a markedly delayed lateral-wall time-to-peak velocity (right arrow,
green curve). Ventricular longitudinal motion between the opposing
segments is discordant or “dyssynchronous.” (D) In the same patient,
a novel myocardial Doppler imaging format uses an automated
time-to-peak delay color scale to effectively show the heterogeneous
left ventricular contractile pattern. Segments with delayed time-to-
peak velocities (>400 ms) are shown in orange (see color scale). Auto-
mated time-to-peak velocity calculations of four myocardial
segments (+’s) are shown in the table [basal septum (1 BS); middle
septum (2 MS); midlateral (3 ML); basal lateral (4 BL)].
monic mode has greatly enhanced endocardial detection and
improved both routine and stress echocardiographic surface
imaging in patients with previous “technically” difficult
exams (Figs. 5.19A,B and 5.36A,B). However, this mode may
make valve leaflets and other easily imaged thin structures
appear unusually thickened even when they are normal in
reality; this illusion is due to the fact that, compared with
fundamental frequency imaging, harmonic imaging has an
increased pulse length requirement. With experience, echo-
cardiographers have learned to “read through” this phenom-
enon and to refrain from calling normal leaflets thickened
because of their appearance in this mode.
Contrast Echocardiography
To clarify the left ventricular endocardial border and improve
spectral Doppler signals, the examiner can intravenously
administer microbubbles, sometimes called microspheres or
12 6 chapter 5

A B

C
FIGURE 5.45. Three-dimensional tissue Doppler imaging: acquisi- three-chamber (C) views. In this case, delayed time-to-peak longi-
tion of a three-dimensional volumetric data set allows the simulta- tudinal velocities are clearly localized to the mid-distal anterior
neous display of apical four-chamber (A), two-chamber (B), and septum and inferior walls (arrows, orange).

A B
FIGURE 5.46. Doppler-derived longitudinal strain rate imaging in ation. Positive strain rate periods: SRE; early diastolic “E” strain
the septum (apical four-chamber view) of a healthy 30-year-old man. rate; SRA, late diastolic “A” strain rate. (B) Anatomic M-mode dis-
A narrow imaging sector was used to maximize the sample rate plays the strain rate throughout the entire septum during a single
(185 fps in this case). (A) Localized strain-rate analysis within an cardiac cycle. Yellow indicates negative strain (myocardial longitu-
oval sample volume, middle septum. Negative strain-rate period dinal shortening/compression rate), while blue indicates a positive
(myocardial shortening): SR IVCT, strain rate of isovolumic contrac- strain rate (myocardial longitudinal lengthening rate).
tion; SRS, systolic strain rate; SR IVRT, strain rate of isovolumic relax-
 i n t roduct ion to echoc a r diogr a ph y 12 7

FIGURE 5.47. Strain rate imaging (SRI) using the speckle tracking
method [two-dimensional (2D) strain] in the left ventricular para-
sternal short-axis view. The circumferential (A, arrows), radial (B,
arrows), and longitudinal (not shown) components of myocardial
strain and strain rate can be analyzed with this method. Color-coded
dots on the anatomic M-mode display (lower left) correspond to dots
placed on discrete myocardial segments of the 2D image (upper left)
and the colored lines of the mean strain-rate plot (on right), allowing
regional SRI comparison.

ultrasound contrast agents as an adjunct to the routine

examination. Microspheres (diameter = 2.5 to 4.0 μm) are
smaller than red blood cells (diameter, 6 to 8 μm), transit the
pulmonary circuit, and variably persist in the circulation,
depending on their shells and the physical properties of the
contained gas. Microspheres strongly reflect fundamental
imaging frequencies and also resonate within ultrasonic
fields, producing relatively strong harmonic frequencies. As
a result, microspheres are hyperechoic in the bloodstream
and “light up” the cardiac chambers, improving detection of
the left ventricular endocardial border. Because more than
half of all echocardiograms are obtained to assess left ven-
tricular function and because 5% to 25% of examinations
(depending on a number of factors) are “suboptimal” for accu-
rately assessing all endocardial segments, the clinical use of
contrast agents, particularly for stress echocardiography, has
increased dramatically. The first FDA-approved agent con-
sisted of an albumen shell containing air. Air is highly
soluble in blood, however, so it rapidly leaks out of the micro-
sphere, causing rapid bubble shrinkage and relatively poor FIGURE 5.48. Apical-window three-dimensional volume data set
representation. “Anyplane” two-dimensional images (apical four-
microsphere persistence in the circulation. Newer FDA- chamber, two-chamber, and short-axis views) have been selected
approved contrast agents have less permeable shells that are retrospectively for simultaneous moving-image display and subse-
filled with high-molecular-weight inert gases with low solu- quent volume and segmental wall-motion analysis.
12 8 chapter
bility; these agents persist longer154 and have greater clinical
utility for left ventricular opacification.
Technical Notes
CONTRAST A RTIFACTS
An ultrasound field with sufficient energy (power) will
destroy exposed circulating microspheres. The ultrasound
system’s power-output setting must be adjusted downward
during contrast imaging to avoid apical swirling, which may
be particularly prominent with low-flow states such as
dilated cardiomyopathy or an apical aneurysm. With local
bubble destruction, absence of near-field left ventricular con-
trast can be mistaken for an apical mural thrombus. On the
display screen, the ultrasound system’s power output is
shown as the mechanical index (MI), which is a unitless
indicator of the negative acoustic pressure within an ultra-
sound field. To achieve relatively uniform blood-pool con-
trast, the MI should be reduced to ≤0.5.
CONTRAST ATTENUATION
This is another common artifact that occurs when overly
concentrated bubbles “overreflect” the ultrasound signal at
shallow depths, obscuring the blood pool at greater depths.
Because of limited contrast persistence and eventual dilu-
tion, attenuation is a transient phenomenon. It can be mini-
mized by gradual contrast injection. Alternatively, image
acquisition can be delayed until the attenuation resolves.
Left ventricular attenuation in the parasternal views can
occur because of overlying contrast material within the
intervening right ventricular chamber, so apical windows are
generally superior for left ventricular contrast echocardiog-
raphy. Other important contrast echocardiography artifacts
exist, and they warrant further detailed study.
Contrast Harmonics
When used with fundamental frequency imaging alone, con-
trast echocardiography improves left ventricular endocar-
dial-border detection. Modern ultrasonographic systems are
also configured to image contrast agents in “harmonic mode”
by transmitting at one frequency (e.g., 2 MHz) and construct-
ing images based only on the returning first harmonic fre-
quency (e.g., 4 MHz for a transmitted frequency of 2 MHz).
Because high-amplitude fundamental frequencies that return
from the soft tissue are “ignored,” the myocardium appears
very dark owing to its relative lack of contrast. Conversely,
the adjacent blood pool is very bright, as it is populated by
high concentrations of microspheres emitting harmonic fre-
quencies. Contrast harmonic mode improves the diagnostic
accuracy of endocardial border detection (Fig. 5.19C), includ-
ing identification of segmental wall-motion abnormalities
and assessment of left ventricular volume. This mode can
also be used to detect luminal filling defects caused by
thrombi.
Color-Scale (B-Color) Imaging
The echocardiograph machine produces a gray-scale image
based on the intensity of the returning signal within a
defined dynamic range. Whereas the most intense echoes
5
appear almost white, the weakest processed signals are
darkest gray. The familiar gray-scale display allows interpret-
ers to roughly distinguish certain tissue types (e.g., scarred
or calcified tissue is usually much brighter than normal
myocardial or leaflet tissue). Manufacturers routinely provide
a “colorized” gray-scale option, also referred to as pseudo-
color or B color (not to be confused with B-mode imaging).
Although resultant recruitment of the high-resolution retinal
cone receptors is theoretically beneficial for recognizing
faint structures (endocardial borders, thrombus, etc.), this
modality is probably only equivalent to gray-scale imaging,155
and its use is based mainly on the examiner’s choice and the
ambient lighting conditions. In our laboratory, selective B
color is used according to sonographer preference (Figs. 5.14C,
5.16, and 5.19C), although it is not used in combination with
color Doppler imaging, since color-flow Doppler information
can be obscured.
Three-Dimensional Echocardiography
The cardiac anatomy is complex, curvilinear, and constantly
moving. Throughout the cardiac cycle, its component
features change their configuration and position within
3D space. While observing the systematically acquired
2D images described previously in this chapter, experienced
echocardiographers, in effect, assemble a 3D construct of
the heart within their brain. Recording, measuring,
and conveying this construct to others is problematic,
however. In the right hands, 2D echocardiography is “good
enough” for many clinical purposes. Nevertheless, real-
time 3D echocardiography (sometimes referred to as four-
dimensional, given the additional time element) became
somewhat of a “holy grail” for echocardiographers. During
the 1990s, static 3D “birdcage” images utilized “spark-gap”
techniques. This approach was time-consuming and not
in real time, although it showed a parity between 3D echo-
cardiography with magnetic resonance imaging (MRI) for
determining left ventricular volume, ejection fraction,
and important anatomic relationships.156–158 The first recog-
nizable moving 3D anatomic reconstructions became
possible during the early 1990s, using painstaking methods
of sequential electrocardiographic and respiratory phase-
gated linear or rotational, incremental, sequential scanning
of planar digital images.159,160 These images, derived from
ordinary 2D imaging transducers, assembled the planar
data (pixels) into a 3D volumetric data set (voxels) for
off-line reconstructions. Because the data sets were acquired
from numerous different cardiac cycles (as in cardiac
MRI or ultrafast computed tomography) the potential for
motion artifacts was great. However, this phase of develop-
ment led to important imaging concepts, such as surface
renderings (Fig. 5.10C), and validation of 3D quantitative
methods.
Recently, after undergoing substantial evolution, real-
time 3D pyramidal volume data sets became obtainable at
acceptable resolutions and frame rates during single cardiac
cycles, without the need for sequential scanning methods.
Now available commercially, this technology is a descen-
dant of matrix-array transducer technology, as initially
described by Sheikh and associates.161 Currently, large-
 i n t roduct ion to echoc a r diogr a ph y
A B
FIGURE 5.49. Parasternal long-axis
three-dimensional volume data set rep-
resentation with simultaneous display
of orthogonal two-dimensional image
planes: left ventricular long- (A) and
short-axis (B) views from the same
cardiac cycles.
volume 3D data sets can be assembled from four cardiac
cycles recorded during a single breath-hold. Data from
each cycle are assembled, reducing the potential for a
motion artifact. Smaller-volume data sets can be acquired
from a single cardiac cycle, permitting high-resolution
morphologic analysis. Current 3D technology permits the
simultaneous display of orthogonal imaging planes selected
from within the volumetric data set. The instantaneous
display of “any-plane” 2D images enhances the viewer’s
appreciation of anatomic relationships and allows “optimal”
2D planar images (Figs. 5.45, 5.48, and 5.49) to be constructed
from a “volumetric” data set off-line, potentially streamlin-
ing image acquisition and avoiding apical foreshortening.
Color Doppler data may also be rendered in 3D, thereby
potentially improving the quantitation of regurgitant lesions.
However, both 3D and 2D imaging remains subject to the
same physical principles of ultrasonography, which can
result in artifacts. Application of various echocardiography
contrast and harmonic-imaging techniques, including 3D
Doppler and 3D parametric imaging, is under clinical
investigation.
Left Ventricular Assist Device Assessment
Several varieties of ventricular assist devices are either
under investigation or have been approved for clinical use.
The standard echocardiography examination, with certain
easy-to-perform modifications, is a viable means of follow-
ing up both device and native cardiac function.60,63,64,162,163
Routine anatomic and hemodynamic echocardiography
12 9
assessment is feasible. M-mode evaluation of the native
aortic valve (Fig. 5.50) during routine device “speed-change”
evaluations can be used to determine the cycle rate (pulsatile
pusher-plate devices) or impeller rotational speed (axial-flow
pumps) at which aortic valve opening ceases, indicating
complete device support. Pulsed and CW Doppler studies of
the device at both its inlet (Fig. 5.51A,B) and outlet (Fig.
5.51C,D) cannulas are done to assess pump performance. By
subtracting the pulsed Doppler-derived LVOT stroke volume
or cardiac output (see Doppler discussion, above) from the
RVOT cardiac output (total cardiac output), flow in the ven-
tricular assist device can be determined. Although few clini-
cal data exist, appropriate pump speed settings may be
selected accordingly.
The Digital Echocardiography Laboratory
Because an echocardiogram consists of a large volume of
moving-image data, super-VHS videotape has traditionally
been the most cost-effective review and archival medium.
However, thanks to recent advances in computer software
and hardware, echocardiography laboratories are rapidly
moving from the videotape era to the digital age. With digital
technology, the examination is broken up into a series of
discrete moving-image loops, each of which can be rapidly
retrieved and viewed as often as necessary for interpretation.
Digital loops from the current and previous exams may be
displayed side by side for comparison. Sharing digital exams
with colleagues is easy, causes no degradation in quality,
and can be done throughout a hospital or clinic via Picture,
13 0 chapter 5

A B

C D
FIGURE 5.50. Left ventricular assist device (LVAD) assessment. which decreases incrementally as the pump speed is increased, with
M-mode imaging of the aortic valve cusps in a patient with a con- shared left ventricular output between the device and the native left
tinuous axial flow left ventricular assist device during different ventricular outflow tract. In D, the aortic valve does not open, indi-
pump speed settings: (A) 8000 rpm; (B) 9000 rpm; (C) 10,000 rpm; (D) cating complete LVAD support. Note: Device inlet location = LV
11,000 rpm. Arrows (A–C) indicate the period of leaflet opening, apex; device outlet location = ascending aorta (not shown).

Archiving, and Collection System (PACS). In contrast, video-
tapes are difficult to retrieve from storage and can be lost or
broken. Videotape examinations can be reviewed only by
using time-consuming rewind and fast-forward procedures,
and video copying degrades the image quality. In addition to
its above-mentioned advantages, digital echocardiography
permits efficient off-line data analysis, reduces overall physi-
cian interpretation times, incorporates standardized report-
ing tools, and reduces storage needs. A digital echocardiography
laboratory facilitates quality-assurance measures. For all
these reasons, conversion to digital echocardiography is
desirable and cost-effective.5
Summary
Since its initial introduction more than 50 years ago, echo-
cardiography has emerged as the most frequently used cardiac
imaging technique. In many cases, it provides a definitive
anatomic and hemodynamic evaluation of simple and
complex cardiac pathology. Although generally safe, this
powerful technique is potentially subject to image acquisi-
tion and interpretation errors. Accordingly, a field of profes-
sional echocardiography has emerged to address matters of
continuing medical education, to establish training, prac-
tice, and quality-assurance guidelines, and to research emerg-
ing technologies and clinical applications. This chapter has
covered basic concepts regarding the physical principles of
ultrasound and has presented a spectrum of common clinical
applications. It has presented the basic transthoracic and
transesophageal echocardiography views as a basis for under-
standing subsequent echocardiography chapters within this
book. This chapter presents the modern echocardiography
machine as a potentially complex multimodal device. Many
of the newer imaging modes are not yet routinely performed.
However, their selected application, when appropriate, may
facilitate pathophysiologic diagnosis and thus improve
patient care.
 i n t roduct ion to echoc a r diogr a ph y
A B
C D
FIGURE 5.51. (A,B) Left ventricular assist device (LVAD) inlet
cannula assessment, apical four-chamber view. Color Doppler
(arrow, A) indicates exit of blood from the left ventricular apex into
a pulsatile, pusher-plate–type LVAD. Apical inlet-cannula flow
ceases (arrow, B) during the pulsatile LVAD ejection phase (no device
filling occurs). (C,D) LVAD outlet cannula flow assessment using
pulsed Doppler with the sample volume placed within the outlet
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 6 Nuclear Cardiology
Arthur Iain McGhie, K. Lance Gould, and
James T. Willerson
Myocardial Perfusion Imaging . . . . . . . . . . . . . . . . . . . . . 137
Single Photon Emission
Tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Myocardial Perfusion Imaging
Physiologic Principles
Briefly, the underlying physiological principles of stress-rest
perfusion imaging are as follows: at rest, coronary flow is
normal even in the presence of a narrowing of up to 85%
diameter stenosis (Fig. 6.1).1 Stress, usually in the form of
dynamic exercise or vasodilatation, results in an increase in
coronary flow. In a normal coronary artery, flow increases
2- to 2.5-fold with dynamic exercise or by three- to four-
fold with maximal coronary vasodilation.2–6 However, the
increase in flow in a stenosed coronary is attenuated. Despite
an increase in flow proximally, there is an increase in the
pressure gradient across the stenosis, resulting in a drop in
pressure and flow distal to the stenosis. This causes a het-
erogeneous distribution of blood flow during stress, with a
greater increase in myocardial perfusion in the area sub-
tended by the normal coronary artery relative to the myocar-
dium supplied by the stenotic artery. In certain circumstances,
coronary flow may actually decrease distal to the stenosis,
resulting in subendocardial ischemia. This phenomenon of
myocardial steal may occur in two circumstances. In the
presence of a severe coronary stenosis, the coronary pressure
distal to the stenosis may decrease enough during stress that
it is insufficient to perfuse the endocardium, resulting in
subendocardial ischemia despite an increase in total flow in
the proximal epicardial artery. This is sometimes referred to
as vertical steal. Alternatively, in the presence of one or more
diseased vessels with collaterals between their distal beds,
there may be an unequal fall in the pressure between the two
distal perfusion beds. This can result in blood being shunted
away from the distal bed with the higher perfusion pressure
to the one with the lower perfusion pressure. This is referred
to as horizontal steal, and also can result in the production
of subendocardial ischemia in the affected area.
Therefore, resting coronary flow or myocardial perfusion
imaging at rest does not sensitively reflect the presence or
severity of coronary artery disease. However, the capacity to
increase flow to high levels in response to exercise stress or
Positron Emission Tomography: Assessment of
Myocardial Perfusion. . . . . . . . . . . . . . . . . . . . . . . . . . 147
Radionuclide Ventriculography. . . . . . . . . . . . . . . . . . . . . 149
pharmacologic coronary arteriolar vasodilators, that is, coro-
nary flow reserve, becomes impaired in the presence of coro-
nary artery stenosis of moderate severity. Coronary flow
reserve, illustrated in Figure 6.2, is defined as the ratio of
maximum flow or perfusion during stress or pharmacologic
vasodilation to resting flow or perfusion. Figure 6.3 relates
stenosis severity (horizontal axis) to coronary flow reserve
expressed as the relative increase of flow in multiples times
the initial baseline resting flow (vertical axis). The dashed
line indicates resting flow and the solid line is flow reserve.
The gray zone indicates the range for multiple observations.
With progressive narrowing, baseline flow remains normal
until the coronary artery is narrowed by 80% to 85% diam-
eter stenosis. However, coronary flow reserve begins to
decrease at 40% to 50% diameter stenosis for a vasodilatory
stimulus increasing flow normally to four times baseline.
For a stimulus increasing flow to five or six times baseline
levels, coronary flow reserve would be reduced by an even
milder 30% diameter stenosis. For the experimental stenoses
upon which Figure 6.3 was based, normal arterial diameter
and stenosis length were constant and relatively uniform for
each stenosis in a progressive series of experimental coro-
nary artery constrictions. Consequently, percent narrowing
related well to flow reserve with some data scatter (gray area
of Fig. 6.3) due to variable physiologic conditions of heart rate
and aortic pressure, which may alter flow reserve somewhat.7
In humans, absolute dimensions and length stenoses are
highly variable, with the consequence that percent diameter
stenosis is poorly related to coronary flow reserve.7–13
However, both experimentally and in humans, it has been
shown that directly measured coronary flow reserve is equiv-
alent to, interchangeable with, and predicted by the arterio-
graphic geometry of coronary artery stenoses if all stenosis
dimensions are accounted for including percent stenosis,
absolute cross-sectional lumen area, length, and shape.7,14–16
Mechanisms Underlying Coronary Flow Reserve
To explain maintenance of normal resting coronary flow but
reduced coronary flow reserve during progressive coronary
137
13 8 chapter 6

Rest no image defect 5

maximum flow
80% diameter stenosis
4
80 cc/min/100 g
80 cc/min/100 g

Coronary flow reserve

3

Image defect 50% of max flow

80% diameter stenosis
2

160 cc/min/100 g 320 cc/min/100 g

×2 increase ×4 increase resting flow
1

Image defect 85% of max flow

40% diameter stenosis 0 20 40 60 80 100

272 cc/min/100 g 320 cc/min/100 g
×3.4 increase ×4 increase
FIGURE 6.1. Principles for the detection of coronary artery disease
with perfusion imaging under conditions of maximal coronary
vasodilation. With an 80% diameter narrowing, coronary flow
reserve is limited to an approximately twofold increase over resting
levels compared with a fourfold increase in nonstenotic arteries.
The abnormal area therefore has 50% less activity, reflecting 50%
decrease in regional maximal flow compared with the normal
maximum. A milder stenosis of approximately 40% diameter nar-
rowing will produce a mild relative defect of approximately 15%
below maximal flow, indicating a mild lesion.
Percent diameter narrowing
FIGURE 6.3. Coronary flow reserve expressed as a ratio of maximal
flow to resting flow is given on the vertical axis, with percent diam-
eter narrowing given on the horizontal axis. With progressive nar-
rowing, resting flow does not change (dashed lines), whereas the
maximal potential increase in flow or coronary flow reserve begins
to fall at approximately 50% diameter narrowing. Shaded areas
represent the limits of variability of data about the mean plotted by
the solid and dashed lines.

constriction, consider the stenotic coronary artery as two

resistances in series, that is, a narrowed tube and a distal
coronary vascular bed, represented schematically in Figure
6.4. Normally, the distal coronary bed resistance at rest is
high. In this schema, the driving pressure for flow is the total

Rest no image defect

80 cc/min/100 g
80 cc/min/100 g

MAX =2 and 4
ABS CFR=
REST

160 cc/min/100 g 320 cc/min/100 g FIGURE 6.4. Diseased coronary circulation as two resistances in
×2 increase ×4 increase series. Rs indicates the resistance of the stenotic artery, and Rb
indicates the resistance of the distal vascular bed. The effects of
reducing Rb with the use of vasodilators are shown by the dashed
line. The equation shows the relation between resistance and flow
MAXs
REL CFR= = 0.5 (F) for various segments of the curves. For a given total pressure
MAXn gradient across the narrowed tube and distal vascular bed, flow is
Image defect 50% of max determined primarily by Rb if Rb is large. Changes in the stenotic
FIGURE 6.2. Concept of absolute coronary flow reserve (ABS CFR) resistance Rs have little effect until the value of Rs approaches that
and (REL CFR) relative coronary flow reserve. of Rb.
 n ucle a r ca r diology
pressure gradient across the stenosis and distal vascular bed,
which is approximately central aortic pressure since venous
pressure is relatively small. Therefore, flow is determined
approximately by aortic pressure divided by the sum of the
resistances of the stenosis (Rs) and of the distal vascular bed
(Rb) in series. If the distal bed resistance is large compared
with the stenosis resistance, as normally found at rest, large
changes in the stenosis resistance will have little effect on
flow, which is determined primarily by distal vascular bed
resistance. Therefore, a progressive stenosis up to a point will
have no hemodynamic effect on resting coronary blood flow.
However, as the stenosis becomes sufficiently severe to
create a resistance comparable to that of the distal vascular
bed, the distal bed vasodilates, loses its ability to autoregu-
late, and further narrowing causes a fall in resting coronary
blood flow. When the stenosis becomes sufficiently severe
that its resistance is much greater than that of the distal
vascular bed, autoregulation will be lost and flow will be
determined predominantly by the stenosis resistance alone.
Further arterial narrowing then causes resting flow to fall as
shown in Figure 6.4. Thus, the coronary vascular system is
normally a low-flow, high-resistance circulation at rest. Cor-
onary vasodilators or stress convert this normally low-flow,
high-resistance system into a high-flow, low-resistance
system in which coronary stenoses, even mild ones, limit
maximum flow. Such logic explains why imaging regional
myocardial perfusion at maximum coronary vasodilation
can be used to detect coronary narrowing.
Absolute and Relative Coronary Flow Reserve
The concept of coronary flow reserve, defined as maximum
flow divided (normalized) by resting control flow, has evolved
into an accepted functional measure of stenosis severity
since first proposed (Fig. 6.2).7–13,17,18 Its validity has been con-
firmed and applied clinically by noninvasive imaging and by
invasive methods. These clinical methods measure pharma-
cologically induced increases in coronary blood flow, most
commonly with intravenous dipyridamole for noninvasive
studies and intracoronary papaverine for invasive studies.
More recently intravenous adenosine has been used.
However, changes in aortic pressure and heart rate are
known to alter cardiac workload and therefore baseline coro-
nary blood flow as well as altering maximum coronary flow
under conditions of maximal vasodilation.18 Consequently,
absolute coronary flow reserve, as measured by flow meter,
also varies with aortic pressure and heart rate independent
of stenosis geometry due to differential effects of these vari-
ables on resting and maximal coronary flow. Under markedly
varying physiologic conditions, or from patient to patient,
absolute coronary flow reserve may not reliably or specifi-
cally reflect severity of coronary artery narrowing since it
may be altered by physiologic factors unrelated to stenosis
geometry.
In contrast, relative maximum coronary flow or relative
flow reserve is defined as maximum flow in a stenotic artery
divided (normalized) by the normal maximum flow in the
absence of stenosis. During maximal coronary vasodilation
physiologic variables, such as aortic pressure, heart rate,
metabolic demand, and vasomotor tone alter distal coronary
13 9
bed resistance equally for both normal and stenotic arteries.
When the maximum flow in the stenotic artery is normal-
ized by normal maximum flow, the effects of pressure, heart
rate, or vasomotor tone on flow in the numerator and denom-
inator of this ratio cancel out. Therefore, relative differences
in regional maximum flow, or relative flow reserve, are deter-
mined primarily by geometric stenosis severity. Relative
flow reserve, therefore, is a measure of stenosis severity rela-
tively independent of physiologic variables.
Rather than considering absolute coronary flow reserve
to be competitive or antithetical to relative flow reserve,
these measurements are independent variables providing
complementary information. Absolute flow reserve is the
flow capacity of the stenotic coronary artery and vascular
bed under whatever conditions of pressure, workload, hyper-
trophy, vasomotor tone, or stenoses are present. It reflects the
cumulative summed effects of these various factors without
being specific for the mechanism or cause of altered flow
reserve. Relative coronary flow reserve reflects more speci-
fically the effects of the stenosis independent of and
not affected by the other physiologic variables if normal
maximum flow is high enough. Thus, absolute and relative
coronary flow reserve are complementary.
Single Photon Emission Tomography
Physics and Instrumentation
Use of radionuclides to image the heart depends on the
ability to detect emitted electromagnetic radiation from
injected radionuclides. The radionuclide is usually either
taken up by the myocardium or remains in the intravascular
compartment. The emitted gamma rays are detected by a
scintillation counter where the emitted electromagnetic
radiation is converted into electrical energy and transformed
into a digital format to produce images either of myocardial
activity or the cardiac blood pool.
Scintillation Counter
These counters are usually made of sodium iodide thallium
[NaI(Tl)] activated crystal. The purpose of the scintillation
crystal is to convert the energy of γ-radiation into visible
light. When a γ-ray interacts with the atom in the crystal, a
high-speed electron is produced. This electron in turn dis-
turbs other atoms in its path, creating more high-speed elec-
trons. The number of high-speed electrons generated is in
proportion to the γ-ray’s total kinetic energy. These electrons
move through the crystal until trapped by an atom of thal-
lium, when their kinetic energy is converted into a photon
of light, that is, a scintillation. This whole process occurs
within a microsecond of the initial interaction between the
high-energy photon and the crystal. Every γ-ray absorbed by
the crystal results in the production of a large number of
photons, which is in direct proportion to the energy of the
γ-rays.
Subsequently, a photomultiplier converts these photons
of light into an electrical signal, which then amplifies the
electrical signal. Photons of light are detected by the photo-
14 0 chapter 6

multiplier using a thin plate, called a photocathode, which

releases electrons in proportion to the photons striking it.
The electrons are then accelerated through a series of usually
10 plates, known as dynodes, which multiply the electrons
striking them in proportion to voltage difference between
the plates. This results in an amplification factor of approxi-
mately 1 million. Following this, the electrons are collected
by an anode, and an electrical impulse is generated by a pre-
amplifier. The energy of the γ-ray absorbed by the crystal and
the subsequent light released by the crystal are directly pro-
portional to the height of this electrical pulse, that is,
voltage.
A device called a pulse height analyzer is used to prese-
lect the range of energies to be counted (energy window) from
the distribution of available energies (energy spectrum). Any
energies corresponding to γ-rays with this predetermined
energy window are rejected. Discriminating the energy of
the γ-ray is important as it facilitates (1) selection of different
radionuclides with different energies and (2) the elimination
of less energetic γ-rays scattered by the patient’s tissue prior
to detection by the scintillation device. However, pulses gen-
erated by the unscattered γ-rays are not all of exactly the
same amplitude, and they are distributed around the exact
characteristic energy of the radionuclide (photopeak). The
less spread of the radionuclide around the photopeak, the FIGURE 6.5. Schematic diagram of a gamma camera.
better the energy resolution of the system, and therefore
the better the inherent counting and imaging characteristics
of the device.

Single-Crystal Gamma Camera

This camera uses a large (300–500 mm), thin (75–125 mm)
NaI(Tl) crystal with an array of photomultiplier tubes cover-
ing one side of the crystal. On the other side of the crystal
is a lead plate with multiple holes in it called a collimator
(Fig. 6.5). This causes selective interference by blocking those
rays not traveling in the selected direction. In some ways,
the collimator is analogous to the lens of a photographic
camera resulting in a preselection of γ-rays before they strike
the crystal. The most commonly used collimator in nuclear
cardiology is a parallel-hole collimator. The lead septa
between the holes absorb most of the γ-rays not traveling
parallel to the holes. The larger the diameter or shorter the
length of the holes, the higher is the sensitivity of the colli-
mator, and the smaller the diameter or longer the length
of the holes, the higher the spatial resolution of the
collimator.
The γ-rays passing through the holes of the collimator
strike the crystal and produce a scintillation. Photons pro-
duced by the scintillation are detected by all the photomul-
tiplier tubes; photomultiplier tubes closer to the event
gather more light than those farther away. All output from
the photomultipliers is relayed into electronic computer cir-
cuitry where it is processed. A positional analyzer deter-
mines and assigns x and y Cartesian coordinates to the
point in the crystal where the scintillation occurs. In addi-
tion, output of all the photomultipliers is summed, repre-
senting the total energy of the γ-ray that interacted with the
crystal, to form an energy or z pulse. The z pulse is sent to
the pulse height analyzer, and it is set to accept a prese-
lected range of energies (see above). If the z pulse is within
the predetermined range, it is referred to as either a trigger
impulse or a signal (s) pulse. This signals that the scintil-
lation event should be counted. Each time a trigger impulse
is received by the cathode ray tube, it allows the emission
of electrons from the electron gun. The x and y positional
impulses are transmitted to the horizontal and vertical
plates, creating a deflection in the path of the electrons cor-
responding to the scintillation coordinates. Electrons hit
the phosphor screen of the cathode ray tube, creating a
small scintillation that can be recorded on photographic
film. However, today computers are used for image display,
processing, analysis, and archiving purposes. Therefore, the
x, y, and z pulses are also relayed to the computer interface
unit. These impulses first must be converted from analog
to digital format using an analog-to-digital converter (ADC).
The ADC converts the pulse height into discrete numbers.
The x and y impulses both have an ADC, whereas the z
impulse signals the ADCs to convert the analog pulses to
digital numbers.
The current generation of gamma cameras performs real-
time corrections for (1) tube drift, (2) energy variations, and
(3) spatial nonlinearity. Tube drift correction automatically
adjusts the photomultipliers so that each one generates the
same pulse voltage when it gathers photons from the same
light source. This correction is required because the earth’s
magnetic field affects the photomultiplier’s output as a func-
tion of its angle and is particularly important in rotational
tomography. The energy correction factor compensates for
differences in response of individual photomultiplier tubes,
differences in the crystal, or differences in regional light-
 n ucle a r ca r diology 141
gathering properties. Energy-specific field floods need to be
acquired periodically to generate the time-dependent energy
maps. This predetermined map is then applied by a correc-
tion circuit in real time. This normalizes the relationship of
the energy window to the shape of the spectrum, practically
abolishing the variations in energy response. Linearity cor-
rection is required because the gamma camera positioning
scheme does not perfectly image straight radioactive line
sources. A phantom of straight lines in horizontal and verti-
cal positions is imaged. The displacement is measured and
stored, allowing the linearity circuit to correct lines so that
they appear perfectly straight in the image.

Acquisition Modes
Planar acquisition is the simplest means of acquisition,
where the γ-camera acquires data in one dimension in mul-
tiple projections, usually in three, that is, anterior, left ante-
rior oblique, and left lateral projection. Right anterior and left
posterior oblique projections may be obtained depending on
the circumstances. Despite obtaining multiple projections,
the spatial resolution is limited. This occurs because of over-
lapping activity from either noncardiac structures or overlap
between normal and abnormal segments within the heart.
For example, the presence of adjacent pulmonary activity
may overlap the posterolateral wall in the left anterior FIGURE 6.6. Schematic representation of the process of backprojec-
oblique, making the anteroseptum appear hypoperfused; tion. Multiple planar views are taken around 360 degrees or 180
alternatively, a small perfusion defect may not be detected degrees, with data being back-projected in space to define the origin
of the data in space (see text for further details).
because of activity in normal myocardium in an adjacent but
different plane.
Tomographic acquisition, also known as single photon
emission computed tomography (SPECT), is now the most
common acquisition mode for myocardial perfusion imaging.
A series of planar images are obtained usually in a 180- high-frequency statistical noise, hence the term filtered
degree rotation from 45 degrees right anterior oblique (RAO) backprojection.
to 45 degrees right posterior oblique (RPO). Using a tech-
nique called filtered backprojection, a computer creates a set
Radiopharmaceuticals
of transaxial images from these planar images, allowing the
radioisotope distribution to be displayed in three dimen- 201
Thallium
sions. From these transaxial images horizontal and vertical
long axis sections and short axis sections are constructed. This cation is a potassium analog and was the first widely
This results in improved contrast and enhanced spatial reso- used radioisotope in the assessment of myocardial perfusion.
lution, when compared to planar imaging. However, this Myocardium uptake occurs by both active and passive
technique is more exacting, in terms both of equipment and mechanisms involving Na,K–adenosine triphosphatase
acquisition technique, and of requiring more rigorous quality (ATPase).19,20 Uptake of 201thallium (201Tl) by the myocyte is
control. not affected by either ischemia or hypoxia unless these pro-
Filtered backprojection uses an algorithm that is depen- cesses result in cell death.21–24 There is a linear relationship
dent on the fact that each photon that interacts with the between 201Tl uptake and coronary blood flow, with a ten-
crystal must pass through the collimator, which defines the dency to underestimate and to overestimate at the upper and
path of the photon because the holes in the collimator are lower limits of the physiologic range, respectively.25–28 Thal-
parallel. The reconstruction algorithm back-projects or sends lium washes out of the myocardium by diffusion with a
back the counts from their recorded position on the crystal, half-life in the myocardium of 4 to 8 hours. The rate is pri-
along a line perpendicular to the face of the crystal (Fig. 6.6). marily dependent on the 201Tl concentration gradient between
The back-projected lines cross at the origin of the radiation, the myocardium and blood.29,30
and these points are recorded in computer memory from In comparison to a normal coronary artery, lower coro-
which tomograms are generated. However, the reconstruc- nary flow rates are achieved in a stenosed artery during
tion algorithm deposits counts in each pixel along the back- stress. As a consequence, there is less 201Tl uptake by the
projected line, producing a star-shaped artifact and in-plane myocardium in this artery’s distribution. Following stress,
blurring of the image. To reduce these artifacts, the images coronary flow returns to baseline levels and is the same in
are modified by a filter that eliminates unwanted low- and both the normal and stenosed artery. However, because of
14 2 chapter
the unequal distribution of 201Tl in the myocardium during
stress, clearance of 201Tl is heterogeneous. The greater
concentration gradient between the normal myocardium
and blood results in a higher washout rate of 201Tl than
in the hypoperfused myocardium where the 201Tl concen-
tration gradient is less. As a consequence, there is a trend
for the myocardial concentration of 201Tl to equalize with
time in the normal and abnormally perfused myocardium.
Therefore, there is apparent “redistribution” of 201Tl, with
the stress-induced perfusion defect apparently reversing
during rest imaging 3 to 4 hours later. A perfusion defect
following stress that has resolved by time of distribution
imaging is considered to represent ischemic and viable
myocardium.
Conversely, a defect still present at the time of redistri-
bution imaging was classically interpreted as representing
nonviable scar tissue. However, several studies, using either
improvement in regional ventricular function following
revascularization or myocardial uptake of 18fluorine-
fluorodeoxyglucose (FDG), have identified viable myocar-
dium in 40% to 60% of fixed 201Tl perfusion defects.31–33
Several studies from Bonow and associates34–36 have shown
that either performing late–24-hour redistribution imaging
or reinjecting an additional dose of 201Tl after 4-hour redis-
tribution in the presence of an apparent “fixed” perfusion
defect results in reversibility of a significant proportion of
these defects, and that this correlates with myocardial
uptake of FDG. The same workers were able to show that
areas of hypoperfused myocardium, where the reduction
in 201Tl uptake is only mild or moderate, that did not
redistribute are still viable.37 However, Kitsiou and asso-
ciates38 have shown that although mild-to-moderate
perfusion fixed defects contain viable myocardium, these
areas are less likely to show functional improvement after
revascularization than mild-to-moderate defects that are
reversible.
99m
Technetium-Labeled Perfusion Agents
99m
Technetium (99mTc)-labeled radiopharmaceuticals were
developed in the early 1980s. Three agents, sestamibi, tebo-
roxime, and tetrofosmin, are approved for clinical use by the
United States Food and Drug Administration. In comparison
to 201Tl, 99mTc-labeled radiopharmaceuticals offer significant
advantages, including (1) a shorter 6-hour half-life, which
allows a larger patient dose to be administered, typically 25
to 35 mCi compared to 3 to 4 mCi of 201Tl; and (2) higher
energy, 140 for 99mTc photons versus 74 keV for 201Tl, reducing
the scatter fraction and resulting in superior energy discrimi-
nation. These advantages typically translate into higher
quality images.39,40
Teboroxime has kinetic properties that are different from
the other currently available 99mTc-labeled radiopharmaceu-
ticals. It is extremely lipophilic, and myocardial uptake cor-
relates closely with coronary blood flow over a wide range of
flow rates and has very rapid myocardial washout.41 Unlike
201
Tl, teboroxime washout is largely flow dependent, and it
appears that the rate of washout from the myocardium may
allow differentiation between viable and nonviable tis-
sue.42–44 Theoretically, it may be possible to evaluate stress
6
and resting myocardial perfusion with one injection at
maximal stress. However, the short residence time in the
myocardium mandates rapid data acquisition, and failure to
do so may potentially lead to image artifacts because of the
changing myocardial distribution of 99mTc-teboroxime during
acquisition. Despite the initially encouraging clinical results
of 99mTc-teboroxime,45 its rapid clearance made it very diffi-
cult to use in the clinical arena, resulting in preference for
the other 99mTc-labeled radiopharmaceuticals and the subse-
quent withdrawal of the product from the marketplace by the
manufacturer.
In contrast, the kinetics of sestamibi are in many ways at
the opposite end of the spectrum to teboroxime. It is a lipo-
philic cation that accumulates in the myocardium in propor-
tion to blood flow, although at higher coronary flow rates the
relationship becomes nonlinear, resulting in an underestima-
tion of coronary flow. It has a first-pass extraction fraction of
65%, which is lower than either 201Tl or teboroxime. However,
its net extraction is higher because it is avidly retained by
myocytes with little bidirectional exchange of sestamibi
with minimal redistribution and slow clearance.46 The
volume of distribution for sestamibi is so large that saturation
of myocardial uptake does not occur. Uptake occurs primar-
ily by diffusion, resulting primarily from negative electrical
gradients across sarcolemmal and inner mitochondrial mem-
branes, and to a lesser extent concentration gradients.47
Carvalho and associates48 demonstrated that 90% of 99mTc-
sestamibi in vivo activity is associated with mitochondria as
the original free cationic complex.
Clinical studies to date indicate that imaging with 99mTc-
sestamibi has demonstrated a similar degree of accuracy for
the overall detection of coronary artery disease, but usually
results in higher quality images and is more accurate for the
detection of individual coronary artery stenoses.34,49 Use can
be made of 99mTc-sestamibi’s long myocardial retention time,
which allows for a patient to be imaged up to 4 to 6 hours
after administration of 99mTc-sestamibi. This has been useful
in triaging patients presenting to the emergency room with
chest pain and also in evaluating therapeutic interventions
in the setting of acute myocardial infarction where 99mTc-
labeled radiopharmaceutical can be given acutely, with
imaging to be performed later when the patient is in a more
stable condition and environment.50–55 The higher count
rates and the lack of redistribution also allow gated tomo-
graphic acquisitions to be performed. This increases the
accuracy of the technique and allows the evaluation of endo-
cardial wall motion and myocardial thickening, providing
important information on regional and global ventricular
function.56–58
Tetrofosmin is the most recent 99mTc-labeled radiophar-
maceutical approved for clinical use. Like its predecessor,
99m
Tc-sestamibi, tetrofosmin is a lipophilic cation, which
diffuses across the sarcolemmal and mitochondrial mem-
branes.59–61 Similar to sestamibi, tetrofosmin tends to under-
estimate flows greater than 2 mL/min/g and to overestimate
flows less than 0.2 mL/min/g.62 Munch and colleagues63
reported that 99mTc-tetrofosmin had a shorter myocardial
half-life and higher heart-liver ratios than 99mTc-sestamibi.
In a canine model using adenosine, Glover and associates64
observed that 99mTc-tetrofosmin uptake underestimated the
flow heterogeneity more than 201Tl. A clinical study65 com-
 n ucle a r ca r diology
paring 99mTc-tetrofosmin with 201Tl SPECT imaging using
dipyridamole stress had findings that tended to support those
reported by Glover and associates. In this clinical study, 201Tl
imaging identified more reversible defects than 99mTc-
tetrofosmin SPECT imaging, and in addition, the authors
noted that the magnitude of reversible perfusion defects also
was more severe in the 201Tl images. Similar findings have
also been reported by others.66,67 However, in general terms,
clinical experience has shown that tetrofosmin is compara-
ble to the other currently available myocardial perfusion
agents.68–70
Choice of Stress
Exercise
The cardiovascular response to dynamic exercise results
in an increase in cardiac output. The peripheral resistance
decreases in active muscles and increases in resting tissues;
overall there is a fall in systemic vascular resistance.71 There
is an increase in heart rate in response to exercise, mediated
by alterations in the autonomic nervous system. The increase
is linearly related to workload and oxygen uptake. The heart
rate response to maximal dynamic exercise is dependent on
many factors, especially the individual’s age and health. The
increases in cardiac output during dynamic exercise increases
systolic arterial blood pressure, with little alteration in the
diastolic pressure. Dynamic exercise is the most commonly
used means of stress when using nuclear techniques. The
procedure is carried out in a manner almost identical to
conventional exercise electrocardiography. In addition, the
patient should have an intravenous cannula placed in a large
vein in the antecubital fossa prior to stress. At peak exercise,
the patient is injected with the radiopharmaceutical and con-
tinues exercising for a further 60 to 90 seconds. The timing
of imaging following exercise is dependent on the particular
radiopharmaceutical being used.
Vasodilator Pharmacologic Stress
Pharmacologic stress is being increasingly used. The main
indication for its use is when the patient is unable to exercise
adequately. Reasons for this are varied and include concomi-
tant medical conditions, such as peripheral vascular disease,
morbid obesity, and neurologic disease; poor motivation;
and antianginal medication (in particular β-adrenergic and
calcium channel antagonists). It is also indicated for stress-
ing patients with left bundle branch block (LBBB) or a paced
rhythm because of the problem of artifactual reversible septal
perfusion defects when exercise stress is used.
Dipyridamole is widely used in conjunction with myo-
cardial perfusion imaging and has a similar diagnostic accu-
racy to exercise imaging.72–74 Dipyridamole is a highly basic
and hydrophobic pyrimidine derivative that induces an
increase in endogenous adenosine levels by blocking uptake
of adenosine by red cells and endothelium.75–77 The increased
concentrations of adenosine in the interstitial fluid results
in relaxation of vascular smooth muscle. This may be medi-
ated by a number of possible mechanisms, including (1) an
inhibition of slow inward calcium current resulting in
14 3
decreased calcium uptake, (2) activation of adenylate cyclase
through A 2-receptors in smooth muscle cells, and (3) possible
modulation of sympathetic neurotransmission.78,79 Dipyri-
damole may alter systemic hemodynamics with a slight
fall in blood pressure and slight increases in the heart
rate and pressure-rate product. Once adenosine leaves the
interstitium, it undergoes rapid intracellular metabolism
via adenosine kinase by phosphorylation to adenosine
monophosphate or deamination by adenosine deaminase.80
Dipyridamole undergoes hepatic biotransformation to a
monoglucuronide and is excreted in the bile.81 Patients
should be in a fasting state and should not have taken
any xanthine medications (theophylline) in the previous 36
hours and caffeine beverages (including decaffeinated coffee
or tea and cola) in the preceding 24 hours. It is contraindi-
cated in patients with a history of significant reversible
airways obstruction. An infusion of 0.142 mg/kg/min of
dipyridamole is given over 4 minutes and with the radiophar-
maceutical being administered 3 to 4 minutes later. Con-
tinuous clinical, electrocardiographic, and blood pressure
monitoring is performed during the procedure, with imaging
being performed in the usual manner. Serious adverse
reactions have been reported following intravenous dipyri-
damole, including fatal and nonfatal myocardial infarction,
ventricular fibrillation, symptomatic ventricular tachycar-
dia, transient cerebral ischemia, and bronchospasm.69 The
effects of dipyridamole are usually rapidly reversed by
the administration of aminophylline, which antagonizes the
effects of adenosine at the A 2-receptor.82 Side effects are
reported in approximately 50% of patients following intrave-
nous dipyridamole at the dose of 0.568 mg/kg. Chest pain
occurs in approximately 15% to 40% and ST segment depres-
sion in 5% to 20% of patients. The presence of either or both
does not reliably predict the presence of angiographically
significant disease, although it is more common in their
presence. Noncardiac symptoms are relatively common and
include flushing, nausea, light-headedness, and mild
headaches.
Adenosine, the mediator of dipyridamole’s vasodilating
action, is a powerful coronary arterial vasodilator.83,84
Maximal coronary vasodilatation is obtained with an intra-
venous infusion rate of 100 to 140 μ/kg/min. This increases
coronary blood flow velocity by 4.4-fold. The effects are
maximal 2 minutes after the onset of the infusion and return
to baseline within 2 to 3 minutes of its discontinuation. It
is widely used as a pharmacologic stress and has a compara-
ble diagnostic accuracy when compared with dipyridamole
myocardial perfusion imaging.85–87 The short half-life of ade-
nosine results in it being better tolerated by patients. Verani’s
group88 reported their experiences with this technique in 607
patients. Small but significant mean increases in heart rate
and falls in the systolic and diastolic blood pressures were
observed. First- and second-degree atrioventricular (AV) block
occurred in 10% and 4% of patients, respectively; ischemic
ST segment depression was identified in 13% of cases. Side
effects were frequent but well tolerated; flushing occurred in
35%, chest pain in 34%, headache in 21%, and dyspnea in
19% of patients. In the majority of patients, the side effects
ceased rapidly after terminating the adenosine infusion. The
side effects were severe in only 2% of patients, and in only
six of 607 patients was it necessary to discontinue the
14 4 chapter
infusion. No serious adverse reactions were reported. Recent
studies of selective adenosine A 2A-receptor agonists have
shown that the vasodilator effects of adenosine can be
obtained without many of the side effects.89–91
Vasodilator stress imaging can be supplemented with
exercise, using either isometric handgrip or low-level tread-
mill exercise.92,93 The former has been used quite exten-
sively following evidence of increased coronary flow when
used in combination with dipyridamole.94 But later data,
using Doppler-derived indices of flow, have produced con-
flicting evidence.6 Therefore, it probably confers benefit by
different mechanisms, including an increase in afterload
or vasoconstriction of small to moderate-sized arteries.
Exercise also improves image quality by improving target-
to-background ratios,95,96 probably by causing splanchnic
vasoconstriction.
Sympathomimetic Pharmacologic Stress
Dobutamine is a potent sympathomimetic agent with stimu-
latory effects on β1-, β2-, and α1-adrenoreceptors with pre-
dominantly inotropic and a lesser chronotropic effects.97,98
Therefore, dobutamine produces an increase in myocardial
oxygen requirement by causing an increase in myocardial
contractility and systolic blood pressure and at higher doses
an increase in heart rate. The dose for dobutamine is usually
10 μg/kg/min increased by increments every 3 to 5 minutes
to a maximal infusion rate of 30 to 40 μg/kg/min. Side effects
that can occur with this agent include palpitation, headache,
paresthesia, nausea, tremor, ventricular arrhythmia, and
marked ST segment depression. Side effects usually resolve
rapidly following discontinuation of the infusion. The effects
of dobutamine are similar to those of dynamic exercise, and
in the presence of coronary artery disease myocardial isch-
emia may be provoked.99,100 It produces an increase in coro-
nary flow of between two- and threefold, which is less than
is typically seen with either dipyridamole or adenosine.101
Studies indicate that dobutamine stress myocardial per-
fusion has clinical utility; however, it is usually reserved
for patients with a contraindication to adenosine or
dipyridamole.102–105
Imaging Protocols
Over the years different imaging protocols have been devel-
oped with the advent of new radiopharmaceuticals with dif-
ferent kinetics and the use of different pharmacologic stress
agents. The American Society of Nuclear Cardiology (ASNC)
has published guidelines in an effort to standardize imaging
protocols.106
Choice of Stressor
If the patient can exercise adequately, exercise is preferred
over pharmacologic stress in most circumstances. Adequate
exercise is achieved when the patient achieves more than
85% of his maximum predicted heart rate for age and exer-
cises of an adequate period of time, that is, longer than 6
minutes on a Bruce protocol. Circumstances where pharma-
cologic stress is preferred is when the patient will not exer-
6
cise adequately to attain these goals for whatever reason, for
example, arthritis, deconditioning, neurologic disease, or
peripheral vascular disease. The presence of LBBB or a paced
ventricular rhythm is an indication for vasodilator stress
because of the reversible septal perfusion defects that can be
produced by abnormal ventricular activation. In addition,
pharmacologic stress is generally utilized when stress myo-
cardial perfusion imaging is performed in the setting of a
recent unstable angina or myocardial infarction, because of
the relative lack of effect on hemodynamics. The main role
of dobutamine in nuclear cardiology is when the use of dipyr-
idamole or adenosine is contraindicated, usually in a patient
with reversible obstructive airways disease.
201
Thallium
Typically 3 mCi of 201Tl is injected at peak stress and imaging
is commenced early, within 10 to 15 minutes, because of the
kinetics of 201Tl. A second set of images is acquired approxi-
mately 4 hours later after redistribution has occurred. If
incomplete redistribution has occurred and myocardial via-
bility is a clinical concern, then either a second injection of
1.5 mCi can be given and the patient reimaged 10 to 30
minutes later (reinjection imaging) or alternatively the
patient can be reimaged 24 hours later. Thallium images are
increasingly being acquired as electrocardiogram (ECG)-
gated images to provide functional data in addition to perfu-
sion. If 201Tl imaging is being performed primarily to assess
viability rather than stress-induced ischemia, then a rest-
redistribution protocol is used. In this protocol, 3 mCi of 201Tl
is injected at rest with imaging being performed 15 to 30
minutes later and again at 4 hours, with the option of obtain-
ing a 3rd set of images after 24 hours.
99m
Tc-Labeled Radiopharmaceuticals
The most widely used protocol for this group of pharmaceu-
ticals is the same-day rest-stress protocol. Typically 8 to
9 mCi are injected at rest with imaging being performed
approximately 1 hour later. The patient is stressed around
1 to 4 hours following the rest injection and receives around
25 to 30 mCi at peak stress. The stress images are acquired
15 to 60 minutes later; if the patient has been exercised,
then imaging can be acquired 15 minutes after stress;
however, if pharmacologic stress has been utilized, then
imaging is delayed 45 to 60 minutes to allow for hepatic
and visceral clearance of the radiopharmaceutical. The
same-day stress-rest protocol involves performing stress
imaging first using the smaller 8 to 9 mCi dose, with rest
imaging being performed 1 to 4 hours later using the 25 to
30 mCi dose. This has the advantage that if the stress images
are normal, then rest imaging does not need to be per-
formed. However, it has the disadvantage that the stress
images are acquired using the lower dose of the 99mTc labeled
radiopharmaceutical and therefore may be of lower quality,
which may adversely affect the diagnostic accuracy of the
images. The third protocol that is used is a 2-day protocol
with the rest and stress images being acquired on separate
days. This protocol is particularly useful in two particular
situations. The first is when imaging is being performed for
diagnostic purposes, usually in patients with a low pretest
likelihood, in which the stress portion is performed first
 n ucle a r ca r diology 14 5
and if these images are normal, rest imaging is not required. Vertical
The second application is in obese patients to maximize Short axis long axis
image quality by using the higher dose of the 99mTc radio-
pharmaceutical (0.31 mCi/kg) for both the rest and the stress Apical Mid Basal Mid
1
images. 7
13 8 12 2 6
Hybrid Protocols 14 16 17
The other protocol that is widely used is the dual-isotope 9 11
15 3 5
protocol. In this protocol, 2.5 mCi of 201Tl is injected at rest 10
with rest images being acquired 10 minutes later. Then the 4
patient is stressed and 25 mCi of 99mTc-labeled radiopharma-
ceutical is injected at peak stress, with the stress images LAD RCA LCX
acquired 15 to 90 minutes later depending on the stressor FIGURE 6.7. Schematic diagram showing the standardized segmen-
used. If a fixed perfusion defect is seen, then 24-hour 201Tl tation and assignment of the coronary artery territories. LAD, left
anterior descending; RCA, right coronary artery; LCX, left circum-
imaging can be performed. The main disadvantage of the
flex coronary arteries.
technique is the greater interpretive skill required to read
the images because of the differences between the rest and
stress images resulting from differences in the physical prop-
erties of 201Tl and 99mTc.
circumflex coronary artery supplies the middle and posterior
portions of the left ventricular wall, and the right coronary
Analysis of Images
artery supplies the apical, inferior, and inferoseptal aspects
For the most part, tomographic imaging has replaced planar of the left ventricle (Fig. 6.7). Figure 6.8 demonstrates 201Tl
techniques because of enhanced contrast and spatial resolu- tomograms following exercise and redistribution from a
tion and consequently improved sensitivity for the identifi- patient with disease of the left anterior descending and right
cation and localization of coronary artery disease.107 The coronary arteries. There are moderate-severe perfusion
myocardial territories subtended by the left anterior descend- abnormalities involving both the anterior and septal as well
ing coronary artery consist of the apical, anterolateral, ante- as the inferior, inferoseptal, and inferolateral aspects of the
rior and anteroseptal portions of the left ventricle; the left left ventricle. In addition, there is evidence of left ventricular

FIGURE 6.8. Exercise-redistribution of

201
Tl from a patient with disease of the
left anterior and right coronary arteries.
Representative short, vertical long, and
horizontal tomograms are shown fol-
lowing exercise and redistribution. Per-
fusion defects are present in the anterior
and septal walls indicative of left ante-
rior descending coronary (LAD) isch-
emia as well as the inferior, inferoseptal,
and inferolateral walls indicative of
right coronary ischemia (RCA). In
addition, there is transient dilatation
of the left ventricle and a fall in the
ejection fraction with exercise indica-
tive of stress-induced left ventricular
dysfunction.
14 6
decompensation with stress as manifested by transient dila-
tation of the left ventricle and a fall in the left ventricular
ejection fraction with stress.
Interpretation of the images begins with analyzing the
raw projection sets looking for potential factors that may
result in image artifacts, for example, diaphragmatic or
breast attenuation, and patient motion. Then, the recon-
structed tomograms are evaluated for the presence of perfu-
sion defects, including the severity (extent and intensity) of
defects, and their location with respect to specific coronary
distributions. The gated tomograms are also reviewed for
global and regional function both at rest and following stress.
Other markers of increased risk such as transient dilatation
of the left ventricle poststress and, in the case of 201Tl imaging,
increased lung uptake are noted. Semiquantitative scoring is
widely used in the analysis of images, where one representa-
tive apical, middle, and basal short axis section and one verti-
cal short axis section at rest and following stress are scored
according to the severity of the perfusion defect. From this
analysis, a sum stress score, sum rest score, and a sum dif-
ference score are generated.108 Semiquantitative analysis of
images using this technique provides important prognostic
information.109 There are important gender-related differ-
ences in tissue attenuation that need to be taken into account
when interpreting images. In males, the anterior and lateral
segments normally demonstrate the highest relative activity,
with the posterior and septal segments demonstrating lower
activity. In contrast, females normally demonstrate some-
what higher activity in the inferoposterior segments as com-
pared to the anterior and lateral segments.110 Subjective
analysis of images is usually also supplemented with com-
puter analysis. Quantitative computer techniques for the
analysis of tomograms evaluate the extent and severity of the
defects and the amount of reversibility present. Improvement
sensitivity with only marginal effects on specificity are
found when computer-generated analysis is combined with
the qualitative visual evaluation of the images.111–113 The
results of these computer-generated analyses are usually dis-
played as polar maps or “bull’s eye” displays (Fig. 6.9). The
center of the polar map is obtained from an apical short axis
Ant Ant
Septal Lat Septal
Post
Post
Stress Redistribution
FIGURE 6.9. Polar maps from a patient with right coronary artery
disease (see Color Plates 5 to 6). There is hypoperfused area involv-
ing the inferior and posterolateral aspects of the left ventricle in the
stress map. The redistribution map shows that this is almost com-
pletely reversible. Ant, anterior; Lat, lateral; Post, posterior.
chapter 6
Anterior
Septal Lateral
Posterior
PATIENT NORMAL
> 2.5 SD
1.0–2.0 SD
0–1.0 SD
1.0–2.0 SD
2.0–2.5 SD
COMPARISON > 2.5 SD
FIGURE 6.10. The patient’s polar map (top left) is compared with
normal polar map (top right) obtained from patients with less than
a 5% likelihood of coronary artery disease. Areas that are outside
of 2.5 standard deviations (SDs) of normal are blacked out (bottom
left).
section, with subsequent short axis sections being obtained
from progressively more basal portions of the left ventricle,
with the most basal short axis section forming the outer
border of the polar map. Polar maps are divided into approxi-
mately 100 segments. The profiles from the patient’s seg-
ments are compared to a data bank of gender-matched normal
profiles previously acquired from a group of normal individu-
als (usually patients with <5% probability of coronary
disease). Any of the patient’s segments falling 2.5 standard
deviations below the normal mean value are plotted
(Fig. 6.10).
Recognition of image artifacts is very important when
interpreting SPECT myocardial perfusion images. Many
factors have been identified as potentially causing artifacts,
including patient motion, soft tissue attenuation (breast
tissue, lateral chest wall fat, diaphragm), overlying visceral
activity, LBBB, left ventricular hypertrophy, reconstruction
Lat
artifacts, flood field nonuniformity, and center of rotation
errors.114 Breast tissue attenuation is a common occurrence,
and results in a lower count density in the anterior wall of
the left ventricle of women (anterior/inferior count density
ratio = 1.0 in women and 1.2 in men). Diaphragmatic attenu-
ation results in perfusion abnormalities involving the infe-
rior wall of the left ventricle and can be minimized by
imaging the patient in the prone position.115 Motion during
acquisition is a common cause of image artifacts. This can
occur following exercise resulting from the phenomenon
sometimes referred to as “upward-creep.” This results from
changes in depth of respiration from deep to shallower
 n ucle a r ca r diology 147
breathing resulting in the heart “creeping” up in the thorax TABLE 6.1. Comparative diagnostic accuracy of attenuation-
during the acquisition. Delaying the start of imaging for 10 corrected and nonattenuation-corrected single-photon emission
computed tomography
minutes after cessation of exercise usually eliminates this
phenomenon. Patient motion during acquisition may result Sensitivity Specificity Normalcy
in the production of factious perfusion abnormalities, and First author NC AC NC AC NC AC
can usually be easily identified by examining a cine display 121
Ficaro 78% 84% 46% 82% 88% 98%
of the planar projection images.116 One of the advantages of
Hendel125 76% 78% 44% 50% 86% 96%
using Tc-labeled radiopharmaceuticals is that it allows for
repeat imaging, as there is no change in the myocardial dis- Links*126 84% 88% 69% 92% 69% 92%
tribution with time, unlike 201Tl. Therefore, if a patient Gallowitsch124 89% 94% 69% 84% NA NA
moves, then the acquisition can be repeated, or if diaphrag- Ficaro†122 93% 93% 84% 88% 78% 85%
matic attenuation is identified, the imaging can be repeated * Includes motion correction and depth dependent blur correction.
using the prone position. Most gamma-camera manufactur- † Includes scatter correction.
ers provide software packages that will help correct for AC, attenuation-corrected single photon emission computed tomography
patient motion. The presence of LBBB can result in septal (SPECT); NA, not available; NC non–attenuation-corrected SPECT.
perfusion abnormalities, which may be reversible when exer-
cise is used for stress and can usually be avoided by using
vasodilator pharmacologic stress.117
The use of ECG-gated acquisitions (see Radionuclide
Ventriculography, below, for details on electrocardio-
graphically gated acquisitions) during myocardial perfusion Positron Emission Tomography:
imaging provides important incremental data over static Assessment of Myocardial Perfusion
imaging. There has been an exponential increase in its use
over the last 10 years, with currently approximately 80% of
Basic Principles
studies being performed using ECG-gated acquisition com-
pared to only 3% in 1993.118 Initially, it was thought that this A positron is a positively charged particle with the same
type of acquisition could only be performed using 99mTc- mass as an electron but with a positive charge. They are
labeled radiopharmaceuticals because of the higher count emitted along with a neutrino by certain unstable atoms,
rates. However, it has been shown that it is also possible to usually elements with a low atomic number, in the process
acquire ECG-gated SPECT images using 201Tl.119 The addi- of radioactive decay. The positron travels 1 to 3 mm in tissue
tional ECG-gated data provide important information regard- before colliding with an electron. When this occurs both the
ing regional and global ventricular function, including wall positron and the electron are annihilated, with conversion
thickening, ventricular volumes, and ejection fraction both of their combined mass into electromagnetic γ-radiation.
at rest and following stress. In addition, the use of gated Two photons are given off, each with an energy of 511 keV,
images appears to improve the specificity of the technique that travel in opposite directions at approximately 180
by better differentiating between attenuation and scar in degrees to each other. When a photon pair is detected by a
“fixed” perfusion defects. pair of radiation detectors, connected through an electrical
Another important development in SPECT imaging that coincidence counting circuit, an annihilation event is
is under continuing evaluation and refinement is the use of recorded. This circuit is set so that one decay is recorded only
attenuation correction techniques to minimize the effects if both detectors are activated simultaneously (within 4 to
of breast and diaphragmatic attenuation artifacts. Several 10 nanoseconds) by the photon pair. All other events are
studies have evaluated the effect of attenuation correction on rejected. Therefore, radioactive decays occurring outside the
the accuracy of stress myocardial perfusion imaging.120–126 sample volume between the detectors are excluded from the
The findings from these studies are summarized in Table count data since an unpaired photon striking only one of
6.1.127 These studies have shown that attenuation correction the detectors is not counted. Therefore, collimation is accom-
does result in an improvement in diagnostic accuracy, mainly plished electronically with coincidence counting, rather
from improvement in specificity, and also an increase in than with lead collimators, as in single-photon imaging. The
interpretative confidence. The combination of attenuation electronic collimation of coincidence counting provides
corrected and ECG-gated images does appear to result in an higher efficiency and better count statistics resulting in posi-
increase in diagnostic accuracy, with improvements in both tron emission tomography’s (PET) superior spatial and con-
sensitivity and specificity. Most gamma-camera manufactur- trast resolution to that of SPECT systems.
ers now offer attenuation correction options on their imaging Generically, PET cameras contain 1000 to 1500 detectors
equipment and both the ASNC and the Society of Nuclear in three to eight banks of rings, attached to photomultiplier
Medicine have concluded that attenuation correction is a tubes (PMTs) in ratios ranging from one to eight detectors for
useful adjunct to myocardial perfusion imaging.128 Despite each PMT. Scintillations from the coincidence detectors are
this, the technology to date has not been widely applied in converted to electronic signals from the PMTs that are sub-
clinical practice. The reasons for this are likely multifacto- sequently converted to digital information; then the data are
rial, but include the added cost of the equipment, increased stored and processed on a computer to reconstruct a tomo-
technical knowledge and quality assurance required to suc- graphic image using filtered backprojection. A transmission
cessfully implement the technology, and lack of reimburse- image for attenuation correction is obtained by placing a ring
ment for attenuation correction. of activity around the patient for imaging the target organ
14 8 chapter
before injection of radiotracer. The positron radiotracer is
then injected intravenously and an emission image obtained
by backprojection techniques. The emission image is cor-
rected for attenuation loss, random coincidences, scattered
radiation, dead-time losses, and variation in detector sensi-
tivity. The burgeoning role of PET imaging in oncology has
resulted in increased availability of PET/computed tomogra-
phy (CT) scanners, which have presented interesting options
for their use in the field of cardiovascular medicine.129 These
scanners have the potential to facilitate evaluation of both
the coronary anatomy from CT coronary angiography and
myocardial perfusion, with PET providing both anatomic
and physiologic data.
Positron-Emitting Radiopharmaceuticals
Several positron-emitting radioisotopes are used in cardiac
PET imaging. Typically, these have a short physical half-life
(rubidium-82, t1/2 = 76 seconds; oxygen-15, t1/2 = 2.1 minutes;
carbon-11, t1/2 = 20.4 minutes; nitrogen-13, t1/2 = 10 minutes;
fluorine-18, t1/2 = 110 minutes) when compared to conven-
tional single-photon–emitting isotopes (Fig. 6.11). The short
half-life minimizes radiation to the patient and enables
sequential studies to be performed over a short period of
time. In addition, O-15, C-11, F-18, and N-13 can be incorpo-
rated into metabolic substrates used by the heart, facilitating
evaluation of the metabolic processes of the myocardium in
vivo. However, synthesis of these radiolabeled substrates is
technically complex and demands both a radiochemist and
an on-site cyclotron. Rubidium-82 is an exception; it is gen-
erator produced from the parent compound strontium-82,
which has a half-life of 25 days and is available
commercially.
6
Evaluation of Myocardial Perfusion
Myocardial perfusion can be evaluated using either a diffus-
ible tracer, such as O-15–labeled water, or by using an extract-
able tracer, such as Rb-82– or N-13–labeled ammonia.
Experimentally it has been shown that there is a very close
correlation between the myocardial distribution of micro-
spheres and O-15–labeled water over a wide range of coronary
flows.130,131 As O-15–labeled water labels both the cardiac
pool and the myocardium, the blood pool activity is sub-
tracted using O-15–labeled carbon monoxide which labels
the red blood cells. Although this technique has been used
successfully in clinical studies, it is technically demanding
and is not used in routine clinical practice.
The extractable tracers, Rb-82– and N-13–labeled ammo-
nia, have been widely used in clinical practice.7,14,16,17,132–134 For
imaging purposes, it is assumed that these tracers are distrib-
uted to and retained by the myocardium in relation to coro-
nary blood flow; however, this is not the case. Myocardial
uptake of N-13–labeled ammonia is nonlinear, starting to
plateau at coronary flow rates greater than 2.5 to 3.0 mL/g/
min.135 However, the relative high first-pass extraction (60–
70%), rapid blood clearance, and comparatively long myocar-
dial retention time results in very good quality images.
Typically, 10 to 5 mCi of N-13 ammonia is injected at rest;
after a 4-minute delay to allow for blood pool clearance, rest
images are acquired with stress images being acquired 40
minutes after the first injection of N-13–labeled ammonia.
The myocardial uptake of Rb-82 is also nonlinear with coro-
nary blood flow, with an underestimation of flows greater
than 2.5 to 3.0 mL/g/min, and it has a first-pass extraction of
50% to 60%. However, it does have the advantage of being
generator produced and readily available commercially, and
FIGURE 6.11. Rubidium-82 images from a patient
showing multivessel ischemia. A severe reversible perfu-
sion defect involving the inferior, inferolateral, and
inferoseptal walls of the left ventricle consistent with
ischemia in the left circumflex and right coronary arter-
ies. In addition, there is a reversible defect involving the
anterior and anterolateral walls indicative of ischemia in
the left anterior descending coronary distribution.
 n ucle a r ca r diology
its short high-life means that rest and stress imaging can be
performed back to back in rapid succession resulting in a
complete study being acquired in 30 to 60 minutes. However,
the short half-life does mandate that pharmacologic stress be
used. Generally, 30 to 50 mCi of Rb-82 are injected in a
volume of 10 mL over 20 to 30 seconds with a fresh generator;
later, toward the end of the generator life (4 weeks), 30 to
40 mL are required to deliver a similar dose of Rb-82. Emis-
sion data are acquired over 5 to 8 minutes with the second,
stress dose being administered 10 minutes later during the
dipyridamole or adenosine infusion (Fig. 6.11).
Evaluation of Myocardial Metabolism
The most widely evaluated and used labeled compounds are
F-18–labeled fluorodeoxyglucose (FDG), carbon-11–labeled
palmitate, and carbon-11–labeled acetate. F-18–labeled FDG
is the most clinically utilized radiolabeled substrate and is
used for assessment of myocardial viability. The relatively
long half-life of F-18 means that although it is cyclotron-
produced, it can be shipped to PET facilities without access
to an on-site cyclotron. Under fasting conditions, fatty acids
are the main energy source for normal myocardium; however,
in the presence of ischemia, the myocardium increases its
utilization of glucose as its source for high-energy phos-
phates. This enhanced utilization of glucose in ischemic
myocardium can be detected by F-18 FDG-PET imaging. The
radiolabeled intermediary undergoes phosphorylation by the
hexokinase reaction, but cannot be metabolized any further
in the glycolytic pathway. Hence, the phosphorylated FDG is
trapped within the cytosol of the myocardium and accumu-
lates in proportion to exogenous metabolism of glucose.136,137
As discussed above, fatty acids are the preferred substrate
under fasting conditions and account for 90% of oxygen
consumed under aerobic conditions, and for this reason
carbon-11–labeled palmitate has been used extensively to
evaluate myocardial metabolism.138–142 The uptake of the pal-
mitate is primarily dependent on blood flow. Thereafter,
clearance C-11 palmitate is biexponential, with an early fast
component that reflects fatty acid β-oxidation and a second
slower component that results from incorporation of the
fatty acids into the endogenous lipid pool. In the presence of
myocardial ischemia, β-oxidation is reduced and therefore
clearance of C-11 palmitate is reduced, with a corresponding
increase in the proportion of fatty acids being incorporated
into the lipid pool.143,144
C-11–labeled acetate has been used to evaluate oxidative
phosphorylation.145–149 The myocardial avidly extracts acetate
and is activated to acetyl–coenzyme A (CoA) in the cytosol
and then is oxidized in the mitochondria via the tricar-
boxylic acid cycle, which is the final common pathway for
oxidative metabolism. The clearance of this radiolabeled
intermediary of myocardial metabolism is also biexponen-
tial. The rapid early phase reflects oxidative phosphorylation,
while the slower, later phase reflects incorporation of the
acetate into the amino acid and lipid pool. Rate constants
calculated from the rapid, early clearance phase correlate
closely with the rate of myocardial oxygen consumption over
a wide range of physiologic values. In the presence of myo-
cardial ischemia, uptake is reduced in proportion to blood
14 9
flow and the clearance is reduced in proportion to the reduc-
tion in oxidative metabolism.150,151
Comparison of SPECT and PET Perfusion Imaging
There are several theoretical reasons to believe that PET is
more accurate than its single photon counterpart. First, the
intrinsic resolution of this technology affords higher resolu-
tion images. Second, the ability to correct for attenuation
using a transmission scan should also improve the diagnostic
accuracy of the technique. It should be remembered, however,
that there is the potential for the production of image arti-
facts.152 The main disadvantages of the PET technology are
its limited availability and the significantly higher capital
expenditure and running and maintenance costs.
Early studies from the 1980s evaluating PET in the diag-
nosis of coronary artery disease indicated that this technique
was accurate for diagnosing coronary artery disease.153–155
Three comparative trials in the 1990s suggested that PET
had a superior diagnostic accuracy to SPECT imaging.141,156,157
However, the evidence was not conclusive; one study did not
demonstrate any statistically significant difference; another,
which showed significantly higher sensitivity and specific-
ity, has been criticized for its methodology and analysis.158
The recent resurgence of interest in cardiac PET imaging,
resulting from the increased availability of PET scanners
from increased oncologic use, has brought the issue of the
utility of cardiac PET imaging in clinical practice to the fore
again. In a recent study, comparing contemporary PET and
SPECT imaging techniques, PET was found to outperform
SPECT imaging, with sensitivities of 81% and 75%, p =. 34;
specificities of 93% and 58%, p =. 0001; and diagnostic accu-
racies of 86% and 68%, p =. 002, for PET and SPECT,
respectively.159
Radionuclide Ventriculography
Radionuclide ventriculography is one of the most widely
used techniques for evaluating ventricular function. This
essentially noninvasive method of assessing ventricular
function can be easily performed and provides a reproducible,
accurate evaluation of both right and left ventricular func-
tion. There are basically two methods of performing radio-
nuclide ventriculography.
First-Pass Radionuclide Angiocardiography
This technique involves following the passage of a radioac-
tive tracer through the central circulation. It requires the use
of a gamma camera with a high count rate capability, usually
1 × 105 to 5 × 105 counts per second. This high count rate
capability is optimally provided by a multicrystal gamma
camera, for example the Baird-Atomic, which is both expen-
sive and can be used solely for first-pass imaging studies.
However, some of the current digital single crystal Anger
gamma cameras have improved count rate capabilities and
are reputed to provide satisfactory count statistics.
The radioisotope is administered as a compact bolus,
1 mL plus 20 mL saline flush, through a large vein, usually
antecubital or jugular.160 An anterior or 30-degree right
15 0 chapter 6

anterior oblique projection is used to optimize separation of A

the atria from the ventricles. The former is preferred because ED3 ED4 ED5
900 ED2
the position is more reproducible, it enhances resolution ED6
EDEND
by minimizing the distance between the detector and the 700
ED1
chest wall, and during exercise studies motion artifact is Counts
500
minimized by pressing the chest wall firmly against the 0.025 sec
ES2 ES3 ES4 ES5 ES6
detector. The right and left ventricles overlap in these pro- 300 ES1
1 second
jections; however, this does not pose a problem during the
first pass of the radionuclide bolus. Data are usually acquired 0
Time (sec)
in a series of images with high temporal resolution. The
optimal framing interval is determined by the sensitivity of
the camera and the patient’s heart rate. For example, when B C
using a multicrystal gamma camera during an exercise 5000 2920 1.00 128
study, the framing interval will be 25 msec. In a patient 2190 .75 96
4000
with normal hemodynamics, the whole first-pass transit is Counts Counts Volume
1460 %EDV .50 (mL) 64
encompassed by 600 frames. The most commonly used 0.025 sec
3000
0.025 sec
radiopharmaceutical is 99mTc, complexed either to diethyl- 730 .25 32
enetriamine pentaacetic acid (DTPA) or sulfur colloid. 0 0 0 0 0 .25.50.75
0 .25 0 .25 .50
This enables optimal excretion of the isotope via the kidneys Time (sec) Time (sec)
to decrease background accumulation, which is an impor- FIGURE 6.12. Calculation of left ventricular ejection fraction and
tant consideration if more than one study is being per- volumes from first-pass radionuclide angiocardiography. (A) Uncor-
formed.161 Clinical studies using 195gold (Au) have found it to rected counts measured within the left ventricular region of interest
be a suitable alternative to 99mTc.162,163 The half-life of 195Au during the levophase. (B) Summed systolic and diastolic segments.
is only 30.5 seconds, allowing multiple studies to be per- (C) Final volume curve after normalization and background correc-
tion. ED, end-diastole; ES, end-systole; EDV, end-diastolic volume.
formed without imposing a prohibitive radiation burden on
the patient or increasing background activity that occurs
with 99mTc.
Following acquisition of the data, right and left ventricu-
lograms are constructed from which ejection fractions and
ventricular volumes can be calculated.164 A number of time- the use of a multicrystal gamma camera or a digital Anger
activity curves are obtained; the number depends on the camera with high count rate capabilities. Additionally, eval-
time taken for the bolus to traverse the chamber of interest, uation of regional wall motion function is poorer in compari-
usually five to ten individual beats in a normal patient. The son to the gated equilibrium technique.
count rate reaches a maximum at end-diastole when ven-
tricular volume is largest and falls in proportion to the ven-
Gated Equilibrium Radionuclide Ventriculography
tricular volume to reach a minimum at end-systole. Data
from individual beats are summed to provide a single curve, In this technique, the patient’s red blood cells are labeled
which is then corrected for background. The ejection fraction with 25 to 35 mCi of 99mTc-pertechnetate, using either an in
and ventricular volumes are then calculated from the vivo or in vitro method. The in vitro or modified in vitro
normalized, background corrected time-activity curve methods result in a consistently higher labeling efficiency.
(Fig. 6.12). Scintigraphic data are acquired using a conventional single
The first-pass technique has the advantage of excellent crystal Anger gamma camera in multiple planar projections.
image contrast and chamber separation because of the Usually an anterior, left anterior oblique and left lateral or
absence of background activity from adjacent great vessels posterior oblique are acquired (Fig. 6.13). The left anterior
and organs, in particular the lung. In addition, acquisition oblique (LAO) that best separates the right and left ventricles
time is short, usually between 20 and 30 seconds, which is is chosen, that is, the best septal projection. The detector is
an advantage for an exercise study’s acquisition of data only also angled to separate the left atrium from the left ventricle.
during peak exercise. The first-pass technique also provides The anterior projection is usually at 45 degrees less than the
a means for the detection and quantitation of intracardiac best septal projection, and the left lateral projection is usually
shunts.165–168 For both right-left and left-right shunts, the at 45 degrees more oblique than the best septal projection.
time-activity curves that are generated resemble dye-dilution In addition, the scintigraphic data are acquired gated to the
curves and are analyzed using a similar methodology. Despite electrocardiogram, with each R-R interval being divided
these advantages, it does have significant limitations. First, equally into a predetermined number of time bins, usually
one is limited to two to three acquisitions per patient study 16 to 32 time bins (Fig. 6.14). During acquisition, scinti-
because of the increasing radiation exposure to the patient graphic data are stored in memory in one of these time bins,
and the increasing background activity. Second, the tech- such that at the end of the acquisition each time bin will
nique is more demanding both on personnel and equipment: contain scintigraphic data from numerous, typically 300, R-
(a) it requires a compact bolus injection; (b) any patient R intervals (Fig. 6.15).
motion or ventricular arrhythmia, for example, coughing or Gated equilibrium radionuclide ventriculography is one
one ventricular ectopic beat occurring during acquisition, of the most accurate means of assessing ventricular func-
can seriously degrade the radionuclide data; and (c) it requires tion and can be easily performed using readily available
 n ucle a r ca r diology
ANT LAO LAT
AL ANT
SEP LAT
AP
AP
P P
I I
AP
FIGURE 6.13. Assessment of regional left ventricular function
from a gated radionuclide ventriculogram. Anterior (ANT), left ante-
rior oblique (LAO), and left lateral (LAT) projections in end-diastole
are shown. Corresponding segmentation is given below. AL, antero-
lateral: AP, apical; I, inferior; P, posterior; SEP, septal; LAT, lateral.
nuclear imaging systems. It facilitates acquisition of multi-
ple projections or multiple studies up to 6 hours after
administration of the isotope. The high count densities
achieved, typically 300 counts/cm2 in the left ventricle,
enable an evaluation of region wall motion that is superior
to the evaluation possible with the first-pass technique. The
FIGURE 6.14. Sixteen frames from a gated
radionuclide ventriculogram in the “best
septal” left anterior oblique projection. The
end-diastolic frame is the first image, located
in the upper left of the figure; the end-systolic
frame is the eighth image of the series.
151
technique does have some limitations: (1) overlap between
cardiac chambers, which can usually be resolved using mul-
tiple views; (2) limited spatial resolution, when compared to
contrast ventriculography or echocardiography; and (3) longer
acquisition times when compared to first-pass techniques,
a minimum of 2 minutes, which can pose a problem during
exercise studies in patients with limited or unpredictable
exercise capabilities.
Many of these problems can be resolved by tomographic
gated radionuclide ventriculography by providing an
accurate three-dimensional representation of the entire
cardiac blood pool.169–171 Using this technique, all chambers
are separated in space, which enables assessment of very
limited ventricular segments without concern about adja-
cent and potentially superimposed segments. This tech-
nique provides an accurate means for assessing both
global and regional ventricular function with a higher diag-
nostic accuracy than either contrast or planar radionuclide
ventriculography.
Exercise Radionuclide Ventriculography
Exercise radionuclide ventriculography is performed using
either the first-pass or gated equilibrium techniques. The
commonly used gated-equilibrium technique is described
here. A resting study is performed in the usual manner, but
performing the left anterior oblique projection last, with the
patient lying supine on a specially designed bicycle table-
ergometer that has adjustable shoulder restraints and handle
bars to minimize movement of the patient’s torso during
exercise. After obtaining the resting left anterior oblique
projection, exercise is commenced. The exercise test is per-
formed in exactly the same manner as with other exercise
15 2 chapter
R Wave R Wave
1 2 3 4 5 6 7 8 9 10 111213141516
A
Frame 1 Frame 2 Frame 3 Frame 4
B measured ventricular activity normalized for the acquisition
Frame 1 Frame 2 Frame 3 Frame 4
C
Frame 1 Frame 2 Frame 3 Frame 4
FIGURE 6.15. Schema explaining the principle of electrocardio-
graphic-gated acquisition in radionuclide ventriculography. The
cardiac cycle is divided into equal intervals (16 in this example).
Counts recorded during each interval are stored in different com-
puter frames. After a single cardiac cycle (row A), there are no rec-
ognizable images. After 20 cardiac cycles (row B), the images begin
to be recognizable. After 400 cardiac cycles (300,000 counts per
frame), image quality has improved considerably (row C).
tests, with continual monitoring of the electrocardiogram,
heart rate, and blood pressure. Typically, the first stage of
exercise is performed at 200 kilo/pound/meters (kpm) for 3
or 4 minutes and increased by 200-kpm increments (less if
patient has a limited exercise capacity) to a symptom-limited
maximum. Scintigraphic data are acquired during the last 2
minutes of each stage of exercise, when the hemodynamics
have equilibrated. The hemodynamic response is different
from that with erect exercise.172,173 During supine exercise,
there is less increase in end-diastolic volume and heart rate,
but a greater increase in systolic blood pressure when com-
pared to erect exercise. This does not appear to adversely
affect the sensitivity of the technique.174 There are signifi-
cant gender-related differences in the left ventricular response
to exercise. Women have a greater increase in end-diastolic
volume and less increase in left ventricular ejection fraction
in comparison to men.175,176
Analysis of Radionuclide Ventriculograms
Data from radionuclide ventriculograms can be used to
provide many parameters of ventricular function. The method
is relatively independent of geometric assumptions because
there is complete mixing of the 99mTc-labeled red cells in the
6
intravascular compartment, and the activity within the ven-
tricle is proportional to ventricle volume.177
Left ventricular ejection fraction (LVEF) is calculated
using the left anterior oblique projection by drawing a region
of interest (ROI) around the left ventricle in end-diastole and
end-systole. After correcting the counts in the ROIs for back-
ground activity, the ejection fraction is calculated from the
formula
LVEF = EDc − ESc/EDc
where EDc and ESc are end-diastolic and end-systolic counts
corrected for background, respectively.
Ventricular volumes can be calculated using a nongeo-
metric count-based technique.178,179 This methodology uses
time per frame and the activity in a known volume from a
peripheral venous blood sample. Estimation of left ventricu-
lar volume is calculated using the formula
Volume = K (Corrected LV counts)/(No. of cardiac cycles)
(Time/frame)(Blood activity)
where K is a correction constant to adjust for attenuation,
which is usually determined from a regression equation
using contrast angiography as a reference. This usually suf-
fices for most individuals who are of normal size and shape,
heart size, etc. However, in some patients, it is necessary to
correct for individual variations, which can be successfully
done using a simple geometric technique.180,181 Using these
data, stroke volume and cardiac output can be calculated
using radionuclide ventriculography.182,183 When the tomo-
graphic technique is used, ventricular volume is usually cal-
culated using a geometric technique. Knowing the pixel
volume, the ventricular volume can be calculated by
summing the number of pixels in each tomographic section
in the left ventricular ROI. Values obtained using this tech-
nique correlate well with other techniques, and have the
advantage of not requiring any correction for attenuation.184
Valvular regurgitation can be evaluated by calculating
the ratio of left to right ventricular stroke counts.185,186 Nor-
mally, the right and left ventricular stroke volumes are equal.
However, in the presence of valvular regurgitation the stroke
volume is greater in the ventricle with the affected valve.
Ventricular stroke counts are obtained by subtracting the
end-systolic from the end-diastolic frame, resulting in a
stroke volume image. In this image, the activity in the left
and right ventricular regions is proportional to their respec-
tive stroke volumes. These data can be expressed in terms of
either the stroke volume ratio (LV stroke counts/RV stroke
counts, normal value <1.2) or as the regurgitant fraction
(LV-RV stroke counts/LV stroke counts ×100, normal value
<20%). The systematic overestimation of this technique
results from right atrial/right ventricular overlap. Assess-
ment of valvular regurgitation using this technique is some-
what crude. It is not possible to detect mild regurgitation or
clearly quantitate the severity of the regurgitation. In addi-
tion, the accuracy is increasingly compromised when the
LVEF is ≤35%. Valvular regurgitation can also be estimated
using Fourier amplitude images.187
Diastolic function can also be assessed by radionuclide
ventriculography.188 The variables used are the peak filling
rate (PFR), measured as the slope of a third-order polynomial
 n ucle a r ca r diology
FIGURE 6.16. High temporal resolution time-activity curve
obtained from radionuclide ventriculography. Each point represents
20 ms. Variables used to assess left ventricular rapid filling include
peak filling rate (PFR), measured as the slope of a third-order poly-
nomial fit to the rapid filling phase; time to peak filling rate (TPFR),
measured from end-systole; and contributions of rapid diastolic
filling (RDF) and atrial systole (AS), expressed as % of stroke volume.
EDV, end-diastolic volume.
fit to the rapid filling phase, time to peak filling rate (TPFR),
measured from end-systole, and the contribution of rapid
diastolic filling (RDF) and atrial systole (AS) expressed as a
percent of stroke volume (Fig. 6.16). However, noninvasive
assessment of diastolic function, whether obtained using
radionuclide or Doppler-echocardiographic techniques, has
several limitations. These result from the dependence of
these variables of diastolic function on other variables, such
as heart rate, preload and afterload, and ejection fraction,
making their interpretation difficult. Therefore, their clini-
cal utility is limited. However, they may be helpful in
patients with clinical features of cardiac failure but with a
normal ejection fraction.
Regional ventricular function can be assessed either
qualitatively or quantitatively using radionuclide ventricu-
lography. The former method, using visual analysis of an
endless-loop cine display, is the most widely used. There is
good correlation between visual assessments of radionuclide
and contrast ventriculograms, and reproducibility of the two
techniques is comparable.189,190 Quantitative techniques have
been developed and can be broadly classified into geometric
techniques (usually modifications of methods developed for
contrast ventriculography) and nongeometric techniques
specifically designed for radionuclide ventriculography.
The most commonly used nongeometric techniques use
the regional ejection fraction and Fourier transform–derived
phase and amplitude images. The regional ejection fraction
image is obtained by subtracting the background-corrected
end-systolic from the background-corrected end-diastolic
frame.191 The resulting image is normally crescent-shaped,
delineating the left ventricular borders. If there is an area of
regional hypokinesis or akinesis, there is thinning or absence
of the crescent in this area. The data can also be presented
in actual regional ejection fraction values with the left ven-
tricle typically being divided into three or five segments.192
Fourier phase analysis has been applied to the evaluation of
15 3
radionuclide ventriculograms.193 Each pixel has its own time-
activity curve, which is maximal in end-diastole and at
minimum in end-systole, whose fundamental frequency is
determined by the heart rate. The time-activity curve is
sinusoidal in shape and can be approximated using a single
cosine function of the frequency of the time-activity curve.
This allows each pixel within the region of the heart to be
expressed as a single mathematical value, which can be
color-coded. The amplitude of this cosine wave, equivalent
to the change in counts during the cardiac cycle, is propor-
tional to the stroke volume of the pixel. Therefore, the ampli-
tude image gives a regional representation of stroke volume.
For example, in a region of akinesis the pixels will show
time-activity curves of reduced amplitude, resulting in the
amplitude image showing absent activity in that region. The
phase of the cosine wave can also be expressed in a similar
fashion. The R-R interval is considered to represent 360
degrees, with the R wave occurring at 0 degrees, which coin-
cides with the peak of the cosine wave. For pixels in areas of
the ventricle where the onset of contraction is delayed, the
peak of the cosine wave will also be delayed. This may be
the result of either abnormal electrical activation or delayed
onset of contraction, for example, myocardial ischemia or
scarring. This delay can be expressed in terms of phase delay
or increased phase angle. For example, an area of dyskinesis
will result in a phase delay of around 180 degrees. Similarly,
pixels in the atria have time-activity curves that are com-
pletely out of phase with the ventricles, equivalent to a phase
delay of 180 degrees. These data can be expressed in a phase
image, in which each pixel is color-coded according to its
phase angle. Fourier images are useful in evaluating regional
wall motion in patients with coronary artery disease at
rest and exercise.194–196 These images can also identify con-
duction abnormalities and have been used to localize the
site of arrhythmias and also atrioventricular accessory
pathways.197–199
Assessment of Right Ventricular Function
The complex geometry of the right ventricular poses major
problems for all imaging modalities. However, radionuclide
techniques are less geometrically dependent than other con-
ventional imaging techniques, for example, contrast ven-
triculography or echocardiography, for the reasons discussed
earlier. Three radionuclide techniques are used to assess
right ventricular function. The first-pass technique, as
described for the left ventricle, can be applied to the right
ventricle.200 This is probably the optimal technique for
assessing right ventricular function, but suffers from the
disadvantages as discussed previously. The gated equilibrium
technique can also be used, but overlap of cardiac chambers
is a significant limiting factor.201–203 The right ventricular
ejection fraction is calculated from the left anterior oblique
projection, because this affords the best separation of the two
ventricles. However, the right atrial and right ventricular
overlap in this projection, resulting in a systematic underes-
timation of the right ventricular ejection fraction. Despite
this, there is a good correlation with other methods of assess-
ing right ventricular function using this technique.204 A good
compromise is the gated first-pass technique that involves
injecting a bolus of 99mTc pertechnetate and acquiring
15 4 chapter
ECG-gated scintigraphic data from the time the bolus is seen
entering the superior vena cava until it leaves the main pul-
monary artery.205 This gives excellent spatial resolution of
the right atrium and right ventricle with no background
contamination from lungs or the left heart chambers. Radio-
isotopes of inert noble gases, 81Kr and 133Xe, have also been
used to assess right ventricular function.206–209 These radio-
isotopes are rapidly excreted during their first passage
through the lungs, allowing repeated studies to be performed
without significantly increasing the radiation burden to the
patient or problems of increasing background activity.
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 7 Cardiovascular Magnetic
Resonance Imaging
Warren J. Manning
Technical Considerations . . . . . . . . . . . . . . . . . . . . . . . . .
Specific Considerations of Cardiovascular Magnetic
Resonance in the Cardiac Patient . . . . . . . . . . . . . . .
Thoracic Aorta and Great Vessels . . . . . . . . . . . . . . . . . .
Pulmonary Embolism, Pulmonary Artery, and
Pulmonary Vein Assessment . . . . . . . . . . . . . . . . . . .
Quantitative Assessment of Ventricular Volumes
and Mass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Detection of Coronary Artery Disease . . . . . . . . . . . . . .
Key Points
• Spin-echo imaging is commonly used for assessment of
cardiac and great vessel anatomy. With classic spin-echo
imaging, rapidly moving blood appears dark.
• At current field strengths (1.5 and 3.0 tesla), cardiovascu-
lar magnetic resonance (CMR) imaging is considered safe
for bioprosthetic and mechanical heart valves.
• Older (pre-2000) cardiac pacemakers and implantable
defibrillators are an absolute contraindication to higher
field (≥0.5 T) CMR. Patients with newer pacemaker
systems may be safely scanned using specific protocols.
• Cardiovascular magnetic resonance is an important
noninvasive technique for evaluating thoracic aortic
aneurysms.
• The clinical “gold standard” for the diagnosis of pulmo-
nary embolism is contrast CT angiography (CTA). For
patients who are not candidates for CTA due to renal
dysfunction or contrast allergic history, pulmonary
artery magnetic resonance angiography (MRA) is an
excellent noninvasive alternative with high sensitivity
and specificity.
• Cine CMR provides an excellent means for quantitative
assessment of left and right ventricular volumes, global
ejection fraction, regional systolic function, and biven-
tricular mass.
• Available data suggest dobutamine stress CMR is a sensi-
tive technique for the noninvasive recognition of coro-
nary artery disease (CAD).
• Coronary artery bypass graft patency is well evaluated
by spin echo, gradient echo, and gadolinium–diethylene-
triamine pentaacetic acid (DTPA)-enhanced three-
dimensional (3D) enhanced coronary magnetic resonance
imaging (MRI).
162 Native Coronary Artery Disease Integrity . . . . . . . . . . . 169
Coronary Artery Bypass Graft Patency . . . . . . . . . . . . . . 171
163 Myocardial Viability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
164 Nonischemic Cardiomyopathies . . . . . . . . . . . . . . . . . . . 172
Valvular Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
165 Cardiac Tumors and Masses . . . . . . . . . . . . . . . . . . . . . . 174
Pericardium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
166 Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . 175
168 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
• Cardiovascular magnetic resonance provides the non-
invasive means to assess myocardial viability and fibro-
sis accurately.
• Cardiovascular magnetic resonance has great value for
characterizing paracardiac and extracardiac tumors and
their extension into the myocardium, cardiac chambers,
or neighboring mediastinal structures.
• Both spin-echo CMR and CT are capable of measuring
pericardial thickness accurately.
• Cardiovascular magnetic resonance has great utility
for both simple and complex congenital heart disease.
Coronary MRI for identification and characterization of
anomalous coronary arteries is widely accepted.
More than any other noninvasive imaging technique, the
flexibility of cardiovascular magnetic resonance (CMR)
imaging offers the promise to dramatically expand our ability
to evaluate patients with known or suspected cardiovascular
disease. The combined attributes of superior image quality
and flexibility for assessment of cardiac anatomy, ventricular
function, viability, perfusion, valvular function, great vessel
anatomy, blood flow, and native coronary artery and coronary
artery bypass graft integrity give CMR unmatched potential
for the comprehensive evaluation of the cardiovascular
system. Currently accepted clinical applications of CMR
continue to expand rapidly1 (Table 7.1). Hardware (gradients
and high field systems) advances now allow for sub-second
data acquisitions with “real-time” imaging, and software
advances and novel contrast agents promise to further exploit
CMR’s advantages over competing noninvasive imaging
methods. The introduction of a comprehensive CMR exami-
nation,2,3 in which cardiac anatomy, function, viability, per-
fusion, valvular, and coronary artery assessment is performed
161
16 2 chapter 7

TABLE 7.1. Current clinical applications for cardiovascular magnetic resonance (CMR)
1. Indications for CMR in acquired diseases of the vessels
a. Diagnosis and monitoring of thoracic aortic aneurysm, dissection, aortic wall hematoma, and penetrating ulcer
b. Assessment of pulmonary artery dilation and dissection
c. Characterization of pulmonary vein stenosis
2. Indications for CMR in coronary artery disease
a. Assessment of global and regional left and right ventricular systolic function at rest and with pharmacologic stress
b. Assessment of regional myocardial perfusion at rest and stress
c. Determination of viability
3. Indications for CMR in valvular heart disease
a. Assessment of the severity of aortic stenosis and mitral stenosis
b. Quantitative assessment of mitral and aortic regurgitation
4. Indications for CMR in cardiomyopathies and pericardial disease
a. Differentiation of ischemic versus nonischemic cardiomyopathy and underlying etiology (including hypertrophic cardiomyopathy,
noncompaction, arrhythmic right ventricular cardiomyopathy (ARVC), and iron deposition)
b. Characterization of mass, biventricular volumes, and ejection fraction
c. Identification of pericardial thickening, circumferential, and local pericardial effusions
5. Indications for CMR in congenital heart disease
a. Anomalous coronary artery disease
b. Quantification of intracardiac shunt
c. Characterization of simple and complex coronary anatomy
d. Identification of aortic and pulmonary pathology (e.g., coarctation, patent ductus arteriosus)
e. Characterization of anomalies of the ventricles
f. Anomalous pulmonary venous drainage
Adapted from Pennell et al.1

during a single 1-hour session, will lead to decreased utiliza-
tion of other imaging tests (e.g., echocardiography, radionu-
clide ventriculography and radionuclide perfusion, diagnostic
x-ray coronary angiography), especially for follow-up care/
monitoring. Cardiovascular magnetic resonance training
guidelines for both those in fellowship4,5 and practitioners
who have completed fellowship have now been developed.5–7
The relative cost advantage/disadvantage of CMR as com-
pared with these other imaging technologies will need to be
defined by future cost-effectiveness studies.
Technical Considerations
A review of magnetic resonance (MR) physics is beyond the
scope of this chapter, and readers are referred elsewhere.8,9
Unlike other imaging techniques, CMR images may depict
blood and other tissues as bright, dark, or of an intermediate
intensity depending on the specific CMR sequence that is
employed, the use of exogenous contrast, and whether the
tissue of interest (e.g., blood) is rapidly or slowly moving,
and whether blood flow is laminar or turbulent. The most
common CMR approaches are the spin echo (“black blood”),
the k-space segmented gradient echo, and the steady-state
free precession (SSFP; trueFISP, balanced FFE, FIESTA;
“bright blood”) sequences.
Spin-echo imaging is commonly used for assessment of
cardiac and great vessel anatomy. With classic spin-echo
imaging, rapidly moving blood appears dark because a pair
(90 and 180 degrees) of sequential radiofrequency (RF) pulses
is applied. Rapidly moving blood will move out of the imaging
plane during the time interval between these two RF pulses,
leading to an absence of signal, or flow void (i.e., “black
blood”). Stagnant blood, which would be exposed to both RF
pulses, will appear relatively bright. Variations may be high-
lighted when viewing an image containing blood experienc-
ing different phases of the cardiac cycle (e.g., early systole,
where there may be rapid flow in the ascending aorta with
relatively stationary flow in the descending thoracic aorta).
The flow void can be emphasized using thin sections or
longer echo times.
With gradient-echo sequences, commonly used for func-
tion/cine CMR, a single RF pulse is applied with a much
shorter echo time. Little signal is then lost due to washout
effects, but stationary tissue (often surrounding blood vessels;
e.g., muscle) will be saturated because of repeated RF stimu-
lation. Thus, signal from stationary tissues is suppressed
(“dark”) due to repeated RF stimulation, while areas of rapid
blood flow (arterial flow) will have continuous inflow of
unsaturated blood with a resultant “bright” signal. There-
fore, on gradient-echo images, rapidly moving laminar blood
flow appears bright, while stagnant blood will appear rela-
tively “dark.” In addition, areas of turbulent/chaotic blood
flow (corresponding to valvular stenoses, aortic insufficiency,
mitral regurgitation) will appear dark due to local turbu-
lence/phase dispersion. The relative “size” of these signal
voids is dependent on the echo time. Steady-state free preces-
sion imaging is relatively insensitive to inflow effects and
also depicts blood as bright.
Both gradient-echo and SSFP imaging are commonly used
for cine CMR imaging of ventricular and valvular function.
For all CMR imaging sequences, specific prepulses may
highlight or suppress specific tissues (e.g., fat saturation pre-
pulse will suppress signal from fat; inversion recovery (180-
degree) prepulses will emphasize T1-weighting). Exogenous
intravenous contrast [e.g., gadolinium–diethylenetriamine
pentaacetic acid (Gd-DTPA)] may be used in combination
with both spin-echo and gradient-echo approaches and has
been particularly valuable for viability assessment of myo-
cardial fibrosis/scar, for assessment of regional myocardial
perfusion, and for characterization of tumors/masses.10 These
extracellular CMR contrast agents are minimally nephro-
toxic with a highly favorable anaphylaxis profile.11,11a
 c a r d i o va s c u l a r m a g n e t i c r e s o n a n c e i m a g i n g 16 3
Another very useful CMR sequence is phase velocity
mapping, in which the velocity of blood perpendicular to
the imaging plane is encoded, providing localized flow data
somewhat analogous to pulsed Doppler echocardiography.
This approach is particularly valuable for quantifying regur-
gitant volumes and flows through the great vessels, conduits,
and valves.
In contrast to general magnetic resonance applications
outside of the heart, the vast majority of CMR applications
depend on accurate R wave detection for electrocardiographic
(ECG) triggering. In the presence of a rate-controlled irregu-
larly irregular rhythm such as atrial fibrillation, image
quality will be acceptable,12 but high-grade ventricular
ectopy or a regularly irregular rhythm (e.g., trigeminy)
often leads to significant image degradation. In these situa-
tions, real-time CMR is often used, with reduction in spatial
and temporal resolution.13 In limited situations, peripheral
pulse (PPU) triggering may be adequate, but we have gener-
ally found image quality to be inferior to ECG triggering.

Specific Considerations of Cardiovascular

Magnetic Resonance in the Cardiac Patient
In addition to general restrictions regarding CMR [ferro-
magnetic intracranial clips, transcutaneous electrical nerve A
stimulation (TENS) units, intraauricular implants, shrapnel,
etc.], there are also special considerations for CMR (and
general magnetic resonance scanning) in the cardiac patient.
A comprehensive discussion of CMR safety with regard to
implanted devices is beyond the scope of this chapter. Readers
are referred to comprehensive sources (www.mrisafety.
com).14 At current field strengths [1.5 and 3.0 tesla (T)], CMR
imaging is considered safe for both bioprosthetic and mechan-
ical heart valves.14 However, a local image artifact (loss of
signal/image distortion) will occur in the region immedi-
ately surrounding the valve prosthesis (Fig. 7.1). Similarly,
sternotomy wires, thoracic vascular clips, and ostial coro-
nary artery bypass graft markers are not a contraindication

B
FIGURE 7.2. (A) Posteroanterior (PA) chest x-ray in a patient with
LV a prior coronary artery bypass graft surgery with sternal wires (solid
arrow) and bypass graft markers (broken arrow). (B) Gradient-echo
CMR in the transverse plane at the level of the origin of the saphe-
nous vein bypass grafts. Note the artifacts from the saphenous vein
markers (solid arrow) as well as sternal wires (broken arrow).

to imaging, but localized artifacts will be present (Fig. 7.2),

FIGURE 7.1. A single image from a cine cardiovascular magnetic
resonance (CMR) in the two-chamber view. Note the artifact (black
arrow) resulting from a bileaflet mechanical mitral valve prosthesis.
LV, left ventricle.
thereby limiting assessment of adjacent structures. The rela-
tive size of the image artifact is increased with gradient-echo
and SSFP sequences (versus spin-echo sequences). While the
composition metal of intracoronary stents will cause a local
16 4 chapter 7

Thoracic Aorta and Great Vessels

For many years, CMR had its greatest clinical impact on the
assessment of the thoracic aorta in the patient with known
or suspected thoracic aortic aneurysm (Fig. 7.4) or aortic
dissection (Fig. 7.5). Cardiovascular magnetic resonance
compares favorably to spiral or multidetector computed
tomography (CT) because CMR employ no ionizing radiation
or requirement for potentially nephrotoxic iodinated con-
trast. Comprehensive data regarding the presence of a dissec-
tion, entry and exit points, the presence of intraluminal
thrombus, involvement of the great vessels, and coexistent
aortic insufficiency and pericardial effusion are also readily
obtained. Transverse, coronal, and sagittal images using
ECG gating T1-weighted spin-echo techniques are initially
acquired for anatomic imaging.19,20 The sine qua non of aortic
dissection for spin-echo imaging is the identification of an
intimal “flap” separating the true and false lumen. Breath-
hold 3D contrast-enhanced (CE) magnetic resonance angio-
gram (MRA) is then obtained to define the aortic lumen
either with21 or without22,23 ECG gating. Cine SSFP or gradi-
ent-echo acquisitions can then be obtained if a dissection
flap is identified. In addition to the classic finding of an
intimal flap, eccentric aortic wall thickening may also be
seen, possibly representing an early dissection or intramural
hematoma.24 In experienced hands, CMR, CT with iodinated
contrast, and multiplane transesophageal echocardiography

FIGURE 7.3. Gradient-echo coronary CMR in a patient with a

widely patent mid-left anterior descending (LAD) stent. Note the
signal void in the area corresponding to the stent (white arrows)
with visualization of the LAD lumen proximal and distal to the
stent.

susceptibility effect (dark area) (Fig. 7.3), no adverse events

have been reported at 1.5 T,15 yet for many years, patients
receiving intracoronary stents were instructed to avoid all
MR scanning for at least 2 months. This error has now been
corrected with the April 2005 decision by the United States
Food and Drug Administration (FDA) to approve immediate
MR scanning for both the Boston Scientific (Boston, MA) and
Johnson & Johnson drug-eluding stents.
The area of safety with regard to CMR scanning among
patients with cardiac pacemakers and implantable cardiode-
fibrillators (ICDs) is currently in a state of flux. When CMR
is the only imaging modality available, uncomplicated CMR
has been performed at low field strengths (0.2 T) using spe-
cific protocols16 and with proper safeguards in place. Such
devices (and the presence of permanent pacemaker leads
alone) had been considered an “absolute” contraindication to
higher field (≥0.5 T) CMR scanning due to the potential for
unpredictable device reprogramming, myocardial stimula-
tion, or heating of the device leads.14 Protocols have now been
described for safe scanning at 1.5 T for patients with modern
(post-2000) pacemaker systems.17,18 This area is likely to
receive considerable attention and will evolve in the coming FIGURE 7.4. Aortic aneurysm: three-dimensional (3D) coronary
years. magnetic resonance angiogram (MRA).
 c a r d i o va s c u l a r m a g n e t i c r e s o n a n c e i m a g i n g 16 5
(TEE) have similarly high sensitivity, specificity, and accu-
racy for identification of thoracic aortic dissection.19,20,25–27
Cardiovascular magnetic resonance and spiral or multidetec-
tor CT have specific advantages (as compared with multi-
plane TEE) for providing information regarding the extent of
the dissection into the great vessels and abdominal aorta.
Both TEE and CMR also permit determination of aortic valve
involvement and aortic insufficiency (Fig. 7.5), though valve
morphology is better defined by TEE. Both TEE and CMR
can often provide information regarding the involvement of
the proximal coronary arteries. Study time and access are
important factors in the choice of imaging test. For CMR
aortic dissection assessment, a comprehensive assessment
can usually be completed within 30 minutes, with close
patient monitoring. We generally recommend CMR (or CT)
for patients who are hemodynamically stable and for follow-
up studies in younger patients with chronic aneurysms or
dissection, refer stable older patients with good renal func-
tion to CT, and utilize TEE for those with clinical instability,
claustrophobia, or renal dysfunction.
In addition to aortic aneurysm and dissection, CMR is
also useful for the assessment of congential aortic lesions
such as aortic coarctation (Fig. 7.6) and patent ductus arterio-
sus, as well as more complex abnormalities involving the FIGURE 7.6. A 3D contrast-enhanced (CE) magnetic resonance
great vessels (discussed later). Phase velocity methods may angiogram (MRA) in a 17-year-old boy with an aortic coarctation
be used to quantify velocity gradients28 as well as flow (arrow). Note the extensive collateral vessels.
through shunts and to quantify pulmonic–systemic flows.
From a practical perspective, patients with congenital car-
diovascular lesions are often referred for CMR imaging for fied or suspected on a prior imaging (echocardiography, x-ray
confirmation or better definition of an abnormality identi- angiography) study.

Pulmonary Embolism, Pulmonary Artery, and

F arteries branch in a complex fashion, with their diameter
T nary trunk and the proximal portions of the right and left
FIGURE 7.5. Coronal diastolic frame cine gradient-echo CMR in a
patients with an ascending aortic dissection (black arrows). Note
the dissection flap (black arrows) begins immediately superior to the
aortic valve leaflet. Flow is seen in both the true (T) and false (F)
lumen. Signal void (white arrow) from local turbulence is seen in
the left ventricular cavity immediately below the aortic valve and
is due to associated aortic insufficiency.
Pulmonary Vein Assessment
Compared to imaging of the aorta, CMR of the pulmonary
artery is more technically demanding of patient cooperation,
with breath-holding due to artifacts related to motion as
the lungs expand and collapse. Additionally, the pulmonary
progressively decreasing at each bifurcation. Finally, suscep-
tibility between the blood–tissue interface and air leads to
signal loss at the vessel–lung interface. Although spin-echo
approaches can be used to define the anatomy of the pulmo-
main pulmonary arteries, 3D CE-MRA is the mainstay of
pulmonary artery assessment.29,30 This is especially applica-
ble to patients who are suspected of having acute (or chronic)
pulmonary thromboembolism. The clinical “gold standard”
for the diagnosis of pulmonary embolism is contrast x-ray
pulmonary angiography and CT angiography (CTA). The
latter has become extremely popular with the widespread
availability of multidetector CT scanners in the emergency
department. For patients who are not candidates for pulmo-
nary CTA due to renal dysfunction or contrast allergic
history, pulmonary artery MRA is an excellent noninvasive
alternative with high sensitivity and specificity. Similar to
conventional angiography, pulmonary emboli present as an
abrupt discontinuation (signal void) of the arterial lumen
(Fig. 7.7). Pulmonary artery dissection is a rare condition
that may mimic aortic dissection in symptoms, for which
16 6 chapter
FIGURE 7.7. Pulmonary artery 3D CE-MRA in a patient with a
pulmonary embolism (arrow) with abrupt loss of vasculature.
pulmonary artery CE-MRA as well as gradient-echo and
spin-echo methods have been shown to be quite accurate.31
With increasing interest in pulmonary vein ablation as
a mainstream therapy for patients with atrial fibrillation,
monitoring of patients for asymptomatic pulmonary vein
stenosis has become important. Pulmonary vein CE-MRA
has been shown to be a very accurate method for monitoring
the size of the pulmonary arteries32–34 and for identifying
stenoses32,34,35 (Fig. 7.8). Preliminary data suggest identifica-
tion of the ablation site is also possible using delayed enhance-
ment CMR methods.35a
Quantitative Assessment of Ventricular
Volumes and Mass
Although rarely used for first-line assessment, volumetric
cine CMR is becoming increasingly recognized as the clini-
cal gold standard for the quantitative assessment of left and
7
FIGURE 7.8. Pulmonary vein CE-MRA in a 65-year-old man with
atrial fibrillation who underwent pulmonary vein ablation 1 month
previously. Note the focal stenosis (arrow) of the left lower pulmo-
nary vein.
right ventricular volumes, global ejection fraction, regional
systolic function, and biventricular mass (Fig. 7.9) in patients
with known disease. Cardiovascular magnetic resonance is
used for validation of ventricular volumes assessed by
new technologies such as 3D echocardiography and cardiac
CT.36–38 Advantages of CMR include the ability to obtain
high temporal and spatial resolution tomographic data in
true short- and long-axis orientations, the outstanding endo-
cardial border definition provided by current SSFP sequences,
and the relative ease of data analysis. Semiautomated
methods allow for the delineation of the endocardial and
epicardial borders with very high accuracy and reproduc-
ibility for determination of ventricular volumes, stroke
volume, and ejection fraction both in normal and focally
deformed ventricles.39–42 As compared with M-mode or 2D
echocardiography, which is limited to acoustic windows
with suboptimal results in many obese and elderly patients,
comprehensive, high temporal and spatial resolution true
short-axis volumetric data sets are easily acquired in nearly
all subjects in less than 8 minutes. Though in theory 3D
echocardiography and cardiac CT offer similar volumetric
data, the superior spatial (versus 3D echocardiography) and
FIGURE 7.9. End-
diastolic (ED) and end-
systolic (ES) images
from cine short-axis
data sets demonstrating
the use of endocardial
border definition and
calculation of end-dia-
stolic and end-systolic
volumes.
 c a r d i o va s c u l a r m a g n e t i c r e s o n a n c e i m a g i n g 167

A A

B
FIGURE 7.10. Cine steady-state free precession (SSFP) images in the
(A) two-chamber and (B) short-axis orientations demonstrating
prominent trabeculations (arrows) consistent with noncompaction.

temporal (versus CT) resolutions of CMR make it the strong

preference when accurate and reproducible assessments are
needed. Volumetric CMR is especially valuable for quantita- B
tive information regarding left ventricular volume and mass
in patients with asymmetric deformations/hypertrophy, and
defining cardiomyopathies (such as hypertrophic cardiomy-
opathy and noncompaction (Fig. 7.10),43 or monitoring ven-
tricular volumes in patients with regurgitant valvular lesions.
Left ventricular aneurysms may be recognized as severe wall
thinning (less than 4 mm) and diastolic bulging of the left
ventricular free wall (Fig. 7.11). Left ventricular pseudo-
aneurysm or false aneurysms may also be readily identified
on CMR due to their lack of myocardium in the wall of the
aneurysm44 with relatively narrow neck. The superior repro-
ducibility of CMR for both left and right ventricular mea-
sures thereby provides more clinical utility in the monitoring

FIGURE 7.11. (A) Cine SSFP two-chamber and delayed enhance-

ment CMR in the (B) two-chamber and (C) short axis orientation of
a 54-year-old patient with an inferior infarction and aneurysm. Note
the transmural hyperenhancement (B,C) that is visible in the infe-
rior and inferolateral walls with a small thrombus (B, arrow) visible
along the subendocardial border.

C
16 8
of patients.42,45,46 Volumetric CMR methods are also ideal for
regional left ventricular assessment with the 17-segment
model (six basal, six middle, four apical, with a true apex)47
that is generally utilized. Left ventricular mural thrombi
may be identified on spin-echo images as a density/mass
filling the left ventricular apex, especially in an area corre-
sponding to a left ventricular aneurysm44,48 or as filling
defects on cine gradient-echo or SSFP imaging. Delayed
enhancement (DE) CMR methods may also depict transmu-
ral hyperenhancement in the wall of a true aneurysm with
the subendocardial area of hypoenhancement corresponding
to a chronic left ventricular thrombus49,50 (Fig. 7.11). Accurate
quantitative evaluation of right ventricular volumes, ejection
fraction, and mass is also a relatively unique attribute of
CMR.51 For regional assessment of both right and left ven-
tricular systolic function, myocardial tagging techniques
have been shown to be more sensitive for quantitation of
local dysfunction,52,53 though their clinical role remains to
be defined.
Detection of Coronary Artery Disease
In addition to ventricular volumes and global/regional sys-
tolic function, CMR offers several approaches for detecting
and evaluating patients with known or suspected coronary
artery disease. These include pharmacologic stress testing
with β-agonists (regional dysfunction), vasodilators (perfu-
sion deficits), viability imaging, and coronary artery
imaging.
Due to distortions of the ECG related to the magnetohy-
drodynamic of pulsatile blood in the aorta, the ECG is unin-
Rest 10 μg/kg/min 20 μg/kg/min
chapter 7
terpretable for ischemia within the CMR environment. Thus
real-time monitoring of wall motion and close patient super-
vision is imperative. Physiologic stress is possible within the
CMR environment, and supine bicycle ergometry units have
been developed for such an application,54 but pharmacologic
stress is more commonly used in combination with graded
doses of dobutamine (similar protocols to that used for dobu-
tamine stress echocardiography), with cine images typically
acquired in the four- and two-chamber orientations along
with three short-axis levels (base, middle, apical) at baseline
and at each level of dobutamine (Fig. 7.12). Data suggest that
dobutamine stress CMR is more sensitive for the detection
of coronary artery disease (versus dobutamine stress echo-
cardiography).55–57 This superiority is directly related to the
enhanced ability of CMR to visualize/define all of the myo-
cardial segments.50 A study that compared dobutamine CMR
stress with vasodilator CMR stress found dobutamine wall
motion CMR to be superior (Fig. 7.13).58 The combination of
CMR resting left ventricular ejection fraction and inducible
ischemia has prognostic value among patients with known
coronary artery disease.59 Cardiovascular magnetic reso-
nance tagging methods may offer superior sensitivity,60 but
they are less commonly used.
Early applications of CMR myocardial perfusion methods
were limited in ventricular coverage, with current methods
now acquiring data at three to six short-axis levels during
the first passage of Gd-DTPA (0.05 mmol/kg) administered
as a tight bolus into the right antecubital fossa. Both visual
and quantitative methods (upslope) have been utilized and
validated in animal models.61–63 Comparison studies with x-
ray angiography and radionuclide imaging are very good.64–66
Cardiovascular magnetic resonance protocols of myocardial
perfusion may include assessment of perfusion at rest and
40 μg/kg/min
FIGURE 7.12. Common display used for real-
time monitoring and subsequent interpreta-
tion of dobutamine stress CMR images. Images
at rest and gradations of stress are displayed
simultaneously for review in the short axis (top
two rows) and horizontal long axis (bottom
row).
 c a r d i o va s c u l a r m a g n e t i c r e s o n a n c e i m a g i n g
0.9
0.8
0.7
0.6 0%
1–25%
0.5
26–50%
0.4
51–75%
0.3
76–100%
0.2
0.1
0 None
A B
FIGURE 7.13. (A) Likelihood of functional recovery following
mechanical revascularization as a function of transmural hyperen-
hancement with delayed-enhancement (DE)-CMR in patients with
regional systolic dysfunction. Dysfunctional regions without any
enhancement have a >80% likelihood of functional recovery while
those with >50% transmural hyperenhancement have <10% likeli-
at peak stress or a single peak-vasodilator assessment with
normal resting systolic function used as a surrogate for
normal perfusion. Vasodilator perfusion CMR has demon-
strated an improvement in myocardial perfusion reserve
after a percutaneous coronary intervention67 and impaired
subendocardial perfusion in syndrome X.68
Native Coronary Artery Disease Integrity
Cardiovascular magnetic resonance is used routinely for
evaluation of vascular beds throughout the body, but coro-
nary MRI is more technically challenging due to the small
caliber, tortuosity, and motion related to both the respiratory
and cardiac cycle. As a result, CMR assessment of native
coronary artery integrity continues to be a field of rapid
evolution with recent competition from coronary CTA
methods. The relative strengths of coronary MRI include
both the lack of substantial ionizing radiation69 or the need
for potentially nephrotoxic/anaphylactic iodinated contrast,
or the need to induce bradycardia with beta-blockade. Another
disadvantage of coronary CTA is the difficulty with lumen
integrity assessment among patients with high risk70 and
older patients due to prominent epicardial calcium.71 Pre-
liminary data suggest that epicardial calcium does not
provide the same interference with coronary MRI depiction
of the lumen (Fig. 7.14).72
Since the initial descriptions of 2D breath-hold coronary
MRI,73–75 the field has advanced to 3D acquisition methods
(double-oblique slab or larger axial stack analogous to coro-
nary CTA) with submillimeter spatial resolution and supe-
rior reconstruction capabilities. The spatial resolution of 3D
coronary MRI remains inferior to coronary CTA and x-ray
coronary angiography, thereby precluding quantitative
assessments, although the magnitude of the local signal void
does correlate with angiographic stenosis.75 Data acquisition
also remains relatively prolonged at 10 to 20 minutes. Despite
16 9
100
90
80
70
60 Prevalence
50 Specificity
40 Sensitivity
30 Correct
20
10
0
1–24 25–49 50–74 75–100
hood of recovery. An intermediate finding demonstrates reduced
predictive accuracy. (B) Sensitivity, specificity, and accuracy of low-
dose dobutamine for prediction of functional recovery after mechan-
ical revascularization appears to be superior to DE-CMR, especially
for those with 1% to 49% transmural hyperenhancement.
this limitation, the feasibility of identifying stenoses in the
proximal and midcoronary segments has been demonstrated
in several single centers.76,77 At present, some approaches
(free breathing navigator with real-time motion correction)
remain vendor specific, making multicenter multivendor
trials difficult to perform and interpretation of the literature
more complicated. We continue to prefer a targeted 3D
free-breathing segmented k-space gradient-echo sequence78,79
using patient specific delay and short acquisition (less
than 90 ms/R-R interval) periods.80 With this approach, high
signal intensity (bright blood) represents normal, laminar
blood flow, with low signal (signal void) at sites of
stenosis and focal turbulence (Fig. 7.15). Despite superior
spatial resolution of multidetector CT, a head-to-head
comparison of 3D coronary MRI with 16-slice multidetector
(using quantitative x-ray coronary angiography as the
gold standard) showed similar diagnostic accuracy,81 includ-
ing sensitivity and specificity of 75% and 77% for coronary
MRI and 82% and 79% for coronary CTA, respectively.
A multicenter trial of over 100 patients from seven
international sites demonstrated high sensitivity but only
modest specificity for identifying focal stenoses, with very
high accuracy for discriminating between patients with
multivessel disease and no disease.82 For this reason, we
offer coronary MRI as a clinical option for patients
presenting with a dilated cardiomyopathy in the absence
of a history of acute infarction. Preliminary data from a
group of patients with depressed left ventricular systolic
function83 suggest that coronary MRI is superior to DE-
CMR for discriminating between these two subsets. Tar-
geted 3D approaches using SSFP methods84 or a “whole heart”
SSFP methodology that supports extensive reconstructions
(Fig. 7.16),85,86 somewhat analogous to multidetector com-
puted tomography (MDCT) acquisitions (though inferior in
spatial resolution), have been advocated. Comparative data
suggest longer vessel segments have been identified, with
improved signal-to-noise ratio (SNR) and contrast-to-noise
 17 0 chapter 7

B
FIGURE 7.15. RCA (A) targeted 3D free breathing navigator coro-
nary MRI and corresponding (B) projection x-ray angiogram in a
patient with a mid-RCA stenosis (arrow).

ratio (CNR) with SSFP whole heart acquisitions,85,86 but

C likely that coronary MRI methods will get faster and more
FIGURE 7.14. Right coronary artery (A) projection x-ray angiogram,
(B) 16-slice multidetector computed tomography (MDCT), and (C)
coronary MRI in a patient with prominent epicardial calcium. Note
that the ostial right coronary artery (RCA) stenosis (arrow) is visible
on the x-ray angiogram and the coronary MRI, but not on the
MDCT.
similar diagnostic results.84,86 Preliminary data suggest
similar overall results with 3T coronary MRI.87 It is very
automated with subsequent application of powerful CT ana-
lytic tools to the 3D CMR data sets.
Although not yet routine due to issues of spatial resolu-
tion, another advantage of coronary MRI (vs. coronary CTA)
is the application of phase velocity flow methods to assess
coronary artery blood flow and flow reserve. For patients who
 c a r d i o va s c u l a r m a g n e t i c r e s o n a n c e i m a g i n g 171

Ao

graft

FIGURE 7.16. Whole heart coronary MRI reconstruction in a

* graft
patient with a proximal left anterior descending branch (LAD)
stenosis.

have experienced a myocardial infarction, phase velocity

CMR can accurately evaluate the presence of antegrade flow
in the infarct-related artery.88 The noninvasive determina-
tion of patency influences therapy and prognosis in these
patients.
A

Coronary Artery Bypass Graft Patency

In comparison with native vessel coronary MRI, CMR of
coronary artery bypass grafts (both saphenous veins
and internal mammary arteries) is facilitated by their rela-
tively stationary anterior location, straight and predictable
course, and their greater lumen diameter. Adequate flow is
visualized as a signal void (spin-echo) or as bright signal
(gradient-echo, contrast imaging) in the anatomic location
corresponding to the expected graft position. Identification
of flow in at least two contiguous slices, or obtained at dif-
ferent planes perpendicular to the expected bypass graft
course suggests patency. If flow is suggested at only one level,
graft patency is considered “indeterminate,” and if there is
no evidence of flow in any portions of the graft, the graft is
considered “occluded.” Spin-echo (dark blood), gradient-echo
(bright blood), and Gd-DTPA–enhanced 3D coronary MRI
have been reported to have higher sensitivity (95–100%) for
patency of both saphenous venous and internal mammary
grafts.89–93 Focal disease can be identified using a 3D coro-
nary MRI sequence94 (Fig. 7.17). The addition of phase veloc-
ity imaging of graft flow95 is also useful for discriminating
vein graft patency, especially for jump grafts.
Implanted metallic clips, markers (Fig. 7.2), or intracoro-
nary stents15,96 (Fig. 7.3) will have a local signal void, preclud-
B
FIGURE 7.17. (A) Targeted 3D free breathing navigator coronary
MRI and corresponding (B) projection x-ray angiogram in a patient
with a stenosis (arrow) of a saphenous vein graft. Ao, aorta.
ing assessment in these regions. These artifacts, which are
commonly located in very close proximity to the coronary
arteries or grafts, preclude the assessment of these vessels.
As mentioned earlier, both drug eluding stents currently
marketed in the United States are FDA approved for CMR
scanning immediately after implantation.
Myocardial Viability
Few applications of CMR have been so rapidly embraced
by the clinical community as its ability to characterize myo-
cardial fibrosis and thereby derive prognostic data regarding
physiologic viability—the likelihood that resting regional
left ventricular dysfunction will improve with mechanical
revascularization. Extensive correlative CMR and histologic
17 2 chapter 7

studies in animal models have demonstrated that extracel-

lular Gd-DTPA will localize/concentrate to areas corre-
sponding to scar/fibrosis on histology and can be recognized
using delayed enhancement CMR imaging.97,98 Using an
inversion recovery sequence with imaging 10 to 20 minutes
following injection of 0.1 to 0.2 mmol/kg of Gd-DTPA, areas
of hyperenhancement correspond to scar/fibrosis (Fig. 7.11)
with highly reproducible results.99 Delayed-enhancement
CMR studies have demonstrated that the lack of hyperen-
hancement is a very strong predictor of functional viability
(Fig. 7.13), while the presence of more than 50% transmural
hyperenhancement is a powerful predictor for the lack of
functional recovery.100–102 An intermediate finding (1% to
49% transmurality) is less useful. For this group, regional
systolic response to low-dose dobutamine appears superior58
(Fig. 7.13). Delayed-enhancement CMR also compares favor- A
ably with electromechanical mapping103 and clinical posi-
tron emission tomography.104
The DE-CMR method appears to be particularly superior
to wall thinning for the discrimination of viable myo-
cardium. Anecdotal reports105 and preliminary data from
a multicenter series106 reported that 20% of subjects with
thinned, akinetic segments have lack of hyperenhancement
of those segments. Following mechanical revascularization,
these segments demonstrate markedly improved systolic
thickening in addition to local hypertrophy/normalization of
diastolic wall thickness. Delayed-enhancement CMR also
appears to be superior to global left ventricular ejection frac-
tion for identification of patients with underlying substrate
for sustained ventricular tachycardia.107

Nonischemic Cardiomyopathies
Initial studies suggested that hyperenhancement may be spe-
cific for coronary artery disease.108 Subsequent studies have
shown that hyperenhancement may occur in a variety of
nonischemic myopathic conditions including hypertrophic
cardiomyopathy109–111 (Fig. 7.18), Fabry’s disease,112 sarcoid-
osis,113 myocarditis,114,115 and Churg-Strauss syndrome.116 A
diffuse pattern of hyperenhancement is seen in amyloid car-
diomyopathy.117 Though not totally specific for myocardial
infarction, a subendocardial hyperenhancement correspond-
ing to a coronary artery distribution is far more common
among patients with ischemic cardiomyopathy, while
patients with nonischemic myopathies more often demon-
strate a hyperenhancement pattern of the midventricular or
epicardial layers that also do not correspond to a coronary
distribution.110,112,114–116 Two studies83,118 have suggested that
the pattern may be used to characterize the cause of a dilated
cardiomyopathy, although 25% of patients with a “coronary
disease” hyperenhancement pattern had a nonischemic
myopathy. Thus, coronary MRI may be superior.83 Among
patients with a dilated cardiomyopathy given carvedilol, the
absence of hyperenhancement predicts a regional improve-
ment in systolic function, global improvement in left ven-
tricular ejection fraction, and decrease in left ventricular
cavity size.119
The ability of CMR to acquire images of the entire heart
in true tomographic planes makes it ideal for the evaluation
of patients with hypertrophic cardiomyopathies, especially
B
FIGURE 7.18. (A) Cine steady-state free precession (SSFP) short axis
and corresponding (B) DE-CMR in a 17-year-old patient with hyper-
trophic cardiomyopathy. Note the prominent septal hypertrophy
with an area of hyperenhancement at the juncture of the right ven-
tricular free wall and septum (arrow).
important for evaluation of patients with focal/asymmetric
hypertrophy (Fig. 7.18). Both DE-CMR109–111 and investigative
CMR “tagging” methods may assist in the assessment of
these patients,120 though the latter remains to be more fully
elucidated. Serial CMR examinations may be useful to
monitor ventricular remodeling and infarction size follow-
ing alcohol ablation.121
In addition to biventricular volumetric and mass data,
CMR may confirm excess iron deposition122 as the cause of
depressed systolic function in a patient with suspected hemo-
chromatosis. Assessment of septal T2* has been shown to
reflect myocardial iron stores, with T2* of less than 20 ms
indicating iron overload.123
Cardiovascular magnetic resonance’s ability to identify
focal areas of fat and fibrosis is particularly valuable in the
evaluation of patients with suspected arrhythmogenic right
ventricular cardiomyopathy. This condition, in which the
right ventricular free wall myocardium is diffusely or focally
replaced with fatty or fibrous tissue with cavity dilation and
focal wall thinning (or aneurysm), is associated with ven-
tricular arrhythmias and sudden death. Spin-echo MRI can
 c a r d i o va s c u l a r m a g n e t i c r e s o n a n c e i m a g i n g
A defined by a cine acquisition oriented orthogonal to the valve
B tion of the dephasing artifact.132 This is particularly true of
FIGURE 7.19. (A) Spin-echo CMR. Note the bright signal in the
thinned right ventricular free wall (arrow) consistent with fatty
infiltration. (B) Delayed enhancement imaging after administration
of Gd-DTPA with enhancement of the right ventricular free wall.
be used to identify transmural or focal fatty infiltration in
the right ventricular free wall as well as focal wall thinning
(Fig. 7.19).124,125 Delayed-enhancement CMR with right
ventricular free wall hyperenhancement has also been
described,126 with the clinical history best able to discrimi-
nate hyperenhancement due to right ventricular infarction
from that of a primary cardiomyopathy.
Valvular Heart Disease
The clinical adoption of CMR in the care of patients with
valvular heart disease is expanding. Once almost solely the
province of 2D and Doppler echocardiography, the unique
quantitative nature of CMR with regard to ventricular
volumes and function, as well as the ease in calculation of
regurgitant volumes, has brought CMR to the clinical arena
for the care of this large group of patients. Valve morphology
(e.g., bicuspid valve) is easily recognized by CMR with acqui-
17 3
sition of a cine SSFP data set through the plane of the aortic
valve. For now, leaflet thickening, calcification, vegetations,
abscess, and minor degrees of mitral valve prolapse largely
remain the province of echocardiography, though obvious
prolapse and partial leaflet flail are readily identified on cine
CMR imaging.
For the assessment of aortic valve stenosis, two CMR
approaches are utilized: a morphologic/2D assessment with
planimetry of the maximum systolic aortic valve area127 on
orthogonal cine SSFP sequences, and a continuity equation
“equivalent.”128 Difficulties with the anatomic (2D measures)
include orientation of the slice among patients with mark-
edly deformed valves, while difficulties with the continuity
equation approach include orientation of the imaging plane
perpendicular to the maximal velocity jet and dephasing/
artifacts due to turbulence in patients with severe aortic
stenosis. Analogous approaches are used for assessing mitral
stenosis, including 2D planimetry of the mitral valve area as
plane129 and with the use of phase velocity mapping at the
level of the mitral leaflet tips,130 thereby applying a pressure-
half-time equivalent measurement. Difficulties with the
former again include proper orientation orthogonal to flow,
while limitations of the latter include the relatively poor
temporal (vs. Doppler echocardiography) resolution and dia-
stolic artifacts among the many patients with coexistent
mitral stenosis and atrial fibrillation.
The use of CMR for the quantitative assessment of val-
vular regurgitation is much more direct and highly quantita-
tive. Qualitative assessment of mitral and aortic regurgitation
had initially been by qualitative estimate of the flow distur-
bance (signal void) in the receiving chamber in a manner
somewhat analogous to color Doppler. These early studies
showed a good correlation with Doppler echocardiography.131
However, the subsequent introduction of strong gradients
and shorter echo times led to attenuation and near elimina-
the newer SSFP acquisitions, which have become “standard”
at most CMR centers, with the nearly complete elimination
of regurgitant jets. Fortunately, CMR offers a more quantita-
tive approach. Using phase velocity mapping, flow is mea-
sured across the aortic valve (from a practical perspective,
this is often obtained in the axial plane at the level of the
bifurcation of the pulmonary artery). Such an assessment
includes a direct quantitative assessment of aortic regurgita-
tion (Fig. 7.20). For mitral regurgitation, we generally quan-
tify the mitral regurgitant volume as the difference between
the left ventricular stroke volume (derived from the contigu-
ous short axis left ventricular stack) and the forward flow out
of the aorta. Another option is to directly measure mitral
regurgitation volume using phase velocity mapping at the
level of the mitral annulus. We have found the latter approach
to be technically more challenging due to the base to apex
motion of the annulus during systole and eccentric, high-
velocity mitral regurgitation jets, which sometimes lead to
errors, analogous to some of the limitations of quantitative
Doppler echocardiography.
Beyond simple calculation of regurgitant volume, CMR
provides for the ready determination of regurgitant fraction
(regurgitant volume/stroke volume), regurgitant volume
index (regurgitant volume/end-diastolic volume), and effec-
 174 chapter 7

3D CMR data sets to be reconstructed in any orientation

Haselkorn STR retrospective helps to guide the surgical approach in such situations.
350 Though rarely difficult to diagnose from echocardio-
300 graphic images, benign lipomatous hypertrophy of the inter-
250 atrial septum as visualized on transthoracic echocardiography
Flow (mL/s)

(TTE) or TEE may sometimes lead to the misdiagnosis of an

200
atrial septal “tumor.” The characteristic, very intense signal
150 Asc Ao from fatty tissue134 with suppression using a fat saturation
100 prepulse readily allows for the CMR diagnosis of this benign
RV.5.12mL
50 disorder.
0
0 200 400 600 800 1000 1200
–50
–100
Pericardium
Time (ms)
A The normal pericardium extends around the heart as a thin
black line between visceral and parietal pericardial fat on
Kass STR retrospective 2
spin-echo CMR imaging. Normal pericardial thickness is
700 3 mm or less.135 Among patients presenting with constrictive
600 cardiomyopathy, often following recurrent pericarditis or
500 mediastinal radiation, the pericardium is thickened (Fig.
Flow (mL/s)

400 7.21), a finding that is readily appreciated by ECG-triggered

300 spin-echo CMR. Gradient-echo methods are slightly less reli-
Asc Ao able for pericardial thickness.136 Computed tomography is
200
also valuable in this situation, and is better suited for the
100
specific assessment of pericardial calcifications (see Chapter
0
0 200 400 600 800 1000 1200 67). It should be remembered, however, that while CMR (and
–100
RV:66.77mL CT) will accurately quantify focal pericardial thickening,
–200 the presence of thickened pericardium alone is not diagnos-
Time (ms)
B tic of constrictive physiology, and constriction may be present
FIGURE 7.20. Integrated phase velocity data acquired in the proxi- in the absence of pericardial thickening.137 Cardiovascular
mal ascending aorta (Asc Ao) in a patient (A) without and (B) with magnetic resonance tagging methods demonstrate adherence
severe aortic regurgitation. Note the persistence of “negative” flow
throughout diastole in the patient with severe aortic regurgitation
of the pericardium to underlying epimyocardium.138 Among
with a total of 56 mL of aortic regurgitation. patients with constriction, CMR also frequently demon-
strates thickened pericardium in concert with an enlarged
inferior vena cava alone, right atrial and right ventricular
enlargement,136 and abnormal septal motion (with real-time
tive forward ejection fraction (net forward stroke volume/ CMR). Though echocardiography is generally adequate for
end-diastolic volume). These same measures can be equally circumferential effusions, CMR depicts transudative effu-
well applied for pulmonic and tricuspid regurgitation. sions as areas of high intensity and may be particularly
Another advantage of CMR versus echocardiography and
invasive measures is the ability to easily quantify the regur-
gitant volumes attributable to each valve in the presence of
serial regurgitant lesions (e.g., mitral regurgitation and aortic
regurgitation).

Cardiac Tumors and Masses

Although the high spatial resolution of CMR allows for
depiction of intracavitary tumors/masses (e.g., myxoma),
these intracavitary “masses” are generally well appreciated
and characterized using conventional echocardiography
(transthoracic or transesophageal). However, the sensitivity
and accuracy of transthoracic echocardiography for mural
left ventricular thrombi has recently been called into ques-
tion by an operative series that suggested far superior accu-
racy of DE-CMR (Fig. 7.11).49,50 Cardiovascular magnetic
resonance also has great value for characterizing paracardiac
FIGURE 7.21. Cine four-chamber SSFP image in a 45-year-old man
and extracardiac tumors133 and their extension into the myo- with recurrent pericarditis and symptoms of constriction. Note the
cardium, cardiac chambers, or neighboring mediastinal thickened pericardium with fluid (arrow) and stranding within the
structures (e.g., vena cavae, pulmonary veins). The ability of pericardial space.
 c a r d i o va s c u l a r m a g n e t i c r e s o n a n c e i m a g i n g
helpful in the delineation of loculated effusions, especially
in patients with suboptimal echocardiographic windows.
Delineation of hemorrhagic and transudative effusions is
another attribute of CMR.
Congenital Heart Disease
An extensive review of CMR applications for congenital
heart disease is beyond the scope of this chapter. As previ-
ously mentioned, CMR has great utility for both simple and
complex congenital heart disease. While hemodynamically
significant atrial septal defects and ventricular septal defects
are usually identifiable by TTE or TEE, phase-velocity CMR
is highly accurate and valuable for quantifying the pulmo-
nary/systemic flow ratio in patients with known defects139
and characterizing congenital heart disease outside of the
cardiac chambers. These defects include aortic coarctation
(Fig. 7.6), anomalous pulmonary venous drainage (Table 7.1;
Fig. 7.22), and complex congenital heart disease in patients
who have undergone corrective or palliative surgery. For
these patients, CMR defines structural components and their
relationships, including serial evaluation and planning of
subsequent surgical interventions.
Coronary MRI for identification and characterization of
anomalous coronary arteries is widely accepted as a clinical
tool. This condition is found in less than 2% of the popula-
tion and is generally benign. However, there is an increased
risk of sudden death and myocardial infarction when the
anomalous vessel courses between the aorta and pulmonary
artery (Fig. 7.23). Even among patients with anomalous coro-
nary arteries identified by invasive x-ray angiography, the
RA
FIGURE 7.22. A 3D CE-MRA in a patient with an anomalous pul-
monary vein (solid arrow) entering the superior vena cava (dashed
arrow). RA, right atrium.
175
RCA
MPA
L
R
LA
RV
FIGURE 7.23. Reconstruction of targeted 3D free-breathing naviga-
tor coronary MRI in a patient with an anomalous right coronary
artery of the “malignant” form originating from the left (L) coronary
cusp. LA, left atrium; MPA, main pulmonary artery; R, right coro-
nary cusp; RV, right ventricle.
anatomic course of the vessel may be misinterpreted owing
to the projection method or operator inexperience, especially
with the declining routine use of right heart catheterization,
making coronary MRI a preferred approach. Several studies
have now reported on the value of MR in this condition,140–143
including the finding of initial misinterpretation by conven-
tional x-ray angiography.141,143 Though coronary MRI data for
anomalous disease are quite extensive, in the absence of a
strong suspicion, data are not sufficient to support routine
coronary CMR screening among young adults who present
with chest pain. Coronary CTA likely has similar efficacy,
though it has been less well studied and would expose young
adults to potentially harmful ionizing radiation.
Summary
Over the past decade, there has been tremendous clinical
growth in CMR. The recent introduction of high field (e.g.,
3 T) CMR systems144 and application of parallel imaging
methods145 in CMR has the potential to dramatically decrease
the time needed for CMR study completion. Moreover, inves-
tigations in the use of CMR for detection of subclinical
disease are ongoing146 and expected to further expand the role
of CMR in clinical care. Finally, the enhancement of real-
time CMR has facilitated the exciting birth of interventional
CMR methods, including placement of percutaneous valves
and atrial septal defect closure devices as well as guidance
for electrophysiologic procedures. Intervention CMR is
expected to have its greatest initial impact in the pediatric
population,147 for which radiation exposure is of greatest
concern.
176 chapter
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 8 Computed Tomographic
Cardiovascular Imaging
Matthew J. Budoff
Tomographic Imaging Modalities. . . . . . . . . . . . . . . . . . .
Noncontrast Computed Tomography Imaging . . . . . . . .
Contrast-Enhanced Computed Tomography
Angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pericardial Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Aorta and Aortic Valve Pathology . . . . . . . . . . . . . . . . . .
C
ardiac computed tomography (CT) is a robust technol-
ogy for the noninvasive assessment of a spectrum of
cardiovascular disease processes. This image modal-
ity has been used to provide assessment of atherosclerotic
plaque burden and coronary artery disease risk through coro-
nary calcium scoring. Although the technology has been
clinically available for 20 years,1 cardiologists and even radi-
ologists are largely unaware of its capabilities. This chapter
reviews the current clinical uses and describes some of the
potential for even greater utility in the near future. Advances
in spatial and temporal resolution, electrocardiographic trig-
gering methodology, and image reconstruction software have
helped in the evaluation of coronary artery anatomy and
vessel patency, providing the ability to noninvasively diag-
nose or rule out significant epicardial coronary artery disease.
Cardiac CT allows the three-dimensional (3D) simultaneous
imaging of additional cardiac structures including coronary
veins, pulmonary veins, atria, ventricles, aorta, and thoracic
arterial and venous structures, with definition of their spatial
relationships for the comprehensive assessment of a variety
of cardiovascular disease processes. This chapter discusses
the role of cardiac CT in the assessment of cardiovascular
pathology, with an emphasis on the detection of coronary
atherosclerosis.
Tomographic Imaging Modalities
Electron Beam Computed Tomography
The tomographic imaging modalities, including electron
beam CT (EBCT), multidetector CT (MDCT), and magnetic
resonance imaging (MRI), have advantages and limitations
in the evaluation of cardiovascular disease, depending on the
particular clinical questions posed. Electron beam CT is a
fourth-generation CT imaging modality that is able to rapidly
obtain thin tomographic cardiac slices for the evaluation of
181 Pulmonary Arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
183 Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . 195
Electrophysiologic Applications of Cardiac
187 Computed Tomography . . . . . . . . . . . . . . . . . . . . . . . . 196
194 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
194
coronary artery anatomy. The speed of image acquisition is
possible due to the fact that the x-ray source is stationary. In
basic terms, instead of rotating the x-ray tube around the
patient as conventional scanners do, the EBCT scanner has
the patient positioned inside the x-ray tube, obviating the
need to move any part of the scanner during image acquisi-
tion. The electron beam is emitted from the cathode, which
is several feet superior to the patient’s head, and then passes
through a magnetic coil, which bends the beam so that it
will strike one of four tungsten anode targets. The magnetic
coil also steers the beam through an arc of 210 degrees. The
x-ray generated from the powerful electron stream striking
the tungsten anode target passes through the patient in a
fan-shaped beam and strikes the detector array positioned
opposite the four anodes.
Three imaging protocols are used with the electron beam
CT scanner. They provide the format to evaluate anatomy,
cardiovascular function, and blood flow. The imaging proto-
col used to study cardiovascular anatomy is called the volume
scanning mode and is similar to the scanning protocol
employed by conventional CT scanners. Single scans are
obtained, and then the scanner couch is incremented a preset
distance, usually the width of the scan slice, so that there is
no overlap of anatomy. This scanning mode is utilized with
and without contrast enhancement and provides high spatial
resolution of cardiovascular anatomy. This technique is ideal
for evaluation of the aorta, coronary arteries, and congenital
heart disease. The thinnest slice available is 1.5 mm, which
is not as thin as now available on multidetector scans (which
have slice thickness as thin as 0.5 mm by one vendor, and
0.625 to 0.75 by most others).
The cine scanning protocol acquires images in 50 ms.
Each scan is separated by an 8-ms delay, which translates to
a scanning rate of 17 scans/second per target. Scanning on
multiple targets simultaneously allows for large volumes of
the heart to be covered with each heartbeat. Scans are
acquired for the duration of the cardiac cycle. Depending on
181
18 2 chapter
the heart rate, up to 8 cm of the heart can be imaged in a
single heartbeat. The images acquired can be displayed in a
cine loop (literally a movie demonstrating motion of the
heart), making assessment of wall motion, segmental thick-
ening, and valve motion possible. Blood pool contrast
enhancement is achieved by injection of contrast medium
boluses via a superficial peripheral vein. The bolus amount
for each image acquisition period averages 30 mL. The flow
mode imaging protocol acquires a single image gated to the
electrocardiogram at a predetermined point in the cardiac
cycle [e.g., end-diastole (peak of the R-wave)]. Images can be
obtained for every cardiac cycle or multiples thereof. Scan-
ning is initiated before the arrival of a contrast bolus at an
area of interest (e.g., left ventricular [LV] myocardium) and is
continued until the contrast has washed in and out of the
area. Time density curves from the region of interest can be
created for quantitative analysis of flow, useful for shunt
fraction determinations, as well as timing of boluses for
imaging of coronary anatomy in the volume (high resolution)
mode.
The ability to rapidly acquire images decreases respira-
tory and cardiac motion artifacts, making the modality well-
suited for the evaluation of the coronary vasculature. The
entire cardiac structure is imaged during a single approxi-
mate 15- to 30-second breath-hold. Electron beam CT
acquires high-resolution images of the heart with temporal
resolution of 50 or 100 milliseconds (ms) and prospective
gating to the cardiac cycle. This allows imaging during the
diastolic phase, when cardiac motion is minimized.2 The
newest generation of EBCT scanner is the e-speed scanner
(GE Medical Systems, San Francisco, CA), which allow for
50-ms image acquisition in both the high-resolution and low-
resolution modes, and imaging more than one level simulta-
neously. The faster image acquisition and multiple level
imaging associated with this device further decreases breath-
hold time, radiation exposure, and motion artifacts. Prospec-
tive gating (identifying the R wave and triggering at a fixed
time thereafter to catch early diastole) allows for imaging of
patients with a spectrum of heart rates and rhythms (includ-
ing premature beats and atrial fibrillation).
Multidetector Computed Tomography
Multidetector CT (MDCT) systems were initially capable of
acquiring four levels simultaneously in 2000,3 now can
obtain up to 64 levels of the heart simultaneously with ECG
gating in either a prospective or retrospective mode. The
MDCT differs from single-slice helical or spiral CT systems
principally by the design of the detector arrays and data
acquisition systems that allow the detector arrays to be con-
figured electronically to acquire multiple levels of various
slice thickness simultaneously. Thus, in the current 16-
channel MDCT systems 16 slices can be acquired at nomi-
nally 0.75-mm slice widths for cardiac imaging. In MDCT
systems, like the preceding generation of single-slice helical
scanners, the x-ray photons are generated within a special-
ized x-ray tube mounted on a rotating gantry. Subsecond
MDCT scanners use a rapidly rotating x-ray tube and several
rows of detectors, also rotating. The tube and detectors are
fitted with slip rings that allow them to continuously move
through multiple 360-degree rotations. With gantry continu-
8
ously rotating, the table moves the patient through the
imaging plane at a predetermined speed. The relative speed
of the gantry rotation table motion is the scan pitch. The
smooth rapid table motion or pitch in helical scanning allows
complete coverage of the cardiac anatomy in 15 to 25 seconds.
A major advantage over EBCT is the improved spatial resolu-
tion and contrast resolution, allowing for a more detailed
look at the coronary anatomy.4
Advances in MDCT technology have led to scanners that
can obtain images with a scan rotation of 333 ms, and with
partial scanning, image acquisition between 175 and 250 ms.
Furthermore, utilizing portions of each of the images, and
adding data from consecutive detectors, allows for further
reduction in temporal resolution. Although it is not always
possible, given the heart rate and regularity of the rhythm,
most vendors are now quoting scan times approaching 110
to 140 ms using this technique (Fig. 8.1).
Multidetector CT also possesses greater versatility for
peripheral vascular imaging, as the gantry opening allows
the patient to be inserted from head to foot without reposi-
tioning. This is in contrast to EBCT, where the cone beam
limits patient motion, where many peripheral studies need
to be done in two phases (iliac to popliteal, and then the
patient is rotated feet first to image popliteal to foot). The
smooth rapid table motion or pitch in helical scanning
allows complete coverage of the cardiac anatomy in 15 to
25 seconds. Use of the 64-slice scanner decreases this
imaging window to 5 to 12 seconds for cardiac and periph-
eral imaging.
With MDCT, the limited temporal resolution is due to
the design. The mechanical detector head has to rotate
around the patient. Present versions complete a 360-degree
rotation in about four-tenths of a second. These scanners’
exposure times can be decreased to as little as 175 ms by
utilizing only a portion of the 360-degree rotation. Approxi-
mately 210 degrees of rotation is necessary for one image, so
the rotation speed can be multiplied by 0.6 to calculate image
acquisition times. For example, a rotation speed of 400 ms
for a 360-degree image will have a total temporal resolution
Snapshot image reconstruction:
Improving effective temporal resolution
Detector 1
Detector 2
Detector 3
Detector 4
Burst 2-Sector: ~ 125 ms
FIGURE 8.1. “Burst” technology allowing parts of each image to
be used for reconstruction. In this example, portions of two consecu-
tive images were used to allow the temporal resolution of multide-
tector computed tomography (MDCT) to be reduced from 265 ms to
about 132 ms.
 c o m p u t e d t o m o g r a p h i c c a r d i o va s c u l a r i m a g i n g
of approximately 240 ms. The manufacturers often quote
50% of the rotation speed (i.e., 200-ms image acquisition),
but this only refers to the central point on the scan, and not
the entire image, so this is most often somewhat misleading
to the clinician or user. Simultaneous imaging from multiple
detectors (now up to 64) during gantry rotation provides
greater spatial resolution than EBCT (specifically thinner
slices through the heart), but at the expense of temporal reso-
lution (time to image an individual level, presenting more
motion artifacts when heart rates are above 60 beats per
minute).4 Newer EBCT systems quote 9 to 11 line-pairs/cm,
while MDCT has improved spatial resolution, with 14 to 16
line-pairs/cm of resolution. Although EBCT suffers from
decreased signal to noise and gantry design, a disadvantage
of MDCT cardiac scanning is an increase in motion artifacts
and radiation exposure.5 For cardiac imaging, there is a nar-
rower window of acceptable heart rates for scanning with
MDCT compared to EBCT, with many patients requiring
pharmacologic decreases in heart rate to less than 60 beats/
minute to extend diastole to the point of minimizing cardiac
motion (see Multidetector Computed Tomography Angiogra-
phy, below). A major current disadvantage of MDCT in
cardiac scanning is an increase in radiation dose (see
below).6
In the near term, the development and introduction of
MDCT systems with increased detectors is likely. In 2005,
most vendors offer a 64-row system, and the additional detec-
tor rows help to improve temporal resolution, reduce breath-
hold time, and reduce contrast dose. We will observe
continued rapid advancement in CT for coronary and periph-
eral angiography and a series of comparative studies evaluat-
ing these new CT techniques with existing measures of
coronary heart disease.
18 3
devices such as pacemakers and defibrillators, and shorter
study times.4
Noncontrast Computed Tomography Imaging
Coronary Artery Calcium
Coronary artery calcium (CAC) is closely associated with
coronary atheromatous plaque. Arterial calcium deposition
occurs in association with atherosclerotic plaque evolution
and is regulated by cellular calcification-regulating pro-
teins.15 A direct relationship has been established between
coronary artery calcium as measured by EBCT and both
histopathologic16,17 and in vivo intravascular ultrasound18,19
studies, which confirm the close correlation between athero-
sclerotic plaque burden and extent of CAC.
Electron beam CT can accurately and noninvasively
quantitate CAC, and several measurements have been used.20
Most centers and research studies have reported a calcium
score measurement (Agatston method)1 that takes into
account the density and area of the calcification. The score
is calculated by multiplying the lesion area by a density
factor derived from the maximal Hounsfield unit (HU) within
this area. The density factor was assigned in the following
manner: 1 for lesions whose maximal density was 130 to
199 Hu, 2 for 200 to 299 Hu, 3 for 300 to 399 Hu, and 4 for
>400 Hu. A total calcium score is determined by summing
individual lesion scores from each of four anatomic sites (left
main, left anterior descending, circumflex, and right coro-
nary arteries) (Fig. 8.2). The other measures are volume

Comparison of Computed Tomography to Magnetic

Resonance Imaging
The strength of magnetic resonance cardiovascular imaging
includes greater definition of tissue characteristics, perfu-
sion, valvular function, lack of x-ray radiation, and lack of
need for potentially nephrotoxic contrast media, compared
to CT technologies. Several studies have been reported com-
paring this modality to coronary angiography.7–9 Limited
temporal and spatial resolution,10 partial volume artifacts,11
reliance on multiple breath holds, and poor visualization of
the left main coronary artery12 all reduce the clinical appli-
cability of MR angiography. Computed tomography angi-
ography offers advantages over MR angiography, including
single breath hold to reduce respiratory motion, higher spatial
resolution, reduced slice thickness, and overall study time of
35 to 50 seconds with CT techniques as compared to 45 to
90 minutes for MR angiography.4,13 Reported sensitivities for
MR angiography range from 0% to 90%.4,7,13 Magnetic reso-
nance angiography remains a technically challenging tech-
nique with certain limitations hindering its clinical use. The
rapidity and ease with which CT coronary angiography can
be performed suggest possible cost advantages compared
with MR angiography and selective coronary angiography.14 FIGURE 8.2. A computed tomography (CT) study (axial image)
demonstrating calcification of the left main and left anterior
In comparison, the strengths of CT include superior descending coronary arteries. The total coronary calcium score was
imaging of coronary arteries, higher spatial and temporal over 1000. Arrow, left anterior descending coronary artery
resolution, ability to scan patients with implantable metallic calcification.
18 4 chapter
measurement and mass score. A large criticism directed at
the Agatston method is increased variability (decreased
reproducibility) due to image noise (a peak HU of 199 would
multiply the area by a factor of 1; if that increased to 201 on
a subsequent scan, it would increase the score twofold, as the
density factor would be two). These small changes in mea-
surement can double the interscan variability, leading to
other measures to be proposed to allow for more accurate and
reproducible measurement of CAC. The volume method of
Callister et al.21 somewhat resolves the issues of density
measures, slice thickness, and spacing by computing a
volume above threshold. This has been shown to be more
reproducible, but fewer data are available on the prognostic
values of such scores. A mass score has been introduced, but
absolutely no prognostic information is available, and this
requires a phantom to make this measure, which has been
shown to increase image noise (which worsens reproducibil-
ity on individual scans).22 Further research using either
volume or mass scores will be needed to allow accurate clini-
cal guidelines to be written.
Data regarding calcium score distribution in large
numbers of asymptomatic persons have been published.23
These tables can be used to classify patients on the basis of
the extent of their atherosclerotic disease compared with the
expected norm. In men, there is a rapid increase in the preva-
lence and extent of coronary calcification after age 45. Com-
pared to men, this increase is delayed for 10 to 15 years in
women.
Reproducibility of Coronary Calcium Assessment
The reproducibility of the CAC measurement is essential to
utilizing this modality for assessment of the efficacy of ther-
apeutic interventions. Reproducibility was initially a concern
for repeated testing, but hardware and software improve-
ments have reduced interscan variability to a median of 4%
to 8%.24 In addressing reproducibility issues with coronary
calcium, it was noted that the most commonly used trigger
time in early studies (80% of the R-R interval) is suboptimal
due to increased coronary motion during atrial kick (atrial
systole causing the right coronary and circumflex arteries to
move rapidly). This has become particularly important with
the increased use of CT for measurement of progression of
atherosclerosis as well as CT coronary angiography (to
improve visualization of the coronary arteries without
motion artifacts). Recent studies suggest that a triggering
should be initiated early in diastole rather than near the end
(80%) as has been done in the past with some scanners.2 The
ideal trigger is, by definition, that which gives the least
cardiac motion, and has been extensively studied for EBCT,
and found to be at the end of systole (late systole or early
diastole). Studies with MDCT usually conclude that 40% to
50% of the R-R interval (early diastole) is the optimal trigger
for visualization of lumina with least coronary motion. Early
diastolic triggering has reduced the variability of CAC to
11% to 15%.25 With excellent inter- and intraobserver vari-
ability (1%), this test can measure plaque burden changes
over time. Multidetector CT reproducibility is currently
higher, although newer scanners (with 16, 32, or 64 detectors)
should help in reducing this measurement error. A study of
537 patients undergoing two studies on four-slice MDCT
8
with cardiac gating demonstrated a mean variability of 36%
for volume scoring and 43% for Agatston scoring.26
Calcium Progression
Much interest has been directed at using CAC to measure
plaque burden, and then remeasuring at some point in time
to assess for progression of disease. Callister et al.21 was one
of the first studies to demonstrate a relationship between
cholesterol control and atherosclerosis progression. There
was a significant net increase in mean calcium-volume score
among individuals not treated with cholesterol-reducing
medications (mean change: 52 ± 36%, p < .001). There was a
graded response depending upon the low-density lipoprotein
(LDL) reduction with statin therapy, with those treated to
LDL < 120 mg/dL demonstrating an average diminution of
coronary calcium (−7% ± 23%), and those individuals treated
less aggressively (LDL > 120 mg/dL) showed a calcium-volume
score increase of 25% ± 22% (p < .001 for comparison with
aggressively treated subjects).
Another study evaluated 299 patients who underwent
two consecutive scans at least 12 months apart.27 The average
change in the calcium score (Agatston method) for the entire
group was 33.2% ± 9.2% per year. Those patients reporting
use of a statin had an annual rate of progression of 15%,
compared with 39% annual increase in EBCT score for non-
statin users.
Prospective studies demonstrating a link between CAC
progression and coronary events have recently been reported.
The first study demonstrated, in 817 persons, that EBCT-
measured progression was the strongest predictor of cardiac
events.28 This observational study suggests that continued
accumulation of CAC in asymptomatic individuals is associ-
ated with increased risk of myocardial infarction (MI) in
asymptomatic individuals. A second study measured the
change in CAC in 495 asymptomatic subjects submitted to
sequential EBCT scanning.29 Statins were started after the
initial EBCT scan. On average, MI subjects demonstrated a
CAC change of 42% ± 23% yearly; event-free subjects showed
a 17% ± 25% yearly change (p = .0001). Relative risk of having
an MI in the presence of CAC progression was 17.2-fold [95%
confidence interval (CI): 4.1 to 71.2] higher than without
CAC progression (p < .0001). In a Cox proportional hazard
model, the follow-up score (p = .034) as well as a score change
>15% per year (p < .001) were independent predictors of time
to MI. The Multi-Ethnic Study of Atherosclerosis will
measure baseline CAC scores and repeat this measurement
after 3.5 years in 6600 patients. Interim events, within the
3.5 years, will be measured. Future events in the subsequent
3.5 years (total 7 years follow-up) will be measured.
Coronary Artery Calcium and Obstructive Disease
In contradistinction to other noninvasive modalities that
focus on diagnosis of obstructive coronary artery disease
(CAD), EBCT coronary calcium represents an anatomic
measure of plaque burden.30 Studies comparing pathologic
and EBCT findings have shown that the degree of luminal
narrowing is weakly correlated with the amount of calcifica-
tion on a segment-by-segment basis, 31 whereas total calcium
score is more closely associated with the presence and severity
 c o m p u t e d t o m o g r a p h i c c a r d i o va s c u l a r i m a g i n g
of maximum angiographic stenosis.32 Detection of coronary
calcium by EBCT has been demonstrated to be highly sensi-
tive for the presence of significant CAD. A report of 1764
persons undergoing angiography and EBCT similarly showed
a very high sensitivity and negative predictive value in men
and women (>99%).33 Therefore, a calcium score of 0, denoting
evidence of coronary calcium, can virtually exclude those
patients with obstructive CAD, making this test an effective
screen prior to invasive angiography. Guerci et al.34 studied
290 men and women undergoing coronary arteriography for
clinical indications and concluded that EBCT scanning
improved discrimination over conventional risk factors in the
identification of persons with angiographic coronary disease.
An important point in the interpretation of CAC scores
relates to the detection of obstructive CAD. A negative test,
indicating no evidence of calcified atherosclerotic plaque, can
virtually exclude obstructive disease. A positive EBCT study,
indicating the presence of CAC, is nearly 100% specific for
atheromatous coronary plaque.35 However, since both obstruc-
tive and nonobstructive lesions have calcification present,
CAC is not specific to obstructive disease. While increasing
calcium scores are more predictive of obstructive CAD, there
is not a 1 : 1 relationship between calcification and stenosis.
The overall specificity of any CAC for obstructive CAD is
approximately 66%.36 In a study of 1851 patients undergoing
angiography and CAC measure,37 EBCT calcium scanning in
conjunction with pretest probability of disease derived by a
combination of age, gender, and risk factors, could assist the
clinician in predicting the severity and extent of angiographi-
cally significant CAD in symptomatic patients. Electron
beam CT is comparable to nuclear exercise testing in the
detection of obstructive CAD.38,39 As opposed to stress testing,
the accuracy of EBCT is not limited by concurrent medica-
tions, ability to exercise, or baseline electrocardiogram abnor-
malities. Moreover, scanning for coronary calcium (CC) does
not require injection of contrast medium; therefore, a CT
technician can perform the study without supervision. The
entire procedure takes less than 10 minutes to perform.
However, cardiac CT does not afford assessment of functional
status of the patient, so many physicians may utilize a tread-
mill test and calcium scan together. This algorithm has been
shown to improve the diagnostic accuracy of both tests,40
without significantly increasing cost.
Role of Coronary Calcium in Risk Stratification
Disease processes related to atherosclerosis are the primary
cause of morbidity and mortality in every industrialized
nation. The initial manifestation of CAD is a MI or death in
up to 50% of patients.41 Most cardiac events occur in the
intermediate risk population, where aggressive risk-factor
modification is not often recommended or applied. Unfortu-
nately, traditional risk factor assessment helps predict only
60% to 65% of cardiac risk; therefore, many individuals
without established risk factors for atherosclerotic heart
disease continue to experience cardiac events.42 Acute coro-
nary occlusion most frequently occurs at the site of mild to
moderate stenoses (<50% lesion severity) in association with
the process of plaque rupture.43,44 Therefore, plaque burden,
and not stenosis severity, is a more important marker of
disease.45 These studies emphasize the importance of mea-
18 5
surement of atherosclerosis burden in the risk stratification
for future cardiovascular events, rather than relying solely
on evidence of obstructive coronary artery disease.
Coronary Artery Calcium Risk Prediction in
Symptomatic Individuals
Studies have demonstrated that CAC has prognostic signifi-
cance in symptomatic individuals. Margolis et al.46 assessed
the significance of CAC found on fluoroscopy in 800 patients
undergoing coronary angiography. The patients with CAC
had a 5-year survival rate of 58%, compared with a rate of
87% for the patients without CAC. A study of 192 patients
observed for an average of 50 ± 10 months, after undergoing
an EBCT study while in the emergency department for chest
discomfort, found that the presence of CAC (calcium score
>0), and increasing absolute calcium score values were
strongly related to the occurrence of hard events (p < .001)
and all cardiovascular events (p < .001).47 The patients with
absolute calcium scores in the top two quartiles had a rela-
tive risk of 13.1 (95% CI, 5.6–36; p < .001) for new cardiovas-
cular events as compared to patients with lower scores. The
annualized cardiovascular event rate was 0.6% for subjects
with a coronary artery calcium score of 0 compared with an
annual rate of 13.9% for patients with a coronary artery
calcium score >400 (p < .001).
A multicenter study of 491 patients undergoing coronary
angiography and EBCT scanning found that higher calcium
scores were associated with a markedly increased risk of
coronary events over the next 30 months.48 In multivariate
analysis, the only predictor of a hard cardiac event was log
calcium score, even with coronary risk factors and angio-
graphic disease included in the model. In another study of
symptomatic patients, EBCT-detected CAC was a stronger
independent predictor of disease and future events than a
sum of all of the traditional risk factors combined.49 Keelan
et al.50 followed 288 symptomatic persons who underwent
angiography and EBCT calcium scanning for a mean of 6.9
years, and found age and CAC score were the only indepen-
dent predictors of future hard coronary events.
Coronary Artery Calcium in
Asymptomatic Individuals
Coronary artery calcium is also a useful predictor of cardio-
vascular events in asymptomatic individuals. Unfortunately,
at least half of all first coronary events occur in asymptom-
atic individuals who are unaware that they have developed
CAD, and often present as sudden death or acute MI.45 Several
lipid-lowering trials have shown that substantial risk reduc-
tion can be attained with both secondary and primary pre-
vention measures.51
Several prospective trials have demonstrated the prognos-
tic ability of EBCT to identify asymptomatic patients at high
risk of cardiac events. Arad et al.52 reported 3.6-year follow-
up of 1173 patients. Asymptomatic individuals were scanned
using EBCT as well as measures of traditional risk factors,
and followed prospectively for cardiac events. This study
demonstrated CAC to be the strongest predictor of future
cardiac events, with patients in the highest score category
over 20 times more likely to suffer a cardiac event (odds ratio
22.3, CI 5.1–97.4).
18 6 chapter
Wong et al.53 followed 926 asymptomatic patients (mean
age 54 years) for an average of 3.3 years. The presence of CAC
and increasing score quartiles were related to the occurrence
of new MI (p < .05), revascularization (p < .001) and total
cardiovascular events (p < .001). The risk ratio for events in
patients whose absolute calcium score was in the upper quar-
tile (score > 271) compared with individuals whose absolute
calcium score was in the lowest quartile (score < 15) was 12
(relative risk 8.8 and 0.72, respectively; p < .001).
Greenland et al.54 published long-term follow-up of the
South Bay Heart Watch. Coronary artery calcium was found
to be predictive of risk in patients with a Framingham Risk
Score of >10%, with a high CAC score able to predict risk
beyond Framingham risk score alone. As compared to a CAC
score of 0, a CAC score of >300 was highly predictive of
cardiac events (HR 3.9, p < .001).
Raggi et al.55 followed 632 asymptomatic individuals
with risk factors for CAD for an average of 32 ± 7 months. A
CAC score of zero was associated with a 0.11%/year event
rate, compared to 4.8%/year with a score >400. The event
rate in patients with calcium scores in the highest quartile
was 22 times the event rate in patients with calcium scores
in the lowest quartile, significantly outperforming risk
factors in cardiac event prediction. Multiple logistic regres-
sion analyses demonstrated that calcium score percentile
was the only significant predictor of events and provided
incremental prognostic value when added to traditional risk
factors for CAD.
Larger trials have been reported, demonstrating approxi-
mately 10-fold increased risk with the presence of CAC.
Kondos et al.56 reported 37-month follow-up on 5635 initially
asymptomatic low- to intermediate-risk adults. In men,
events (n = 192) were associated with the presence of CAC
[relative risk (RR) = 10.5, p < .001), diabetes (RR = 1.98, p =
.008), and smoking (RR = 1.4, p = .025), whereas in women
events (n = 32) were linked to the presence of CAC (RR = 2.6,
p = .037) and not risk factors.
A prospective study of 5585 subjects aged 59 ± 5 years, a
calcium score ≥100 predicted all atherosclerotic cardiovascu-
lar disease events, all coronary events, and the sum of non-
fatal MI and coronary death events with relative risks of 9.5
to 10.7 at 4.3 years.57 The calcium score also predicted events
independently of and more accurately than measured risk
factors. The area under the receiver operating characteristic
curve for event prediction with risk factors alone in this
study was 0.71, increasing to 0.81 with EBCT testing (p < .01).
This prospective study strongly demonstrated the ability to
utilize this test to rule out patients who do not require
therapy. In this study, only 19% of patients had scores above
the diagnostic threshold (calcium score ≥100), yet relying on
this threshold had a negative predictive power of 99.2%.
Thus, clinicians can focus on a smaller, yet higher risk popu-
lation (10.7-fold increased risk in this group), for risk reduc-
tion therapy.
Shaw et al.58 demonstrated the power of coronary artery
calcium to predict all-cause mortality over the next 5 years.
A cohort of 10,377 asymptomatic individuals undergoing
cardiac risk factor evaluation and CAC measure with EBCT
reported a mean follow-up of 5.0 years. In a risk-adjusted
model, CAC was an independent predictor of mortality (p <
.001). Coronary calcium was a better predictor than tradi-
8
tional cardiovascular risk factors, and very high scores
(>1000) were associated with a 13-fold increased risk of death
as compared to persons with lower scores.
Coronary Artery Calcium: Guidelines
and Applications
The above-mentioned studies demonstrate the ability of CAC
to provide risk stratification in asymptomatic and symptom-
atic populations with incremental prognostic information
beyond traditional risk factors. Based on the results of these
studies, modification of the Framingham Global Risk Score
by using a weighted factor based on the patient’s individual
calcium score percentile has been suggested.59 In this modi-
fication, the Framingham Risk Score assigned to a subject
undergoing EBCT screening for asymptomatic CAD is
increased if the calcium score is in a high percentile.
The greatest potential for CAC detection could be as a
marker of CAD prognosis in asymptomatic persons at risk
of CAD, beyond that detected by conventional coronary risk
factors. Since the 2000 American College of Cardiology
(ACC)/American Heart Association (AHA) expert consensus
document on EBCT noting inconclusive risk stratification
evidence on CAC scanning,60 a number of studies have
reported that the presence and severity of CAC has indepen-
dent and incremental value when added to clinical or histori-
cal data in the measure of death or nonfatal MI. Since those
early recommendations, the National Cholesterol Education
Program (NCEP) has made recommendations specifically for
the use of EBCT to assist in risk stratification in elderly and
intermediate risk patients. The new NCEP guidelines (Adult
Treatment Panel III)61 support the conclusions of the AHA’s
Prevention Conference V62 and the ACC/AHA report60 that
high coronary calcium scores signify and confirm increased
risk for future cardiac events, and state, “Therefore, measure-
ment of coronary calcium is an option for advanced risk
assessment in appropriately selected persons. In persons with
multiple risk factors, high coronary calcium scores (e.g.,
>75th percentile for age and sex) denotes advanced coronary
atherosclerosis and provides a rationale for intensified LDL-
lowering therapy.” New guidelines for prevention of CAD
recommend coronary calcium as a method of risk stratifica-
tion, with positive scores placing individuals at intermediate
risk by the Framingham model (10–20% 10-year risk) and
high CAC scores at high risk for future cardiac events.63
The absence of CAC in the asymptomatic patient identi-
fies a group of patients at very low risk of events over the
next 3 to 5 years. An annual event rate of only 0.11% has
been reported for patients with scores of zero.55 Both the
ACC/AHA writing group and the Prevention V Conference
agreed that the negative predictive value of EBCT is very
high for short-term events.60,62 Whether a calcium score of
zero will allow therapy to be withheld remains to be prospec-
tively tested.
Current guidelines suggest that intermediate risk patients
would benefit most from further risk stratification, as most
cardiac events occur in this population.61 “Recent work
suggests that electron-beam tomography (EBCT) can also
improve risk prediction in intermediate-risk patients. Thus,
with a prior probability of a coronary event in the intermedi-
ate range (>6% in 10 years but <20% in 10 years), a calcium
 c o m p u t e d t o m o g r a p h i c c a r d i o va s c u l a r i m a g i n g
score would yield a posttest probability in virtually all such
patients greater than 2% per year, that is, a level similar
to that in secondary prevention, or a “coronary risk
equivalent.” Furthermore, CAC screening with EBCT was
demonstrated to be a cost-effective screening strategy in
asymptomatic individuals between 45 and 65 years of age.64
The ability of CAC scoring to identify patients who require
aggressive risk factor modification, coupled with effective-
ness of cholesterol lowering medications, aspirin, and other
therapies, should allow physicians to focus aggressive pre-
ventative treatment on those individuals with underlying
atherosclerosis who are at highest risk of having cardiovas-
cular events.
There are some potential specific applications of CAC
assessment that warrant mention. Based on the fact that a
CAC score of zero is associated with a <1% chance of obstruc-
tive CAD, the use of EBCT prior to angiography has been
recommended for certain persons of low-to-intermediate risk
of obstructive CAD. In the symptomatic patient, evidence
suggests that calcium scanning may be more cost-effective
at diagnosing CAD than traditional noninvasive testing,
especially in women.64,65,66
Another potential application of cardiac CT relates to the
triage of chest pain patients. Electron beam CT has been
shown to be an efficient screening tool for patients admitted
to the emergency department with chest pain to rule out
myocardial infarction.47,67,68 These studies demonstrate sen-
sitivities of 98% to 100% for identifying patients with acute
MI, and very low subsequent event rates for persons with
negative tests. The high sensitivity and negative predictive
value may allow early discharge of those patients with non-
diagnostic ECG and negative calcium scans. Exclusion of
coronary calcium, therefore, may be used as an effective
screen prior to invasive diagnostic procedures or hospital
admission.
In patients with cardiomyopathy, CAC has been shown
to be useful in determining the etiology of cardiomyopathy.
The clinical manifestations of patients with ischemic car-
diomyopathy are often indistinguishable from those patients
with nonischemic dilated cardiomyopathy. Budoff et al.69
demonstrated in 120 patients with heart failure of unknown
etiology that the presence of CAC was associated with a 99%
sensitivity for ischemic cardiomyopathy.
Electron Beam versus Multidetector CT for
Assessment of Coronary Artery Calcium
The higher tube currents available with MDCT allow for
images with a better signal-to-noise ratio and higher spatial
resolution in comparison to EBCT, but at the expense of
higher radiation exposure and lower temporal resolution.
Retrospective gating involves acquiring hundreds of cardiac
image, but only uses those that occurred with appropriate
diastolic timing. This retrospective approach markedly
increases the radiation dose, image analysis time, inter- and
intra-reader variability, and interscan variability. A more
practical approach is prospective gating, which is similar to
the methods employed by EBCT. This methodology allows
for image acquisition only at the specified time (diastole), and
therefore reduces variability and radiation. For MDCT, the
images are best when the resting heart rate is less than 60
18 7
beats per minute; at faster heart rates, motion artifacts may
become more prominent.
Protocols are being developed that may reduce radiation
doses with MDCT, by attempting to decrease beam current
during systole, when images are not used for interpretation.
New AHA guidelines are being published discussing the
advantages and disadvantages of each modality.70 These
guidelines conclude that “some limitations remain for mul-
tidetector CT, including: (1) slower speed of the acquisition
(EBCT = 50–100 msec, MDCT = 200–330 msec); (2) higher
radiation dose (EBCT dose = 0.7 mSv, MDCT dose = 1.5–
1.8 mSv); and (3) possibly greater interscan variability of mea-
surement (EBCT = 11–16%, MDCT = 23–35%).” Two ongoing
trials [multi-ethnic study of atherosclerosis (MESA) trial in
the United States and the Heinz Nixdorf Recall Study in
Germany] are examining the value of EBCT and/or MDCT-
derived CAC in the general population, and will provide
more answers in relation to the role of CAC in the primary
prevention of atherosclerosis.
Position of the Professional Societies
and Guidelines
In 1996, the AHA assembled a writing group on the applica-
tion of EBCT coronary calcium scanning. This group con-
cluded that EBCT CAC was a useful surrogate for
atherosclerosis, with a negative test most likely associated
with normal coronary arteries and a low risk of cardiac
events in the next 2 to 5 years, and a positive test being
associated with atherosclerosis.33
Fortunately, the AHA and the ACC have taken responsi-
ble positions on this issue. Given the strong literature in
support of risk stratification with this tool, the issue of CAC
scanning is undergoing a current revision and should have
stronger support from both organizations, especially given
the incremental and independent predictive value found in
all studies to date.
Recent guidelines and expert consensus documents have
recommended the use of CAC (or the use of other tests of
atherosclerosis burden) in clinically selected intermediate
CAD risk patients (e.g., those with a 10% to 20% Framing-
ham 10-year risk estimate) to refine clinical risk predic-
tion62,71,72 and to select patients for altered targets for
lipid-lowering therapies.61,73
Contrast-Enhanced Computed
Tomography Angiography
Electron Beam Angiography
The ability to visualize the coronary artery lumen has revo-
lutionized CT imaging. An alternative, less expensive, and
noninvasive test for use as a diagnostic tool before possible
intervention could have a major impact on health care prac-
tice and cost containment.4 Contrast-enhanced CT angi-
ography is an emerging technology with the potential for
obtaining essentially noninvasive coronary arteriograms.
Studies have reported contrast-enhanced, electrocardiogram
(ECG)-triggered, 3D-EBCT angiography for detecting and
grading coronary stenosis.74,75,76,77,78,79 Coronary electron beam
angiography (EBA) was first introduced in 1995,80 and since
18 8 chapter 8

that time has improved due to technology and methodology

advances. Electrocardiogram triggering is employed, so that
each image is obtained at the same point in diastole. Iodin-
ated contrast is administered through an antecubital or
jugular vein with an injection rate of approximately 4 mL/sec
and total volume of 80 to 160 mL, depending on the version
of scanner used. Images are obtained over a single breath-
hold, usually over approximately 30 seconds. This entire
protocol can be performed within 15 to 20 minutes. Image
processing is rapid, with detailed analysis through the assess-
ment of two-dimensional (2D) and 3D views as well as
maximum intensity projections in which serial overlapping
thin slices are viewed in unison (Figs. 8.3 to 8.5).81 As com-
pared to invasive angiography, this modality has been dem-
onstrated to identify significant coronary lumen narrowing
(>50% stenosis) with an overall sensitivity of 87% and speci-
ficity of 91% for the 10 or so studies now reported.4
These early studies, while demonstrating sensitivities
and specificities in the range of 88% to 94%, were somewhat
limited by nonevaluable segments, despite the high temporal FIGURE 8.4. Electron beam angiography demonstrating the obtuse
resolution of EBCT (100-ms imaging). Historically, the most marginal (OM) and circumflex without evidence of obstructive coro-
common trigger time used is 80% of the R-R interval. nary artery disease.
However, this trigger occurs on or near the P wave during
atrial systole. Electrocardiogram triggering at 80% of the R-R
interval (late diastole) used in most prior studies might not coronary angiography. Patients were divided into two groups
be optimal for imaging of the coronary segments near the based on different ECG triggering used: 80% R-R interval
right or left atria, since atrial contraction during end-diastole trigger method (group 1, n = 53) and end-systolic triggering
causes rapid movement of the base of the heart,82 and the (group 2, n = 80). Overall sensitivity (including all segments,
least motion among all heart rates occurs earlier in the not just evaluable segments) to detect a ≥50% luminal ste-
cardiac cycle (late systole).83 A study was subsequently nosis was 69% in group 1 and 91% in group 2 (p = .002);
reported demonstrating a marked improvement in results specificity was 82% and 94% in group 1 and group 2, respec-
with EBCT when using end-systolic triggering rather than tively (p < .001). Nonassessability of coronary segments on
late diastolic triggering. 3D-EBA images was reduced from 35% in group 1 to 9% in
Lu et al.84 studied 133 patients with suspected coronary group 2 patients (p < .001). The number of motion-free coro-
disease with intravenous coronary EBA and conventional nary images increased from 67% to 95% from group 1 to
group 2 (p < .0001).
Another study by Budoff et al.85 reported the improve-
ment with image quality and diagnostic accuracy with newer
triggering techniques was also reported. Eighty-six patients

1st Diagonal

Conus

RV

AM

FIGURE 8.5. Computed tomography angiography demonstrating

FIGURE 8.3. E-Speed (General Electric, San Francisco, CA) electron
beam angiography demonstrating the left and right coronary arter-
ies, without evidence of obstructive coronary artery disease. LAD,
left anterior descending coronary artery; RCA, right coronary
artery.
the left and right coronary arteries, without evidence of obstructive
coronary artery disease. The conus artery, as well as the right
ventricular vein and acute marginal branches are well visualized.
1st Diag, first diagonal artery; AM, acute marginal branch of right
ventricle; RV, right ventricular vein.
 c o m p u t e d t o m o g r a p h i c c a r d i o va s c u l a r i m a g i n g 18 9
were studied; EBT correctly classified 49 of 53 patients (92%)
as having at least one coronary stenosis. Overall, 103 steno-
ses exceeding 50% diameter reduction were present, and of
these 93 lesions were correctly detected by EBT (sensitivity:
90%; specificity: 93%; positive predictive value: 84%; and
negative predictive value: 96%). Only 5% of vessels could not
be assessed, predominantly due to significant calcification.
Newer advances in both modalities will lead to routine
use of noninvasive angiography. In regard to the EBCT
scanner, newer electron beam technologies are now available
(e-speed, General Electric, San Francisco, CA) that provide
greater spatial and temporal resolution and may provide
greater visualization of smaller branch veins as well as distal
tapering sections of branch veins than the scanner used in
this study.86 Early results from this scanner demonstrate FIGURE 8.6. Quantum 64 (Toshiba Medical Systems) multidetec-
sensitivities of 92% and specificities of 98% for the detection tor CT image demonstrating a multiplanar reconstruction of the
of obstructive CAD.87 right coronary artery (RCA). This allows the entire vessel to be
viewed in one image.

Multidetector Computed Tomography Angiography

Multiple studies with four-slice MDCT have been reported, tively), and high specificities were maintained (94% and
with most studies reported a diminished overall sensitivity. 93%, respectively).
Achenbach et al.88 reporting 68% of vessels interpretable by These studies concluded the MDCT with beta-blocker
angiography, with 32 of 58 high-grade stenoses were detected premedication permits detection of CAD with improved
(sensitivity 55%). All four major coronary arteries could be accuracy. When using MDCT as a noninvasive diagnostic
evaluated in only 30% of patients. The authors note that “its
clinical use may presently be limited due to degraded image
quality in a substantial number of cases, mainly due to rapid
coronary motion.” Giesler et al.89 reported that 115 of 400
(29%) coronary arteries were uninterpretable, and in only
39% of patients were all coronary arteries assessable by
MDCT. Overall, 51 (49%) of 104 stenoses were revealed on
MDCT. Additionally, most studies demonstrate a significant
heart rate interaction. One study demonstrated that overall
sensitivity for stenosis detection decreased from 62% (heart
rate <70 bpm) to 33% (heart rate >70 bpm),89 while in another
sensitivity dropped from 82% (mean heart rate 55.8 bpm) to
32% (mean heart rate 81.7 bpm).90
The use of eight or more detectors improves spatial reso-
lution by decreasing slice thickness, and it allows for a higher
sensitivity and specificity. Average sensitivity and specificity
over the first six studies reported an average sensitivity of
80% and specificity of 86%, when including all segments for
analysis.91 Excluding those with motion artifacts and other
reasons for nonassessability increases the sensitivity and
specificity to approximately 90%. The use of eight 64-slice
MDCT scanners allows for faster and thinner imaging than
the four-slice scanners (Figs. 8.6 to 8.8). Three studies have
recently been reported with 16-level scanners,92,93,94 each
with improved accuracy as compared to prior reports with
4-level scanners. These studies reported a sensitivity of 73%
to 95% and a specificity of 86% to 93%. The most recent
study was a prospective, blinded, standard cross-sectional
technology assessment; analysis of all 530 coronary seg-
ments demonstrated moderate sensitivity (63%) and excel-
lent specificity (96%), with a moderate positive predictive
value of 64% and an excellent negative predictive value of
96% for the detection of significant coronary stenoses. FIGURE 8.7. Volume rendered image of the left coronary system
using a Lightspeed 16 multidetector computed tomography (General
Assessment restricted to either proximal coronary segments Electric, Milwaukee, WI) demonstrating mild, nonobstructive
or segments with excellent image quality (83% of all seg- disease. LAD, left anterior descending artery; OM, obtuse
ments) led to an increase in sensitivity (70% and 82%, respec- marginal.
19 0 chapter 8

FIGURE 8.8. Maximal intensity projection demonstrating signifi-

cant disease at the origin of the left anterior descending artery
(LAD). C, circumflex coronary artery; D, diagonal.

modality to assess advanced CAD, it appears to be manda-

tory to preselect patients (sinus rhythm, lower calcium score, FIGURE 8.9. Noninvasive angiography demonstrating patent saphe-
steady heart rates) in order to achieve reliable results, and to nous vein grafts to the first obtuse marginal (OM) and a patent
use scanners with eight or more detectors. internal mammary artery (white arrows) to the left anterior descend-
ing coronary artery (LAD).

Computed Tomography Angiography

after Revascularization tion for the clinical assessment of the according arterial
segment by EBA, MDCT, and MR angiography. Pump et al.100
Computed tomography angiography may play a role in the
reported a sensitivity of 78% (18 of 23 stenoses detected) and
assessment and follow-up of patients who have undergone
specificity of 98% (189 of 193 stents correctly assessed to be
coronary interventions, potentially replacing some invasive
angiographic procedures. The utilization of EBA to detect
coronary artery bypass graft (CABG) patency has been
reported as early as 1986.95 Saphenous vein grafts, which are
generally of large caliber and have minimal cardiac motion,
are especially well suited for noninvasive imaging with CT
angiography (Figs. 8.9 and 8.10). Using 3D visualization in
post-CABG patients, both MDCT and EBCT can demon-
strate graft stenosis and patency. Recent studies for both CT
techniques demonstrate sensitivities of 92% to 100% and
specificities of 91% to 100% for establishing patency of
saphenous vein grafts as compared to coronary angiogra-
phy.96,97,98 These studies demonstrated sensitivity and speci-
ficity for patency of left internal mammary of 80% to 100%
and 82% to 100%, respectively.
In patients who experience chest pain after stenting or
angioplasty, visualization of the site of angioplasty to assess
for restenosis is often required. A noninvasive method to
visualize the site of angioplasty could potentially be used for
less typical presentations of acute closure (no typical angina
or ECG changes suggestive of ischemia). Computed tomog-
raphy angiography has been shown to permit imaging of the
coronary arteries and detecting high-grade restenosis after
coronary angioplasty. Achenbach et al.99 reported 50 cases in
which a coronary angioplasty was performed without coro-
nary stent implantation. The sensitivity and specificity of
FIGURE 8.10. Noninvasive angiography demonstrating multiple
EBA was 94% and 82%, respectively, to detect severe stenosis closed saphenous vein grafts (black arrows) and a right coronary
(≥70% stenosis). The widespread utilization of metal stents artery (RCA) occlusion with a patent saphenous vein graft to the left
during revascularization procedures provides a major limita- anterior descending artery (white arrow).
 c o m p u t e d t o m o g r a p h i c c a r d i o va s c u l a r i m a g i n g
FIGURE 8.11. Noninvasive angiography using the Lightspeed 16
multidetector computed tomography demonstrating a stent (black
arrow) in the left anterior descending. It is not possible to determine
whether the stent is patent or partially occluded.
free of stenosis) for the detection of significant in-stent reste-
nosis by flow measurements. The difficulties in imaging
stents (with scatter from the metal, coupled with motion
artifacts and small interior diameters) make CT angiography
very limited in this application currently (Fig. 8.11).101
Although some authors have reported mixed results with CT
imaging within stents, current studies are limited, and the
scatter artifact of the metal, coupled with the small diame-
ters and coronary motion, suggest that invasive coronary
angiography is required to evaluate stent patency accurately.
Assessment of Noncalcified Plaque
Computed tomography angiography’s ability to visualize and
characterize “soft” noncalcific coronary plaque is an emerg-
ing area of interest (Fig. 8.12). Autopsy and coronary intra-
vascular ultrasound (IVUS) studies have shown that
angiographically “normal” coronary artery segments may
contain a significant amount of atherosclerotic plaque;102
IVUS allows for a direct, 360-degree visualization of the
coronary atheroma within the vessel wall and identifies both
plaque distribution and composition.103 The utility of coro-
nary IVUS over coronary angiography in recognizing these
smaller plaques is somewhat limited, though, by a higher
procedural complication rate secondary to its more invasive
nature.
The potential identification of early, nonobstructive coro-
nary plaques with CT angiography requires further investi-
gation. The noncalcified “soft” plaque in coronary arteries
is measured as the volume under 130 HU on nonenhanced
images corresponding to filling defects on enhanced images.
The noncalcified plaque can be divided into low (<0 HU) and
higher-density noncalcified plaques (0–130 HU). A compari-
son study with EBCT and IVUS demonstrated a linear rela-
tionship between coronary segments with calcified and with
noncalcified plaques.104 In comparisons of MDCT with IVUS,
investigators found a sensitivity of 82% to detect coronary
artery segments containing atherosclerotic plaque in patients
191
without significant coronary artery stenoses.105,106 However,
segments containing exclusively noncalcified plaque were
identified with a sensitivity of only 53%, and MDCT sub-
stantially underestimated plaque burden. Accuracy for plaque
detection was lower for smaller plaques and in distal versus
proximal vessel segments.
The limitations of soft plaque detection may be much
more significant than a limited sensitivity or underestima-
tion of plaque burden. The reproducibility of the measure has
not been reported. Additionally, there are no prognostic data
assessing whether noncalcific plaque adds any prognostic
information to traditional risk factors, angiographic disease
severity, and calcified plaque quantitation. Finally, this pro-
cedure requires both contrast and radiation, and the risks
may outweigh the benefit in individual patients. These
factors require further investigation in order to define the
possible role and importance of CT coronary angiography as
a noninvasive modality for soft plaque imaging.
Radiation Dose and Cardiac CT
Computed tomography utilizes x-rays, a form of ionizing
radiation, to produce the information required for generating
CT images. One drawback of MDCT as compared to EBCT
is the potential for higher radiation exposure to the patient,
depending on the tube current selected for the examination.
Hunold et al.6 recently performed a study of radiation doses
during cardiac exams. Cardiac scanning was performed with
EBCT and four-slice multidetector CT (Siemens Volume
Zoom, Ehrlangen, Germany) utilizing prospective triggering
to assess patient effective radiation exposure, compared
to measurements made during cardiac catheterization.
1000
400
150
A
R
J
60
–10
100 %
FIGURE 8.12. Noninvasive angiography with significant stenosis
consisting of noncalcified plaque (depicted as yellow) in the distal
right coronary artery. The red structures represent calcium and the
green is the contrast.
19 2 chapter
Electron beam CT CAC protocols yielded effective doses of
1.0 and 1.3 mSv for men and women, while MDCT CAC
protocols using 100 mA, 140 kV, and 500-ms rotation yielded
1.5 mSv for men and 1.8 mSv for women. Invasive coronary
angiography yielded effective doses of 2.1 and 2.5 mSv for
men and women, respectively. The doses obtained for MDCT
angiography were significantly higher. Since radiation is con-
tinuously applied (retrospective gating) while only a fraction
of the acquired data is utilized, high radiation doses (doses
of 6 to 10 mSv/study) still limit the clinical applicability of
this modality.6,107 In females, the effective radiation doses is
another 25% higher than in males, raising the mean dose
from 8 mSv in men to 10 mSv per study in women.108 These
radiation doses are two to five times higher than can be
expected for conventional angiography, and five- to tenfold
higher than doses obtained during EBCT angiography (1.1–
1.7 mSv). In two studies of radiation dose comparing EBCT
and four-slice MDCT, the first reported EBCT angiography
doses of 1.5 to 2.0 mSv, MDCT angiography 8.1 to 13 mSv,
and coronary angiography 2.1 to 2.3 mSv, while another
reported EBA doses of 1.1 mSv and MDCT doses of 9.3 to
11.3 mSv.6,109 Newer MDCT studies report that radiation
doses are still significant with newer 16+-level multidetector
scanners,110 and dose modulation should be employed when-
ever possible.111
For MDCT, increased numbers of detectors (64-slice
systems are now available) will allow for better collimation
and spatial reconstructions. Having more of the heart visual-
ized simultaneously will also allow for reductions in the
contrast requirements and breath holding, further improving
the methodology. Multisector reconstruction (combining
images from consecutive heart beats) and dose modulation
(to reduce radiation exposure during systole, when images
are not used for reconstruction) are increasingly being
applied.
Limitations of CT Angiography
Some limitations are inherent to both CT modalities in
regard to coronary artery imaging. One major limitation is
dense calcification of the coronary arteries, with investiga-
tors citing scores of >500 or >1000 as problematic. Another
limitation of all noninvasive angiography is the relative
inability to visualize collaterals. The main determinant of
false-positive results for diagnosing ≥50% coronary luminal
stenosis was small vessel size, and the diameter of stenotic
segments tends to be underestimated by CT angiography.112
Applications of CT Coronary Artery Angiography
The most common clinical application of CT angiography is
to evaluate patients with symptoms post-CABG surgery and
coronary angioplasty evaluation, assessment of congenital
heart disease and coronary anomalies,113 and measurement
of wall motion, myocardial mass, as well as right and left
ejection fractions.114
Some current uses of noninvasive CT angiography include
the following: after the nondiagnostic stress test; for those
persons with intermediate likelihood of CAD (where the step
to coronary angiography might be premature); for symptom-
atic persons postcoronary angioplasty and possibly poststent;
8
evaluating graft patency post-CABG; and for early detection
of obstructive CAD in the high-risk person. Given the current
utility of these techniques, we can expect a rapid growth in
both the knowledge and experience with noninvasive angi-
ography, leading to much wider clinical applications for the
assessment of obstructive coronary artery disease.
Ventricular Structure and Function
Advances in image acquisition and data processing have
allowed for characterization of ventricular structures and
function with CT angiography, with reproducible quantita-
tive measurement of left ventricular ejection fraction,115,116
ventricular volumes,117,118 ventricular mass,119,120 wall thick-
ness,121 and regional wall motion122 in cardiomyopathic pro-
cesses (Fig. 8.13). These data can be integrated with coronary
artery assessment for a comprehensive assessment of the role
that coronary artery disease plays in the cardiomyopathic
process.
Cine scanning allows for assessment of systolic and dia-
stolic function. The spatial resolution and contrast enhance-
ment adequately defines the endocardium of both the right
and left ventricles, so that precise measurement of biven-
tricular cardiac volume and ejection fraction is feasible.
Rumberger et al.123 have demonstrated the feasibility of eval-
uating diastolic performance of the LV. Diastolic filling vari-
ables, such as those measured by blood pool scintigraphy, can
be determined with EBCT. Application of this technique
may prove useful for detecting subtle changes in LV diastolic
function induced by myocardial ischemia.
Left ventricular mass can also be quantified. Quantita-
tive measurement of regional wall motion and wall thicken-
ing can be performed, which is particularly useful for
evaluating CAD patients. Application of this technique may
prove useful for detecting changes in LV function induced by
myocardial ischemia, as well as accurately diagnosing ejec-
FIGURE 8.13. Profound thickening of the interventricular septum
(IVS) in a patient with hypertrophic cardiomyopathy.
LV, left ventricle; RV, right ventricle.
 c o m p u t e d t o m o g r a p h i c c a r d i o va s c u l a r i m a g i n g
RV
LV
FIGURE 8.14. Severely dilated left ventricle (LV) in a patient with
ischemic cardiomyopathy. The apical-lateral infarction can be well
visualized by the dark region (lower contrast enhancement due to
infarcted tissue, black arrow). RV, right ventricle.
tion fraction postinfarction.124 Bicycle exercise can be coupled
with CT scanning to detect exercise-induced ischemia. A
decrease in ejection fraction and development of a new wall
motion abnormality have been shown to be accurate for
detection of ischemia, with data indicating that exercise CT
may be at least as sensitive and more specific than techne-
tium-99m sestamibi stress testing.125 A study was reported
evaluating the diagnostic value of dobutamine stress EBCT
as compared with exercise stress thallium-201 single-photon
emission computed tomography and found comparable sen-
sitivity and specificity for the detection of myocardial
ischemia.126
Noninvasive quantitation of myocardial blood flow is
also possible by evaluating flow patterns of iodinated con-
trast on CT. Myocardial blood flow is proportional to the
peak iodine concentration in the myocardium after intrave-
nous injection of contrast medium. The technique is accu-
rate for myocardial flows up to 2 mL/min/g. Technical factors
related to Compton scatter and beam hardening may cause
inaccuracies. Further research is necessary, for the develop-
ment of clinically useful methods for accurate quantification
of blood flow measurements. Based on the principle that
blood flow is proportional to iodine concentration during
contrast medium infusion, acute MI can be imaged by CT as
a region of little or no iodine (low density, Fig. 8.14). This
technique has been used to detect MI and to quantitate the
infarct size as well as the patency of the infarct vessel, using
both flow and 3D techniques. Complications of myocardial
infarction, including ventricular septal defects, thrombi,
aneurysms, and pericardial effusions, can all be easily visu-
alized by CT.
The ability to document abnormalities of ventricular
structure and function coupled with the ability to assess
coronary artery calcium and angiographic coronary artery
disease make cardiac CT a useful tool in the assessment of
cardiomyopathic processes. Definition of the etiology of car-
diomyopathy, to quantitate function, can facilitate decision
19 3
making as well as approaches to intervention in patients
with dilated and ischemic cardiomyopathy.
Hypertrophic cardiomyopathy can lead to heart failure
symptoms and sudden cardiac death.127 Echocardiography is
the main diagnostic modality for the diagnosis of hypertro-
phic cardiomyopathy, and in addition to anatomy can assess
resting and exercise gradients and associated valve func-
tion.128 The diagnosis can be made by CT angiography (Fig.
8.13)129,130 and MRI,131 which can provide details of regional
wall thickness, indexed ventricular mass, and ejection
fraction.
Assessment of right ventricular structure and function
abnormalities has risen in importance due to the recognition
of significant disease processes involving the right ventricle.
Visualization and assessment of right ventricular function is
difficult by echo and cardiac catheterization. Computed
tomography angiography potentially may be an effective tool
for assessment of right ventricular anatomy and function.132
Right ventricular pathology, such as right ventricular dyspla-
sia, can be difficult to diagnose, and often the initial presen-
tation is sudden death. In terms of visualization of right
ventricular abnormalities, echocardiography lacks sensitiv-
ity.133 Magnetic resonance imaging has been the modality of
choice for anatomic evaluation of right ventricular dysplasia
due to its superior ability to define tissue characteristics such
as myocardial fat deposits, but the variation in fat content
and location in patients without this process makes this cri-
terion only of modest clinical utility.134 Computed tomogra-
phy angiography has been assessed for the ability to diagnose
anatomic features associated with right ventricular dyspla-
sia, such as epicardial and myocardial fat, low-attenuation
trabeculations, and right ventricular free wall scalloping, but
has not been assessed as a screening tool.132,135,136
Cardiac CT can provide excellent depiction of ventricular
aneurysms and pseudoaneurysms (Fig. 8.15). The 3D aspects
Thrombus
LV
FIGURE 8.15. A patient with a transmural apical infarction dem-
onstrating a large thrombus in the apex. The white structure sur-
rounding the thrombus is calcified myocardium replacing normal
tissue after a large infarction. LV, left ventricle.
19 4 chapter
of the aneurysm can be determined, and global and regional
function assessed. Ventricular thrombus can also be easily
identified. There is some evidence indicating that CT is more
sensitive in detecting LV thrombus than transthoracic
echocardiography.137
Pericardial Disease
The combination of excellent spatial resolution, tomographic
format, and exquisite density differentiation makes EBCT an
ideal tool for diagnosis of pericardial disease. Because the
normal pericardium is 1 to 2 mm thick, spatial resolution
must be very good for any imaging technique to define this
structure. X-ray CT is aided by the fact that epicardial and
extrapericardial fat often outline the normal pericardium.
Fat, being of very low density, serves as a natural contrast
agent. Therefore, even minimal pericardial thickening (4 to
5 mm) is well recognized by cardiac CT (Fig. 8.16).138 The high
density of pericardial calcium makes its detection easy. The
3D representation of anatomy by CT provides the surgeon
with precise detail of the extent of calcification and the
degree of myocardial invasion.
In addition to providing an excellent description of the
anatomy of pericardial constriction, EBCT also defines the
degree of hemodynamic abnormality by describing diastolic
filling from ventricular volume measurements every 50 ms
throughout diastole.123 Cine mode images of the right atrium
and RV can also detect diastolic collapse when pericardial
tamponade is present. Enlargement of the superior and infe-
rior vena cavae can also be identified when either constric-
tion or tamponade is present. Pericardial effusion is easily
detected by CT. Occasionally, very small effusions cannot
be distinguished from pericardial thickening, as the CT den-
Pericardium
Pericardium
FIGURE 8.16. Severe pericardial thickening of the anterior and
posterior sections of the pericardium. Normal pericardium is very
thin and barely seen on computed tomographic images. Thickened
pericardium is quite visible.
8
sities are similar. However, pericardial fluid, if free in the
pericardial space, appears as layers, making differentiation
from pericardial thickening relatively simple.
Cardiac CT is an excellent diagnostic technique for eval-
uation of pericardial cysts and tumors.139 Because CT images
the entire thorax and provides clear definition of mediastinal
structures, pericardial involvement by metastatic tumors is
easily identified. Congenital anomalies, such as absence of
the left hemipericardium, are well seen by this modality.
Aorta and Aortic Valve Pathology
Computed tomography angiography can diagnose aneurysm,
dissection, and wall abnormalities such as ulceration, calci-
fication, or thrombus throughout the full length of the aorta
as well as involvement of branch vessels. The superior tem-
poral and spatial resolution of cardiac CT significantly
improves imaging of the aorta, because motion artifacts are
eliminated. Computed tomography is a superior method for
identification of aortic dissection (Fig. 8.17).140 The intimal
flap is usually well delineated, even in branches of the aorta.
In the flow mode, flow can also be assessed in the true and
false lumina.
Cardiac CT is also an effective method of imaging aortic
aneurysms throughout the extent of the aorta (Fig. 8.18). It
is particularly useful for imaging ascending aortic aneu-
rysms before and after surgical treatment. Accurate mea-
surements of aortic root diameter can be made easily and the
extent of the aneurysm defined. The origin of the coronary
arteries is also well visualized. Thrombus within any aortic
aneurysm is easily identified by differences in tissue density
during contrast enhancement. The tomographic format of
CT provides excellent definition of the relationship of aortic
aneurysms to adjacent structures. Leakage of blood from the
aneurysm may be recognizable with contrast enhancement
of surrounding tissues.
PA
Ao
RV D Ao
FIGURE 8.17. Large aortic dissection (black arrows), originating in
the ascending aorta (Ao) and ending in the descending aorta (D Ao).
PA, pulmonary artery; RV, right ventricle.
 c o m p u t e d t o m o g r a p h i c c a r d i o va s c u l a r i m a g i n g
FIGURE 8.18. An 8-cm ascending aortic aneurysm (Ao) is well
delineated by ultrafast contrast-enhanced CT. DAo, descending
aorta; LA, left atrium; RV, right ventricular outflow tract; S, superior
vena cava.
Pulmonary Arteries
Computed tomography can also be utilized to image the
pulmonary arteries. Large chronic thrombi, presumably
resulting from previous embolization, have been success-
fully detected by this technique (Fig. 8.19).141 The cross-
sectional view of the main and proximal right and left
pulmonary arteries provides clear delineation of the proxi-
mal extent of the thrombi, which is essential for successful
surgical treatment.142 Research has indicated that CT may
also be a valid method for diagnosis of acute pulmonary
embolism.143,144 Accurate measurement of pulmonary artery
size may also be useful in estimating the severity of pulmo-
nary hypertension.145
FIGURE 8.19. Large chronic pulmonary embolism (arrows) is
shown by contrast-enhanced ultrafast CT to involve the proximal
right and left pulmonary arteries. Ao, ascending aorta; DAo, descend-
ing aorta; PA, pulmonary artery; SVC, superior vena cava.
19 5
Congenital Heart Disease
Due to advances in surgical management, many patients
with congenital heart disease are living into adulthood. The
ability to assess the 3D relationships among cardiac, arterial,
and venous structures makes CT angiography useful in the
diagnosis and follow-up of patients with congenital heart
disease in its native and postoperative forms.146
Computed tomography angiography is well-suited to the
evaluation of congenital abnormalities of the coronary arter-
ies (Fig. 8.20). A rare but important abnormality relating
specifically to coronary arteries is anomalous origin of the
coronary arteries, with sudden death in young persons during
exertion often being the initial presentation.147 Identification
can be difficult by other modalities. Specific anatomies
are associated with risk of sudden cardiac death including
takeoff of the left coronary artery from the pulmonary
trunk, left coronary artery from the right aortic sinus, and
right coronary artery from the left aortic sinus.148 Anomalous
coronary arteries can be defined noninvasively by CT
angiography,149,150 as well as by MRI151 and transesophageal
echocardiography.152
Considerable experience has been obtained with MRI.153
Very similar results are now seen with CT high-resolution
scanning.154 The disadvantages of CT are the requirement for
injection of contrast medium and exposure to x-ray. Com-
puted tomography offers advantages over MRI, including a
single breath-hold to reduce respiratory motion, higher
spatial resolution,155 and reduced slice thickness.4 An addi-
tional advantage of CT is the overall study time of 1 to 2
minutes as compared to 45 to 90 minutes for MR angiogra-
phy, reducing the time for patients (especially children) to lie
perfectly still. As many congenital abnormalities are associ-
ated with significant conduction abnormalities or ventricu-
lar arrhythmias, many patients with congenital heart disease
have pacemakers or implantable cardiac defibrillators in
place, contraindicating the use of MRI for imaging. However,
MRI may be more applicable to younger patients due to lack
Ao
PA
FIGURE 8.20. Anomalous coronary artery with left main coronary
artery arising from the right coronary cusp [black arrows depicting
the course of the artery between the aorta (Ao) and the pulmonary
artery (PA)].
19 6 chapter
FIGURE 8.21. Secundum atrial septal defect with predominant left
to right shunting. Right atrial (RA) enlargement and right ventricu-
lar (RV) hypertrophy are present. Ao, ascending aorta; LA, left
atrium.
D Ao
FIGURE 8.22. Coarctation of the aorta. Prominent vertebral artery
vessels are noted entering the descending aorta (DAo).
8
of radiation exposure, but longer study times require a greater
need for anesthesia.156
Computed tomography imaging can almost always be
completed without the need for sedation. The high-resolu-
tion images provide excellent detail of the anatomic struc-
ture of the cardiac chambers and great vessels. The flow
mode can be used to detect and quantitate left-to-right and
right-to-left shunts.157 The cine mode can be used to evaluate
RV and LV function, as well as valvular motion. One of the
great strengths of cardiac CT is its capacity to study cardiac
anatomy, cardiovascular function, and blood flow during a
single study period.
A spectrum of cyanotic and acyanotic congenital anoma-
lies can be visualized and characterized by CT angiography
(Fig. 8.21).158 Studies can assess patency of shunts, pulmonary
hemodynamics associated with shunts, central pulmonary
artery anatomy, anomalous vascular connections, pulmo-
nary vein obstruction, partial anomalous pulmonary venous
connections, and other associated thoracic abnormalities
such as tracheobronchial abnormalities.159,160,161,162,163 CT
angiography can provide detailed and comprehensive assess-
ment of complex anatomy for surgical planning.164,165 Con-
genital abnormalities of the aorta such as coarctation can be
easily identified and assessed with 3D imaging (Fig. 8.22).166
Electrophysiologic Applications of Cardiac
Computed Tomography
Coronary Veins
The same techniques that allow visualization of coronary
arteries also visualize the coronary veins (Fig. 8.23). The
coronary venous anatomy has become increasingly impor-
tant as many interventional procedures use the coronary
veins to obtain venous access to the left atrium and left
ventricle. Computed tomography angiography is effective for
visualization of the coronary sinus and its tributaries.167,168
Computed tomography angiography can provide detailed
CS
Lateral
vein
FIGURE 8.23. The coronary venous system is visualized with iden-
tification of the coronary sinus (CS) and a large lateral cardiac vein.
Distances and diameters can easily be measured.
 c o m p u t e d t o m o g r a p h i c c a r d i o va s c u l a r i m a g i n g
assessment of the coronary venous anatomy, with coronary
sinus dimensions, branch vessel locations, diameters, angu-
lations off the coronary sinus/great cardiac vein, and associ-
ated myocardial segment location.169
Particular attention has been the focus on coronary
venous anatomy with the increasing application of resyn-
chronization therapy. In resynchronization therapy, simulta-
neous biventricular pacing is performed in patients with
dilated or ischemic cardiomyopathy, significant heart failure,
and prolonged interventricular conduction in order to “resyn-
chronize” right and left ventricular activation and contrac-
tion. The left ventricular component of pacing is provided by
a chronic pacing lead placed in a coronary sinus branch
vessel, with placement often being challenging due to the
need to locate small coronary vein branches for adequate
pacing sites. As potential left ventricular pacing sites are
defined by an individual patient’s coronary venous anatomy,
detailed anatomic information could potentially play a role
in the approach to resynchronization therapy. Many patients
undergoing resynchronization therapy already have devices
in place with upgrade to a biventricular system, precluding
visualization of anatomy by MRI.
Pulmonary Veins
Characterization of pulmonary venous anatomy is important
to catheter-based therapies for atrial fibrillation. Atrial fibril-
lation has become a major area of research focus due to its
increasing incidence in an aging population.170 Procedural
efforts have focused on ablation of the pulmonary vein. Com-
puted tomography angiography and MRI can provide detailed
information on pulmonary vein location, variation, size, and
complexity, which are difficult to visualize by other tech-
niques; this is important for ablation of pulmonary vein
triggers and electrical isolation of pulmonary veins (Fig.
8.24).171 Endoscopic views of the left atrium can now be
2 1. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte
180∞
RSPV
RIPV
FIGURE 8.24. Endoscopic view of the right superior and inferior
pulmonary veins (RSPV and RIPV).
19 7
achieved through software advances to visualize the com-
plexity of each pulmonary vein os. Additionally, follow-up of
patients for such complications as pulmonary vein stenosis
is extremely important.172 The incidence and time course of
pulmonary vein stenosis requires further definition, through
serial evaluation of pulmonary vein structure.
Summary
Computed tomography coronary artery calcium assessment
and CT coronary angiography using EBCT or MDCT are
technologies that can provide risk stratification for future
cardiac events and definition of patient populations requir-
ing aggressive risk factor modification or interventional
therapy for CAD. Computed tomography angiography is a
robust technology that can identify a spectrum of cardiovas-
cular disease processes and facilitation of invasive cardiac
procedures. Further advances in technology and methodol-
ogy will broaden the research applications for the under-
standing of cardiovascular pathophysiology and clinical
applications for diagnosis and treatment of cardiovascular
disease. The availability of many other imaging modalities
and the relatively high cost of CT scanners and limited or
lack of reimbursement have slowed its adoption for diagnosis
by cardiologists, radiologists, and primary caregivers.
However, the technology offers some truly unique capabili-
ties, with unmatched prognostic capabilities for cardiac
events and noninvasive imaging of the coronary arteries and
veins, and clinicians are increasingly employing this imaging
technique. Cardiac CT is considered by some to be the gold
standard in evaluating congenital heart disease, pulmonary
vein anatomy, and coronary venous anatomy. Further experi-
ence and utilization will undoubtedly increase the interest
and knowledge of this multifaceted tool.
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SEC TION II

Congenital Heart
Disease in
the Adult
 9 Normal and
Abnormal Anatomy
Robert H. Anderson and Anton E. Becker
Normal Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
Abnormal Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
Normal Anatomy
To understand the various anatomic abnormalities of the
heart, we first need to appreciate the structure of the normal
heart. So as to describe the cardiac components in appropri-
ate fashion, it is also necessary to appreciate the location of
the normally structured heart within the thorax. Thereafter,
we can describe the location and morphology of the cardiac
chambers and arterial trunks, the arrangement of their vas-
cular supply, and the location of the so-called specialized
conducting tissues.
In the normal individual, with usually arranged organs,
so-called situs solitus, the heart is positioned within the
mediastinum, with one third of its bulk to the right and two
thirds to the left of the midline. When projected to the frontal
plane, the cardiac silhouette is trapezoidal, with the apex of
the trapezium extending to the left (Fig. 9.1). The trapezium
can be divided into atrial and ventricular triangles, which
meet one another in the plane of the atrioventricular and
ventriculoarterial junctions. This plane also represents the
base of the ventricular mass (Fig. 9.1). According to conven-
tion, all structures within the body should be described rela-
tive to the anatomic position, with the subject viewed
standing upright and facing the observer (Fig. 9.2). The subject
thus positioned has three orthogonal planes: the first frontal,
with right and left borders; the second lateral, with anterior
and posterior borders; and the third in the short axis. Relative
to the orthogonal planes themselves, there is any number of
companion planes. For example, those in the short axis extend
from the head, which is superior and cranial, to the feet,
which are inferior and caudal. Unfortunately, those describ-
ing the heart over the years have not followed this conven-
tion, but instead have described the heart in terms of its own
orthogonal planes, with the heart considered as removed
from the body and positioned on its apex (Fig. 9.3A). This leads
to the unfortunate situation in which the diaphragmatic
surface of the heart, located inferiorly, is usually described as
being the posterior part, with the artery irrigating the mid-
portion of this surface, in reality positioned in inferior and
interventricular position (Fig. 9.4), usually described as being
Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
posterior and descending. It has also led to the atrial and
ventricular chambers being described as “right” and “left,”
when in truth they are located more anteriorly and posteriorly
(Fig. 9.3B). Because the chambers are not always in their
anticipated position when the heart is congenitally mal-
formed, we will describe them as being “morphologically
right” and “morphologically left,” meaning that they possess
the anatomic features expected for the so-called right- and
left-sided structures as seen in the normal heart. With regard
to the arteries, and other structures within the heart, we will
follow the anatomic convention, and describe them in attitu-
dinally appropriate fashion,1 since with the increasing use in
clinical practice of tomographic techniques and three-dimen-
sional reconstruction, the cardiologists of tomorrow will
need to understand the structure of the heart within the body,
not as it is visualized on the autopsy table. Thus, the so-called
posterior descending coronary artery will be described as
being inferior and interventricular, which is the anatomically
accurate terminology (Fig. 9.4).
The morphologically right atrium (Fig. 9.5) lies predomi-
nantly in front of its alleged left-sided counterpart, although
also somewhat right-sided and inferior, with the atrial septum
positioned more or less in the frontal plane. In addition to its
well-recognized venous component, it also has a muscular
vestibule, which supports the leaflets of the tricuspid valve,
and an extensive appendage. The appendage, the most con-
stant component of the right atrium, has a broad base, and
is lined throughout by the prominent pectinate muscles,
which take their origin in parallel fashion from the broad
muscle bundle, the terminal crest, which separates the
appendage from the smooth-walled venous component. The
appendage forms the entirety of the anterior wall of the right
atrium, with the pectinate muscles radiating from the ter-
minal crest to reach the vestibule all around the right atrio-
ventricular junction.
Entering the superior part of the smooth-walled systemic
venous component is the superior caval vein, with the infe-
rior caval vein entering inferiorly, and the coronary sinus
opening inferiorly and posteriorly, having traversed the left
atrioventricular groove. The location of the terminal crest is
205
206 chapter 9

Ventricular
Atrial triangle
triangle

A B
FIGURE 9.3. The cast has been made by filling the so-called right
se

heart chambers with red silicon, and the left heart chambers with
Ba

blue silicone. Only when the heart is removed and positioned on

its apex (A) is it possible to see the four chambers in right-left posi-
tion, with the atria above the ventricles. This is wrong. When the
Apex heart is appropriately positioned within the chest (B), the so-called
right chambers are positioned in front of their allegedly “left”
Diaphragmatic surface
counterparts.

marked externally by a prominent groove, the terminal

FIGURE 9.1. The silhouette of the cardiac shadow has been super-
imposed on the chest radiograph. The silhouette is trapezoidal,
formed by atrial and ventricular triangles meeting at the base of the
ventricular mass.
Coronal
- Sagittal
groove. The sinus node lies in the groove, usually lying just
inferior to the crest of the appendage, although in one tenth
of the population it extends in horseshoe fashion across the
crest. The node is sandwiched subepicardially between the
musculature of the superior caval vein and the terminal
crest. The orifice of the inferior caval vein may be guarded
by a flap-like valve, the eustachian valve, whereas the orifice
of the coronary sinus is often guarded by another flap-like
valve, the thebesian valve. When present, these two valves
come together to form a tendinous structure that extends
from their point of union into the atrial musculature, running
Head
Anterior Posterior
Feet

Transverse Short axis

Right Left
ventricle ventricle
Long axis

FIGURE 9.2. The standing anatomic position, facing the observer.
By convention, all structures within the body, including the heart,
should be described relative to the three orthogonal planes shown
here.
FIGURE 9.4. The short axis of the ventricular mass as seen in the
left anterior oblique orientation, and pictured relative to the ana-
tomic landmarks of the thorax. As can be seen, the right ventricle
is located anterior to the left ventricle, and the so-called posterior
descending coronary artery (arrow) in reality is positioned in infe-
rior and interventricular position, occupying the diaphragmatic
surface of the ventricular mass.
 nor m a l a n d a bnor m a l a natom y
FIGURE 9.5. The morphologically right atrium is shown having
made a cut in the appendage and reflecting the wall to reveal the
posterior septal surface. Note that the wall of the appendage is
marked by the multiple pectinate muscles, in contrast to the smooth-
walled contours of the systemic venous component, the vestibule of
the tricuspid valve, and the septum. The location of the triangle of
Koch is marked by the red dotted lines, the mouth of the coronary
sinus forming the base of the triangle.
Superior caval vein
Right
pulmonary
vein
Flap valve
Infolded
superior
rim
Antero-
inferior
rim
Inferior caval vein
FIGURE 9.6. The atrial chambers have been sectioned in so-called
four-chamber fashion to reveal the structure of the atrial septum.
As can be seen, the so-called septum secundum is no more than the
deep fold between the attachments of the caval veins to the right
atrium and the right pulmonary veins to the left atrium.
207
superiorly and anteriorly within the muscular wall between
the oval fossa and the septal hinge of the tricuspid valve. This
is the tendon of Todaro, which forms the posterior border of
an important triangle, the triangle of Koch (Fig. 9.5). The
atrioventricular node lies at the apex of this triangle.
In the center of the posterior wall of the right atrium is
the oval fossa (Fig. 9.5). The fossa marks the site of the atrial
septum, with obvious borders around its superior, anterior,
and inferior margins, the so-called rims of the oval fossa, or
the superior and inferior limbic bands. The superior rim is
often described as the “septum secundum.” In reality, it is
no more than the deep infolding between the attachments of
the caval veins to the right atrium and the right pulmonary
veins to the left atrium (Fig. 9.6). The atrial septum itself is
the thin fibromuscular floor of the fossa, which overlaps the
margins of the fossa on the left atrial side (Fig. 9.7). The flap
is also described as the valve of the oval foramen. The antero-
inferior margin of the foramen is also a true septal structure,
but the right atrial wall in this location then runs over the
base of the ventricular septum to insert into the vestibule of
the septal hinge of the tricuspid valve. This is the area of
offsetting of the mitral and tricuspid valves identified by the
echocardiographer as one of the features of the normal heart
(Fig. 9.8).
In the fetus, a channel in the anterior aspect of the oval
fossa provides the extensive and essential interatrial com-
munication. This opening is the oval foramen. In about one
third of adults, this channel persists as a probe-patent oval
FIGURE 9.7. A probe has been passed through the oval foramen,
which in this heart is probe patent, and the heart photographed from
the left atrium. The flap valve overlaps the margin of the oval fossa
(see also Fig. 9.9).
208 chapter 9

FIGURE 9.8. This four-chamber section is taken through the area

offsetting the attachments of the tricuspid and mitral valves to the
right and left sides of the septum, respectively. The edge of the atrial
wall overlaps the crest of the ventricular mass in the area marked
by the arrows. Note the extension of the inferior atrioventricular
groove separating the muscular walls in this area, and carrying the
artery to the atrioventricular node.

foramen (Fig. 9.9). Potential effects of such patency are dis-

cussed below (see Interatrial Communications).
The valve supported by the vestibular musculature of the
right atrium is the tricuspid valve. It has three leaflets, each
supported by tendinous cords and papillary muscles of the
right ventricle. The right ventricle itself has inlet, outlet, and
apical trabecular components (Fig. 9.10). The inlet portion lies
posteriorly, rightward and inferiorly, while the outlet portion
is located anteriorly, superiorly, and leftward. The coarsely FIGURE 9.9. The right atrial aspect of the probe-patent oval foramen
trabeculated apical part is the most constant component of illustrated from the left side in Figure 9.7. Note how the probe passes
between the margins of the oval fossa and the flap valve, the latter
the right ventricle in congenitally malformed hearts. forming the floor of the fossa. Such probe-patency is present in up
The septal wall of the right ventricle has well-defined fea- to one third of the normal adult population.
tures. At the atrioventricular junction, at the site of the zone
of apposition between the septal and anterosuperior leaflets,
the septum is composed of fibrous tissue, and is known as the
membranous septum. In part, this structure separates the two
ventricles, but because it is crossed by the hinge line of the
septal leaflet of the tricuspid valve, part of the septum inter-
poses between the right atrium and the left ventricle. This is
the fibrous atrioventricular septum (Fig. 9.11).
Superior to the membranous septum is the medial papil- Outlet
lary muscle, also known as the papillary muscle of the conus,
the muscle of Luschka, or the muscle of Lancisi. This receives
tendinous cords from the adjacent portions of the septal and
anterosuperior leaflets of the tricuspid valve. The medial
papillary muscle takes its origin from a prominent muscle
bundle that reinforces the right ventricular aspect of the
muscular ventricular septum. This muscle band takes the Inlet
shape of an inverted Y, with the supraventricular crest, Apical
the muscular wall of the right ventricle interposing between component
the attachments of the tricuspid and pulmonary valves,
inserting between the two limbs of the Y. The Y-shaped
muscle itself is the septomarginal trabeculation, or septal
band. The anterior limb of the Y extends to support the leaf-
FIGURE 9.10. The morphologically right ventricle extends from the
lets of the pulmonary valve, while the stem of the Y extends atrioventricular to the ventriculoarterial junctions (red lines). It is
to the ventricular apex, where it gives rise to the anterior best analyzed in terms of its inlet, apical trabecular, and outlet
papillary muscle of the tricuspid valve. Arising from the components.
 nor m a l a n d a bnor m a l a natom y
FIGURE 9.11. This section shows the so-called membranous
septum. This is the part of the septum made of fibrous tissue. It is
crossed on its right-sided aspect by the hinge of the septal leaflet of
the tricuspid valve, dividing it into atrioventricular and interven-
tricular components.
anterior margin of the septomarginal trabeculation are a
series of septoparietal trabeculations. One of these crosses to
the anterior papillary muscle, and is known as the moderator
band (Fig. 9.12).
SVC
SMT
Tricuspid
valve
FIGURE 9.12. The right ventricle has been opened to show the
septal surface. The supraventricular crest (SVC) inserts between the
limbs of a prominent septal trabeculation, known as the septomar-
ginal trabeculation (SMT), or septal band. Note the series of septo-
parietal trabeculations (asterisks) extending from the anterior
margin of the strap-like septal trabeculation. One of these septopa-
rietal trabeculations (yellow asterisk) extends to the anterior papil-
lary muscle. This is the so-called moderator band.
209
The right ventricular outlet, or infundibulum, is a cylin-
drical muscular tube that extends from the level of the Y of
the septomarginal trabeculation to support the leaflets of
the pulmonary valve. Part of the infundibulum is formed
by the supraventricular crest, which separates the leaflets of
the tricuspid and the pulmonary valves.
The pulmonary valve is in the most anterior and superior
part of the four cardiac valves. It separates the cavity of the
right ventricle from that of the pulmonary trunk, the latter
being a relatively short vessel that bifurcates into the left and
right pulmonary arteries. The arterial duct of fetal life and
early infancy, which becomes the arterial ligament, connects
the superior aspect of the left pulmonary artery and the
inferior part of the aorta at the junction of its distal arch and
descending portions.
The morphologically left atrium (Fig. 9.13) lies posterior
and somewhat to the left and superior relative to the mor-
phologically right atrium. Like the right atrium, it possesses
a venous component, a vestibule, and an appendage, but the
Venous component
Appendage
Body
Vestibule Septum
FIGURE 9.13. The left atrium is the most posterior of the cardiac
chambers. It has a venous component, a tubular appendage, the
vestibule of the mitral valve, and the flap valve aspect of the atrial
septum, and also possesses an extensive body.
210 chapter 9

left atrium also has an extensive body. The venous compo-

nent receives the pulmonary veins at the four corners of its
roof. In most instances, the veins open superiorly and infe-
riorly on the right and left sides, although anatomic varia-
tions in their number are common.
The left atrial appendage joins the body of the atrium
anteriorly and inferiorly relative to the entrance of the left
inferior pulmonary vein. The left atrial appendage is much
narrower than the right atrial appendage, and is often crenel-
lated along its length. The pectinate muscles of the left
atrium are confined within the appendage, so that the pos-
terior atrial wall is smooth throughout the vestibular, body,
and venous component. Although emptying to the right
atrium, the coronary sinus is an integral part of the left
atrioventricular junction (Fig. 9.14). The flap valve of the oval
foramen forms the characteristic left atrial side of the septum,
with its leftward and superior margin overlapping the right
atrial rims of the fossa, albeit without being fused to the rims
in the three tenths of the population that has probe-patency
FIGURE 9.15. The short axis of the ventricular mass is shown as it
of the oval foramen (Fig. 9.9). lies within the body. Although the papillary muscles of the mitral
The left atrial vestibule supports the two leaflets of the valve are usually described as being posteromedial and anterolat-
mitral valve, with the solitary zone of apposition between eral, this reflects the bad habit of describing the heart as if posi-
the leaflets supported at its two ends by tendinous cords tioned on its apex (Fig. 9.3B). In reality, the papillary muscles, as
shown, are positioned inferoanteriorly and superoposteriorly.
attached to the two left ventricular papillary muscles. The
two muscles are usually described as being anterolateral and
posteromedial. When considered in the setting of the heart
within the body, however, the muscles are positioned antero- inferiorly and posterosuperiorly (Fig. 9.15). The free edges of
both leaflets are attached by tendinous cords to the same
papillary muscles.
The left ventricle itself, like the right ventricle, possesses
inlet, outlet, and apical trabecular components (Fig. 9.16).
The apical component is somewhat conical, with its apex
forming the apex of the cone. The left ventricular outflow
tract to the aorta lies behind the right ventricular infundibu-
lum. Unlike the right ventricle, the outlet from the left ven-
tricle is made up in part by muscle, and posteriorly by the

Outlet

Inlet
Apical
component

FIGURE 9.14. The cast shown in Figure 9.3 is photographed to show

its diaphragmatic aspect. Note that the coronary sinus, although
occupying the left atrioventricular groove, opens into the morpho-
logically right atrium. It commences at the union of the great vein
with the oblique vein of the left atrium (Marshall’s vein). ICV, infe-
rior caval vein.
FIGURE 9.16. As with the morphologically right ventricle, the
left ventricle extends from atrioventricular to ventriculoarterial
junctions, and possesses inlet, apical trabecular, and outlet
components.
 nor m a l a n d a bnor m a l a natom y 211
area of fibrous continuity between the leaflets of the aortic
and mitral valve (Fig. 9.17). Because of this arrangement, the
leaflets of the mitral valve can conveniently be described as
Pulm.
being aortic and mural. The leaflets of the aortic valve take
trunk
their origin from the muscular ventricular septum and pari-
etal wall of the left ventricle anteriorly and laterally, whereas
posteriorly is found the aortomitral intervalvar fibrous area.
This area is thickened at its right end as the right fibrous
trigone, which joins the membranous septum to form the
so-called central fibrous body (Fig. 9.17).
The mural leaflet of the mitral valve takes its origin from
the left atrioventricular junction, the point of attachment at
the junction often being called the mitral annulus or ring,
although it is rarely a complete fibrous ring. The aortic valve
has three semilunar leaflets, best named according to whether L R
or not the sinus supporting them gives rise to a coronary
artery. Thus, the leaflets are described as being left coronary,
right coronary, and noncoronary (Fig. 9.18). NC
The left and right coronary arteries originate from the
left and the right aortic coronary sinuses, respectively. The
main stem of the left coronary artery is short before its divi-
sion into the anterior interventricular and circumflex coro-
nary arteries (Fig. 9.19). A third branch, sometimes called the FIGURE 9.18. The base of the heart is shown from above, having
intermediate coronary artery, may be present should the removed the arterial trunks. Note that coronary arteries (arrows)
main stem trifurcate instead of bifurcating. The anterior arise from two of the three aortic sinuses, permitting these to be
named as the left (L) and right (R) aortic sinuses. The third sinus is
interventricular artery, also called the anterior descending the noncoronary (NC) sinus.
artery, passes in the anterior interventricular groove toward
the cardiac apex. The circumflex artery runs within the left
atrioventricular groove. The right coronary artery runs in ously as the “posterior descending” coronary artery. This
the right atrioventricular groove toward the posterior and arterial pattern is termed right dominance (Fig. 9.20). In the
inferior aspect of the heart. Most often, it turns abruptly less common left dominant pattern, it is the circumflex
downward in the inferior interventricular groove as the artery, which continues in the left atrioventricular groove to
inferior interventricular artery, usually described errone- give rise to the inferior interventricular artery.

FIGURE 9.17. In this heart, the leaflets of the aortic valve have been
removed, revealing the fibrous triangles (hatched lines) that extend
between the valvar sinuses to the level of the sinutubular junction. Circumflex
The triangle between the right and noncoronary sinuses is continu-
ous with the membranous septum (see Fig. 9.11), the conjoined area
being described as the central fibrous body. This, together with the Anterior interventricular
right fibrous trigone, forms the right end of the area of fibrous con-
tinuity between the leaflets of the aortic and mitral valves, The two FIGURE 9.19. The main stem of the left coronary artery is very
fibrous trigones anchor the area of valvar fibrous continuity in the short (double-headed arrow), branching almost immediately into the
roof of the left ventricle. circumflex and anterior interventricular arteries.
212
FIGURE 9.20. The right atrioventricular junction has been dis-
sected to show the course of a dominant right coronary artery. Note
that, at the crux, the artery gives rise to the inferior interventricular
artery, then continuing into the left atrioventricular groove to
supply the diaphragmatic surface of the left ventricle.
The coronary veins run in the epicardium, either over the
ventricles or in the different cardiac grooves, and largely
terminate for the most part in the coronary sinus. As already
emphasized, the sinus itself, although draining to the right
atrium, is an integral part of the left atrioventricular groove
(Fig. 9.14). The coronary veins draining the wall of the right
atrial appendage open directly into the cavity of the right
atrium, as do the smallest coronary veins, known as thebes-
ian veins, some of which may also drain directly into the left
atrium. It is the remaining larger veins that drain directly
into the coronary sinus (Fig. 9.21). They are the great cardiac
vein, which accompanies the anterior interventricular artery;
the middle cardiac vein running with the inferior interven-
tricular artery; and the small cardiac vein, which accompa-
nies the right coronary artery.
Oblique vein
Great
vein
Small vein
Middle vein
Coronary sinus
FIGURE 9.21. The venous tributaries that drain to the coronary
sinus. (See also Figure 9.14.)
chapter 9
Abnormal Anatomy
This section discusses obstructive lesions, lesions promoting
valvar regurgitation, abnormal communications between
the chambers and the arterial trunks, abnormal connections
between the different cardiac segments, combinations of
anomalies, abnormal aortic and arterial branching, and syn-
dromes with cardiac disease.
Obstruction
Congenital obstructions in the cardiovascular system that
are seen in the adult include valvar, paravalvar, and vascular
conditions.
Valvar and Paravalvar Obstructions
Congenital valvar obstruction may affect any valve, but most
commonly it is the aortic valve that is involved. Lesions
producing aortic stenosis can be broken down into subvalvar,
valvar, and supravalvar entities. There can also be atresia of
any of the cardiac valves. Atresia of the left-sided valves used
to be lethal in early life, but this has now changed with the
increasing use and improvement of the Norwood sequence
of operative interventions. Because of this, patients with
so-called hypoplasia of the left heart will now be seen as
adults with increasing frequency by the cardiologist. With
the success of the Fontan procedure, those with atresia of the
tricuspid valve are already presenting as adults to the cardi-
ologist, and atresia of the pulmonary valve can itself be well
tolerated, allowing some patients to survive to adulthood
even without surgical intervention.
AORTIC STENOSIS
The major cause of obstruction at the aortic valve in the
adult is the congenitally bifoliate, or bicuspid, aortic valve.
Although this condition may be intrinsically obstructive,
this is not usually the case in individuals who reach adult-
hood with a congenitally bicuspid aortic valve. The congeni-
tally bicuspid aortic valve, nonetheless, has a strong tendency
over time to become calcified and stenotic. It is probable that
an aortic valve with only two leaflets is present in about 1%
to 2% of the adult population.2 Most but not all of these
valves become calcified with time, producing the rigidity
that causes aortic stenosis.3 This type of aortic stenosis in
the adult accounts for approximately half of prosthetic valvar
replacements.4,5 The calcified valve has two leaflets, with one
being the so-called conjoined leaflet. A ridge, or raphe, typi-
cally extends from the sinutubular junction onto the center
of the aortic aspect of the conjoined leaflet (Fig. 9.22). The
conjoined leaflet usually lies anteriorly, with the conjoined
sinus supporting it giving rise to both coronary arteries. Less
commonly, the leaflets lie in a lateral orientation, and then
one coronary artery arises from each of the two aortic
sinuses.
Another anomaly of the aortic valve is the so-called
unicuspid and unicommissural arrangement, in which the
valve has the shape of a keyhole. This valve is intrinsically
stenotic, the degree of obstruction varying from case to case,
but is more typically the cause of aortic stenosis in infants
and children. Occasionally, however, a lesser degree of ste-
 nor m a l a n d a bnor m a l a natom y
Level of sinutubular junction
Raphe
FIGURE 9.22. This congenitally bifoliate aortic valve, photographed
from above, shows the raphe on the aortic aspect of the conjoined
leaflet.
nosis can be tolerated for years, even into adulthood. Eventu-
ally, calcification may develop, and the patient with aortic
stenosis then becomes symptomatic (Fig. 9.23). The calcifica-
tion does not change the caliber of the intrinsically stenotic
valve. Because it also allows regurgitation, the increased flow
through the orifice is responsible for the transformation from
asymptomatic to symptomatic disease.6
SUBAORTIC STENOSIS
Adults exhibit two principal types of subaortic stenosis:
muscular and fibrous. An uncommon third type, tunnel sub-
aortic stenosis, has also been described.
Muscular Subaortic Stenosis. This entity has been
described under myriad names,7 including idiopathic hyper-
trophic subaortic stenosis, muscular subaortic stenosis,
asymmetric septal hypertrophy, and hypertrophic obstruc-
tive cardiomyopathy. Asymmetrical septal hypertrophy is
characterized by asymmetrical hypertrophy of the muscular
ventricular septum associated with histologic features of
FIGURE 9.23. This unicuspid and unicommissural valve, seen in
an adult, has become calcified. It is the calcification of the leaflets,
producing immobility that heralds the onset of symptoms.
213
myocardial disarray. The degree of this change varies quali-
tatively and quantitatively, as does its specific location.
The condition is now well established as a genetically
transmitted condition, characterized by a clinically con-
tinuous spectrum that includes asymptomatic individuals,
symptomatic patients without obstruction to outflow, and
symptomatic patients with typical obstructive lesions.7
Obstruction of the left ventricular outflow tract is caused in
part by the systolic anterior motion of the aortic leaflet of
the mitral valve. As this leaflet of the mitral valve impinges
against the ventricular septum, it not only obstructs the
outflow tract, but also irritates mechanically the septal
endocardium, producing a fibrous imprint over the promi-
nence of the ventricular septum (Fig. 9.24).
Fibrous Subaortic Stenosis. So-called discrete, or
fixed, subaortic stenosis is characterized by encirclement of
the left ventricular outflow tract with dense fibrous tissue.
The fibrous tissue produces a diaphragmatic shelf that is
attached to the endocardium over the ventricular septum
and the parietal wall of the left ventricle, as well as involving
the ventricular aspect of the aortic leaflet of the mitral valve.
The fibrous tissue not only narrows the left ventricular
outflow tract but also often extends to become attached in
irregular fashion to the leaflets of the aortic valve (Fig. 9.25).
Contracture of this fibrous tissue may lead to aortic regurgi-
tation. The degree of obstruction may increase with age8,9 as
Right ventricle
Septum
Aorta
Parietal
wall Left atrium
FIGURE 9.24. This heart with hypertrophic cardiomyopathy has
been sectioned to replicate the parasternal long axis echocardio-
graphic section. Note the asymmetric septal hypertrophy, and the
ridge on the septal surface facing the aortic leaflet of the mitral
valve.
214 chapter 9

atherosclerosis, with the potential for early manifestations

of coronary arterial obstruction. The intimal aspect of the
aortic lesion may encroach on the orifices of the coronary
arteries. In exceptional cases, the free edge of the aortic
leaflet may be attached along its full length to the sinutubu-
lar junction, thus producing effective coronary arterial
atresia. Infective endocarditis is another potential complica-
tion of the hourglass variant.

FIGURE 9.25. The subaortic outflow tract has been opened from
the front to show the typical fibrous diaphragm that produces dis-
crete subaortic stenosis. Note that the shelf extends onto the aortic
leaflet of the mitral valve, and also onto the leaflets of the aortic
valve.
the result of contracture of the fibrous tissue. In addition,
turbulence of the blood flowing through the narrow channel
may lead to an increase in deposition of fibrous tissue. Among
the significant complications of shelf-like subaortic stenosis
are major left ventricular hypertrophy and sudden death.
Infective endocarditis is a complication seen in the adult,10
and it is more common in fibrous than muscular subaortic
stenosis.
Tunnel Subaortic Stenosis. The tunnel variant is
characterized by a long tubular narrowing in the subaortic
region.11 The orifice of the valve itself is also relatively
narrow, and the valvar leaflets typically show fibrous thick-
ening. Marked left ventricular hypertrophy is the rule, often
with associated asymmetric septal hypertrophy.
PULMONARY STENOSIS
Individuals with isolated, so-called dome-shaped pulmonary
stenosis, even untreated, may survive to adulthood. Although
dome-shaped stenosis of the pulmonary valve can also com-
plicate patients with deficient ventricular septation, when
seen in isolation the ventricular septum is usually intact.
There is then major right ventricular hypertrophy. Indeed,
there may be acquired subpulmonary stenosis secondary to
the myocardial hypertrophy. With few exceptions, the valve
takes the shape of a truncated cone with a central orifice,
unlike the keyhole arrangement seen in the aortic valve.
Three equidistant raphes are characteristically present at the
initial zones of apposition of the trifoliate pulmonary valve
(Fig. 9.26). In exceptional cases, there may be four raphes,
indicating initial presence of a quadrifoliate valve, or a single
raphe, indicating stenosis in the setting of a pulmonary valve
with two leaflets. Poststenotic dilation of the pulmonary
trunk is common, extending more into the left than into the
right pulmonary artery.15
When the oval foramen is patent in the setting of pulmo-
nary stenosis with intact ventricular septum, a right-to-left
shunt may develop at the atrial level. Even though the right-
to-left shunt is minor, such patients may develop cerebral

SUPRAVALVAR AORTIC STENOSIS Fused leaflets

This is the least common form of congenital obstruction of
the left ventricular outflow tract. There are two major vari-
ants, the tubular and hourglass types, although rarely there
can be a diaphragmatic variant. The tubular variant fre-
quently involves also the pulmonary trunk and arteries. It is
doubtful whether patients with this form survive to adult-
hood. Patients with the hourglass type, nonetheless, cer-
tainly do survive to adulthood,12 and this variant may also
be associated with obstruction of the branches of the aortic
arch and the pulmonary arteries. Experience in children and
adolescents has shown that, in untreated patients, the degree
of obstruction of the left ventricular outflow tract increases
with age, whereas the associated pulmonary arterial stenosis
may become less severe.13,14
One of the significant problems with supravalvar stenosis
is that, in reality, the major level of obstruction is at the
distal attachments of the valvar leaflets to the sinutubular
junction. Thus, the lesion is valvar just as much as it is Narrowed orifice
supravalvar. Because of the involvement of the sinutubular
junction, the coronary arterial orifices lie within the hyper- FIGURE 9.26. This picture, taken in the operating room, shows the
tensive compartment during both systole and diastole. The fused ends of the zones of apposition between the valvar
condition, therefore, is associated with premature coronary leaflets that produces typical pulmonary valvar stenosis.
 nor m a l a n d a bnor m a l a natom y 215
abscess.16 This infectious process is a recognized complica-
tion in instances of chronic right-to-left shunts without a
focus of infection within the heart. In other instances, infec- Arterial ligament
tive endocarditis may develop on the valvar leaflets, or infec-
tious pulmonary arteritis may occur at the area where the
jet-like stream has an impact at or near the pulmonary arte-
rial bifurcation.
In patients treated by adequate pulmonary valvotomy,
right ventricular hypertrophy may remain for years. Sudden
death has occurred in such cases, perhaps as a consequence
of residual myocardial hypertrophy.

M ITRAL STENOSIS
In the past, most cases of mitral valvar stenosis were consid-
ered to be of acquired or rheumatic origin. This is still likely
to be the case in less well-developed countries. In the Western
world, however, cardiologists are increasingly confronted by
adult patients with surgically treated congenital malforma-
tions of the mitral valve.
The so-called parachute valve is among the causes of
congenital mitral stenosis observed in adults. The condition
is characterized by a solitary papillary muscle, into which
all the tendinous cords from both leaflets of the valve con-
verge and insert. It may be associated with three other
obstructive anomalies in the left side of the heart, aortic
coarctation, subaortic stenosis, and supravalvar left atrial
ring, together forming the so-called Shone syndrome.17
Narrowed orifice
T RICUSPID STENOSIS
Seen most frequently in the setting of Ebstein’s malforma-
FIGURE 9.27. The descending aorta is viewed from beneath to show
tion, it is common for patients with this variant of tricuspid the typical curtain formed from the aortic media that produces
stenosis to reach adulthood. Typically, however, Ebstein’s coarctation in the adult.
malformation produces regurgitation as well as stenosis,
with the regurgitation being more common. We will discuss
Ebstein’s malformation, therefore, in greater detail later.
Tricuspid atresia is a relatively common condition in the represent the major channels carrying blood from the proxi-
young, but until recently was rare in adults. Nowadays, mal to the distal compartments of the aorta. Dilation and
however, many patients with tricuspid atresia are becoming tortuosity of the internal thoracic arteries represent part of
the province of the cardiologist as they survive into adult- the subclavian source of blood to the lower body.19 The ori-
hood with the Fontan circulation. We will also discuss the fices of the intercostal and lumbar arteries are also typically
underlying anatomy of this lesion in greater detail later. wider than normal, and the left ventricle is hypertrophied.
A congenitally bifoliate aortic valve is common, reputedly
present in at least half of cases.20 The anterior spinal artery
Aortic Coarctation
may also contribute to the collateral circulation, making it
Among the various arterial obstructive anomalies that allow enlarged and tortuous. It connects with arteries at levels both
patients to survive into adulthood, coarctation of the aorta above and below the coarctation, including branches of the
is the most common. The usual site of coarctation is at the vertebral, intercostal, and lumbar arteries.
union of the arterial duct with the aorta, although in adults The potential complications of coarctation are numerous,
the duct has typically become ligamentous, so it is difficult and include changes in the commonly occurring congeni-
to judge the precise location of the initially obstructing shelf. tally bifoliate aortic valve, such as calcific aortic stenosis,
Externally, in such adults, there is an indentation of the primary aortic valvar regurgitation, and infective endocardi-
superior wall of the aorta at the site of the obstruction. Inter- tis.3 Various aortic complications include saccular aneurysm
nally, this site corresponds to a curtain-like protrusion of the and aortic dissection.21 The latter condition is confined to
aortic media toward the lumen. The curtain extends from the compartment in which it begins. Usually this is the
the anterior, superior, and posterior walls of the aorta but not proximal compartment, leading to the potential for obstruc-
from the inferior aspect, the latter being the site of initial tion of the coronary arteries, and of the brachiocephalic
insertion of the arterial ligament. The position of the medial arteries arising from the aortic arch. External rupture leading
curtain causes the narrowed aortic lumen to lie eccentrically to fatal hemopericardium is usual when a dissecting aneu-
near the inferior wall (Fig. 9.27).18 rysm originates in the proximal compartment. In the aorta
Beyond the obstruction, there is poststenotic dilation of distal to the coarctation, infection may arise at the site of jet
the aorta. The subclavian arteries are typically wide, as these impact of the blood passing through the narrow segment.
216 chapter
The infection may lead to a localized mycotic aneurysm.
Rupture of the latter may cause hemorrhage into the left lung
or left pleural space and, uncommonly, into the right pleural
cavity.
Valvar Regurgitation
A variety of valvar anomalies may be associated with valvar
incompetence.
Mitral Valve
Congenital mitral regurgitation in adults is most commonly
caused by prolapsed myxomatous leaflets.22,23 This condition
is characterized by an increase in the spongy middle layer
of the valve. Excessive proliferation of the spongy layer
invades the fibrous layer, which is the part most responsible
for the strength of the leaflets. As the leaflets become weak-
ened, there is intercordal prolapse (Fig. 9.28), characterized
by intercordal hooding of the leaflets. This feature may be
responsible for mitral insufficiency. In the myxomatous
valve, other features causing regurgitation include an increase
in the width of the orifice. Another major cause for appear-
ance or accentuation of mitral regurgitation is rupture of the
cords. Although this may involve cords attaching to either
leaflet, the most common site involves those attaching to
the central scallop of the mural leaflet. In this situation, the
systolic regurgitant stream strikes the atrial septum at the
same horizontal level as the aortic valve.
It has been shown that, when the leaflets prolapse, fric-
tion may develop between the cords of the mural leaflet and
the related mural endocardium of the left ventricle.24 The
secondary effect is the appearance of multiple fibrous thick-
enings of the mural endocardium. In some cases, the fibrous
lesions may coalesce and bind to the cords, shortening them
further and exacerbating the regurgitation by restraining the
upward excursion of the leaflets. Patients with mitral valvar
prolapse experience transient cerebral ischemic attacks,
probably caused by embolization related to the valvar disease.
One potential source is thrombosis on the contact surface of
the leaflets. A second site is in the angle between the left
atrial endocardium and the base of the atrial surface of the
Prolapsed scallops
FIGURE 9.28. The mural leaflet of this mitral valve lacks
cordal support to the middle scallop, which prolapses into the
atrium.
9
leaflets. Grossly, this yields a line of thrombosis. Such throm-
bosis may be accentuated when prolapse is associated with
calcification of the left atrioventricular junction.
Mitral valvar prolapse is also associated with a tendency
toward development of chronic obstructive pulmonary
disease. Other sites of potential disease include the aortic
and pulmonary valvar leaflets and the aortic media. The
latter may show cystic medial necrosis, a condition associ-
ated with widening of the thoracic aorta. When mitral valvar
prolapse and changes in the aorta and aortic valves coexist,
one of these conditions is usually dominant and claims the
primary diagnosis. Thus, one may observe primary mitral
valvar prolapse and associated secondary changes in the
aorta and its valve. Conversely, the aortic and aortic valvar
changes may be primary, whereas the mitral valvar prolapse
occupies a secondary position.
Tricuspid Valve
The leaflets of the tricuspid valve may also exhibit prolapse,
but typically in association with dominant mitral valvar
prolapse. When chronic obstructive pulmonary disease is
associated with tricuspid valvar prolapse, the later process
may be more fully developed than when pulmonary disease
is absent. The challenge of right ventricular hypertension
tends to expose the valvar abnormalities when the potential
for valvar prolapse exists.
The more typical lesion producing tricuspid regurgita-
tion, however, is Ebstein’s malformation. It is characterized
by so-called downward displacement of the hinge points of
the mural and septal leaflets of the valve, the leaflets hinging
within the ventricular cavity rather than at the atrioven-
tricular junction (Fig. 9.29). The anterosuperior leaflet, in
contrast, usually retains its attachment at the atrioventricu-
lar junction, but there is “atrialization” of the inlet of the
right ventricle. The functional disturbance is reduction in
the effective volume of the ventricular cavity, which is rep-
resented only by the apical trabecular and outlet components
(Fig. 9.30).25 Minor degrees of tricuspid regurgitation may
contribute to the inefficiency of the right ventricle, which
tends to develop fibrotic and thinned walls. In the majority
of cases, there is an interatrial communication, either an
atrial septal defect or a probe-patent foramen ovale, and
therefore some right-to-left shunting. In patients who reach
adulthood, a cerebral abscess may complicate the right-to-
left shunt. Another frequent associated malformation,
reflecting the abnormal formation of the parietal atrioven-
tricular junction, is the presence of accessory atrioventricu-
lar muscular tracts that produce the Wolff-Parkinson-White
variant of ventricular preexcitation.
Aortic Valve
Congenital aortic regurgitation may result from primary
intrinsic disease of the aortic valve, or can be a secondary
event due to disease of the ascending aorta, with secondary
changes in the aortic valvar sinuses. Aortic regurgitation
may also be associated with a ventricular septal defect.
Primary regurgitation is usually caused by a congenitally
bifoliate valve. In this condition, the conjoined leaflet is
wider than the opposite single leaflet. In some cases, however,
the conjoined leaflet is excessively wide and, during ven-
 nor m a l a n d a bnor m a l a natom y 217
tricular diastole, prolapses beyond the single leaflet, thus
permitting regurgitation. Uncommonly, the characteristic
raphe of the congenitally bifoliate valve is represented by a
strand, rupture of which may cause loss of support of the
conjoined leaflet, and either establishment or accentuation
of aortic regurgitation. The congenitally bifoliate valve is
sometimes subject to infective endocarditis, which may be
an indirect cause of regurgitation through destruction of the
tissue of the leaflet.
Abnormal width of the aorta caused by cystic medial
necrosis, either idiopathic26 or associated with Marfan’s syn-
drome,27 may be a primary basis for aortic regurgitation. In
many such cases, the aorta has a tear in the intimal lining
and medial wall in its ascending portion. Such a tear may be
stable and fail to extend, but it can also progress to the begin-
ning of an intramural tract of aortic dissection. Aortic valvar
regurgitation caused by aortic laceration results from loss
of support of the leaflets or widening of the sinutubular

Mural

Valvar orifice
- “keyhole”

FIGURE 9.30. In this specimen with Ebstein’s malformation,

viewed from the ventricular aspect, there is a slit-like keyhole
between the anterosuperior leaflet, which is abnormally tethered in
a linear fashion at the ventricular apex, and the displaced septal
leaflet. This “functional” ventricle is made up of the apical trabecu-
lar and outlet components of the right ventricle.

Septal
junction. Prolapse is an important mechanism that underlies
aortic regurgitation.
Aortic regurgitation may also be associated with defi-
cient ventricular septation. Typically, the defect is doubly
committed and juxtaarterial, lying directly beneath the left
and right coronary aortic leaflets.28 Less commonly, the
defect can be perimembranous, or even muscular (Fig. 9.31).
The basic reason for the aortic regurgitation is that the
portion of the aortic root related to the defect is unsupported.
This allows the involved part of the aorta to move out of line
from its normal position, causing a “tipping” of the related
leaflet or leaflets. The consequence of the tipping is malalign-
ment of the zones of apposition, resulting in incompetence
of the valve.
Thinned wall
Pulmonary Valve

FIGURE 9.29. The right atrioventricular junction has been opened
and the diaphragmatic aspect reflected upward to show the essence
of Ebstein’s malformation. The septal and mural leaflets are both
hinged within the right ventricle (dotted lines) rather than at the
atrioventricular junction (solid line). The anterosuperior leaflet,
however, is normally attached at the atrioventricular junction. Note
the thinning of the myocardium in the inlet component of the right
ventricle.
Congenital pulmonary valvar regurgitation is usually associ-
ated with so-called absence of the leaflets.29 In reality, the
valve is represented by hypoplastic units of valvar tissue
arrayed in annular fashion (Fig. 9.32). In some instances,
there are no other associated anomalies. Most cases, however,
exhibit features of tetralogy of Fallot with mild infundib-
ular stenosis. If untreated, congenital pulmonary valvar
218 chapter 9

Abnormal Communications Between the

Chambers and the Arterial Trunks
It is convenient to divide deficiencies of septation into those
in which the communication begins proximal to the atrio-
ventricular junctions and those in which it begins distal to
these junctions.

Pulmonary Proximal to Atrioventricular Junctions

valve
Of the communications that begin proximal to the atrioven-
tricular junctions, the most common is the interatrial com-
munication. Less common are various types of anomalous
pulmonary venous connections. Although anomalous pul-
monary venous connections resemble interatrial communi-
cations in many respects, we consider them in a separate
section.

Muscular INTERATRIAL COMMUNICATIONS

outlet
Prolapse
defect
of aortic leaflet
FIGURE 9.31. In this specimen with a muscular outlet ventricular
septal defect, there is prolapse of one of the leaflets of the aortic
valve through the upper margin of the defect.
insufficiency does not usually allow survival to adulthood
because, in most cases, there is also major dilation of the
pulmonary arteries, extending into the pulmonary paren-
chyma. If severe, this complication can prevent surgical
correction in infancy.
Dilated pulmonary arteries
There are several anatomic types of interatrial communica-
tion that allow patients to reach adulthood.30,31 Perhaps para-
doxically, not all are positioned within the atrial septum.32
The commonest defect, often called the “ostium secundum,”
is found in the floor of the oval fossa (Fig. 9.33). The less
common sinus venosus type is found at the entrance of either
the superior or inferior caval vein, and is associated with
anomalous pulmonary venous connection from the right
lung (Fig. 9.34). The rarest communication is found at the
site of the mouth of the coronary sinus. It exists because of
effacement of the walls, which usually interpose between
the coronary sinus and the left atrium (Fig. 9.35).
The other defect that produces an interatrial communica-
tion is the so-called ostium primum defect. This lesion,
however, exists because there is a common atrioventricular
junction rather than separate right and left junctions.33 It is
part of the spectrum of anomalies with atrioventricular
septal defect in the setting of common atrioventricular junc-
tion. The left atrioventricular valve in this setting is a trifoli-
ate structure, rather than an abnormal mitral valve. Although
the space between the two leaflets attached to the ventricu-
lar septum is often called a cleft, in reality it is the zone of

Rudimentary leaflets

Deviated outlet septum

FIGURE 9.32. This heart has tetralogy of Fallot, with so-called

absence of the leaflets of the pulmonary valve. As can be seen,
however, the valvar leaflets are formed in rudimentary fashion as a
ring of tissue at the ventriculoarterial junction. The symptoms in
patients such as this are due to the gross dilation of the pulmonary
arteries.
FIGURE 9.33. In this heart, there is a large hole within the oval
fossa due to deficiency of the flap valve. This gives the so-called
ostium secundum defect.
 nor m a l a n d a bnor m a l a natom y
SCV
Probe thru’
superior rim
of fossa
RPV
Overriding Intact oval fossa
orifice
FIGURE 9.34. In this heart, the mouth of the superior caval vein
(SCV) overrides the upper rim of the oval fossa, which is intact. Note
the anomalous connection of the right pulmonary veins (RPV), and
the probe passed through the intact upper rim of the septum. This
is the so-called sinus venosus defect, which produces the potential
for interatrial shunting, but outside the confines of the atrial
septum.
apposition between two leaflets that bridge the ventricular
septum and form the distal extent of the interatrial com-
munication (Fig. 9.36).
In all the patients having an interatrial communication,
there is a tendency for the increased pulmonary flow to be
associated with normal pulmonary arterial pressure for
many years. In some patients, obstructive pulmonary vascu-
lar disease may develop, followed by pulmonary hyperten-
sion and right ventricular hypertrophy. The resulting right
ventricular hypertrophy is responsible for a difference in the
filling characteristics of the ventricles, leading to a basis for
right-to-left shunting through the interatrial communica-
LSCV
Oval fossa
Mouth of sinus
FIGURE 9.35. The left atrium of a patient who had so-called unroof-
ing of the coronary sinus. A persistent left superior caval vein
(LSCV) drains to the upper corner of the left atrial roof. The walls
that should separate this vessel from the left atrial cavity (lines)
have disappeared. Because of this, the mouth of the coronary sinus
functions as an interatrial communication.
219
“Ostium primum”
Bridging leaflets
Mural leaflet
FIGURE 9.36. The left ventricular aspect of the so-called ostium
primum defect, in reality an atrioventricular septal defect with
common atrioventricular junction, but with a separate trifoliate
valve guarding the left half of the common junction. In this speci-
men, there is a dual orifice in this left valve (arrow).
tion. This complication tends to occur relatively early in
adulthood, but usually not before the mid-30s.
There is marked variation in the histologic features of the
pulmonary vascular bed. In the stage characterized by high
flow of blood to the lungs, but at low pressure, the vascular
bed is dilated. Early changes leading to obstructive disease
are represented by intimal fibrous proliferation of the pulmo-
nary arterioles. Medial hypertrophy of the muscular arteries
follows. Ultimately, nonspecific fibrous proliferation may
produce the so-called plexiform lesion. At this stage, right
ventricular hypertrophy has become established. The result-
ing right-to-left shunt may be manifested by delayed cyano-
sis. Cerebral abscess, in concert with other states in which
a chronic right-to-left shunt is associated, may complicate
the course.
In those patients with pulmonary hypertension compli-
cating an interatrial communication, the wide right and left
pulmonary arteries may become aneurysmal. At aneurysmal
sites, there is a tendency for the development of laminated
thrombus.
The natural history of patients with an interatrial com-
munication was well described in 1970.31 The intent was to
chart the progress of patients having defects in the oval fossa,
but some were included with partially anomalous pulmo-
nary venous connection, and these were likely to be sinus
venosus defects. Of the patients studied, about one quarter
had died before 27 years, over half by 36 years, three quarters
by 50 years, and nine tenths by 60 years of age. The mean
age of death for all patients was no more that 38 years.
Persistent patency of a competent valve of the oval
foramen, a feature of about one third of the normal popula-
tion,34 although not usually problematic, may have func-
tional consequences in certain circumstances. The valve
220 chapter 9

will close the patent oval foramen postnatally as long as left

atrial pressure exceeds right atrial pressure. The potential
exists for a right-to-left interatrial shunt through the patent
foramen ovale if, for any reason during the cardiac cycle,
right atrial intracavitary pressure exceeds left atrial pressure,
and thus opens the valve of the foramen. In addition, with
anatomic patency of the foramen, the valve may enlarge, or
appear to enlarge, creating an aneurysm of the oval fossa.
With such an aneurysm, the floor of the fossa may bulge into
the right or left atrial cavity concomitant with variations in
interatrial pressures such as occur with normal respiration.
In this situation, the interatrial shunt could be either from
left to right, or right to left. If the shunt is from the right to
the left atrium, the potential exists for embolic material
from systemic venous sources to enter the left atrium and
thereby be distributed to the systemic arterial circulation as
a paradoxical embolus. Such an event is recognized to be a
cause of so-called cryptogenic ischemic stroke.35–37

Communications Distal to
Atrioventricular Junctions
Among the abnormal communications beginning distal to
the atrioventricular valves are those hearts with an atrioven-
tricular septal defect with common atrioventricular junction
and the potential for shunting at ventricular level, ventricu-
lar septal defects in the setting of separate atrioventricular
junctions, patency of the arterial duct, aorticopulmonary
window, common arterial trunk, double outlet from the
right or left ventricle, and all forms of functionally single
ventricle.
In all these conditions, it is possible to define two par-
ticular subsets of lesions. In one, the communication between
the ventricles or the arterial trunks is narrow and restrictive.
In the other, the communication is wide and nonobstructive.
In the first category, we find those patients with small ven-
tricular septal defects or the classic form of patent arterial
duct. The list of those with unobstructive lesions includes
those with large ventricular septal defects or widely patent
arterial ducts, as well as many of those with the other condi-
tions listed above.
The distinction is of significance because, when a ven-
tricular septal defect or patent duct is small, survival to
adulthood is usual even in the absence of surgical correc-
tion. The ventricular septal defect itself can be muscular
(Fig. 9.37), or adjacent to the central fibrous body, the latter
now being known as the perimembranous type of defect
(Fig. 9.38). Often, both of these types of defect tend to reduce
in size during childhood, or even close spontaneously. When
they remain patent but small, the ventricular systolic pres-
sures are different, and the left and right ventricular pres-
sures are near normal, as is the volume of flow of blood to
the lungs. The pulmonary arterial pressure is not elevated.
Such small ventricular septal defects, or narrow arterial
ducts (Fig. 9.39), nonetheless, also permit a stream of blood
to jet across the communication. This promotes the poten-
tial for infection at the sites of impact of the jetlike stream,
in the right ventricle in those with a ventricular defect, and
in the pulmonary artery when there is a narrow but patent
arterial duct. Nowadays, however, there is an increasing ten-
dency to close such communications even when small, since
FIGURE 9.37. This section, made to replicate the four-chamber
echocardiographic cut, shows a muscular defect opening between
the ventricular inlets (double-headed arrow).
this can now be achieved using catheterization techniques
without having to resort to open-heart surgery. It is then
important to note that the pulmonary vascular bed will be
within normal limits in this setting.
When the ventricular septal defect is large, it is far more
likely to be of the so-called doubly committed and juxtaarte-
rial variety, when the major feature is fibrous continuity in
the roof of the defect between the leaflets of the aortic and
pulmonary valves (Fig. 9.40), or else a perimembranous defect
opening between the ventricular outlets with overriding of
the leaflets of the aortic valve but an unobstructed subpul-
monary outlet, the so-called Eisenmenger defect (Fig. 9.41).
In most patients with these defects, or those with a widely
patent arterial duct, or with any of the other conditions pro-
viding unobstructed communications between the ventricles
and the arterial trunks, the pulmonary arterial pressure is
elevated. The pulmonary and systemic systolic arterial pres-
sures are equal. The pulmonary vascular bed is prone to a
variety of obstructive lesions. Ultimately, the most severe
forms of pulmonary vascular disease will become estab-
lished, setting the scene for reversal of the shunt so that it
occurs from right to left, the so-called Eisenmenger reaction.
In the group of anomalies under consideration, nonetheless,
there is considerable variation among individuals. Although
the majority of patients, if not offered surgical treatment
during the first months of life, will develop major obstructive
 nor m a l a n d a bnor m a l a natom y 2 21

Aortic valve
Ventricular septal defect

Ventricular
septal defect

Mitral
valve

FIGURE 9.40. The ventricular septal defect in this heart is directly

beneath the pulmonary valve, and is roofed by fibrous continuity
between the leaflets of the aortic and pulmonary valves. This is the
so-called doubly committed and juxtaarterial defect.

Tricuspid pulmonary vascular lesions by adulthood, occasional adult

Valvar valve patients do not have significant pulmonary vascular lesions,
continuity and may exhibit different degrees, sometimes large, of left-
to-right shunting.
FIGURE 9.38. This specimen is also cut to replicate the four- A special condition to be considered in this group is the
chamber plane (compare with Fig. 9.37), but in this heart, the roof atrioventricular septal defect with common atrioventricular
of the ventricular septal defect is made up of fibrous continuity junction, but with shunting possible at ventricular level
between the leaflets of the aortic and tricuspid valve. This is the
so-called perimembranous defect. (Fig. 9.42). In uncomplicated cases, survival beyond infancy
or childhood is highly unusual. When this condition is asso-
ciated with the tetralogy of Fallot, however, survival to adult-
hood is common because the subpulmonary stenosis, which
is an integral part of the tetralogy, provides a natural banding
of the pulmonary trunk, thus overcoming the feature of an
unobstructed interventricular communication.38
The congenital aneurysm of an aortic sinus of Valsalva
Pulmonary trunk usually involves either the right or the noncoronary aortic

Arterial duct

Descending aorta
FIGURE 9.39. The aortic arch and left pulmonary artery are
viewed from the left side. There is a small persistently patent arte-
rial duct.
FIGURE 9.41. This heart has been sectioned to replicate the sub-
costal oblique echocardiographic cut. It shows the leaflets of the
aortic valve overriding the crest of the ventricular septum in the
presence of an unobstructed subpulmonary outlet. This is the so-
called Eisenmenger defect. SMT, septomarginal trabeculation.
222 chapter
Atrial
septum
Bridging
leaflet
Septal
defect
FIGURE 9.42. This heart has a common atrioventricular junction
and an atrioventricular septal defect. The bridging leaflets of the
common valve, however, are attached to the leading edge of the
atrial septum. Because of this, shunting through the atrioventricu-
lar septal defect can only take place at the ventricular level.
sinus. The fact that the lesion is congenital indicates that
there may be a congenital weakness in the attachment
between the aortic sinus and the supporting ventricular
structures, which in the left ventricle are partly fibrous. This
allows slippage or avulsion of the medial wall of the afflicted
sinus.39 If this occurs, then the aortic wall is supported only
by the wall of the right atrium or ventricle. The sinus itself
can then become aneurysmal, and may rupture, producing a
shunt from the aorta to either the right atrium or the right
ventricle (Fig. 9.43). When the right aortic sinus is involved,
then frequently the aneurysm is also associated with a ven-
tricular septal defect, which is then either perimembranous
or doubly committed and juxtaarterial (see above).
FIGURE 9.43. In this heart, there is an aneurysm of the right coro-
nary aortic sinus of Valsalva, which has been transilluminated from
the aortic side, but is photographed from the right side. As can be
seen, if the sinus ruptured, it would communicate with the right
atrium.
9
Abnormal Connections
Another group of anomalies that may be seen in adulthood
by cardiologists is characterized by arteries or veins abnor-
mally joining certain other vessels or chambers.
Communication of a Coronary Artery with a
Cardiac Chamber or a Major Thoracic Vessel
Communication of a coronary artery with a cardiac chamber
or a major thoracic vessel not infrequently presents in adult
life. Such fistulas taking their origin from the right coronary
artery are more common than those originating from the left
coronary artery.40,41 In almost nine tenths of such cases, the
fistulous channels drain to the lesser circulation, usually the
right ventricle.42 In such situations, the artery proximal to
the fistulous connection is usually wide, but distal to the
fistula the artery narrows precipitously (Fig. 9.44). The artery
proximal to the fistula may also show aneurysmal dilation.
The fistulous communications can also be the seat of infec-
tious endocarditis, this complication being observed in up to
one tenth of patients.
Discordant Ventriculoarterial Connections
The situation in which the arterial trunks take their origin
from morphologically inappropriate ventricles is usually
described simply as transposition. But since the lesion
involves only a part of the heart, it can obviously be condi-
tioned by further changes occurring at the atrioventricular
junctions. The changes at the ventriculoarterial level can be
further conditioned by variations in the relationships of the
arterial trunks themselves, or by variations in infundibular
morphology. These different patterns often led to disagree-
ments in the past as to how best the abnormalities should be
Normal coronary artery
Ends of divided fistula
FIGURE 9.44. This picture, taken in the operating room, shows the
cut ends of a fistula that extended from the right coronary artery to
the right atrium. Note the caliber of the normal segment of the right
coronary artery.
 nor m a l a n d a bnor m a l a natom y
described and defined.43 Nowadays, however, it is accepted
that the best criterion for definition is the discordant ven-
triculoarterial connections, since it is this feature that deter-
mines the abnormal hemodynamic pattern. It is also the case
nowadays that patients with these lesions undergo surgical
treatment in infancy, and most now survive to adult life. In
one important variant, however, the discordant connections
at the ventriculoarterial level are accompanied by discordant
atrioventricular connections. The two discordancies then
cancel each other out, so that the circulations are congeni-
tally corrected. Patients with such congenitally corrected
transposition can first present to the cardiologist in late adult
life if they have no other associated intracardiac lesions.44
Regular Transposition
The commonest variant of transposition is that in which the
atrioventricular connections are concordant, or normal, as
are the venous connections to the heart (Fig. 9.45). Because
of the discordant ventriculoarterial connections, the circula-
tions are then in parallel rather than in series. Without surgi-
cal treatment, this common condition used to cause death
in early life. Nowadays, almost all patients undergo surgical
correction, enabling them to survive to adulthood.
Most adult patients presenting at the current time with
transposition almost certainly have undergone an atrial
“switch” operation, such as the Senning or Mustard proce-
dure. Some of these patients may develop obstruction of the
caval venous channels, or the channel of pulmonary venous
flow into the heart. In addition, because of the multiple inci-
sions made in the atrial chambers during the surgical cor-
rection, many patients suffer atrial arrhythmias, particularly
sick sinus syndrome. Very soon, patients will be surviving
to adult life after the arterial switch procedure, which
involves detachment of the coronary arteries from the initial
aortic root, switching of the arterial trunks relative to their
initial ventricular origins, and reattachment of the coronary
arteries to the arterial root initially supporting the pulmo-
nary trunk. The intricate surgery needed to reattach the
FIGURE 9.45. The segmental arrangements producing the malfor-
mation usually known simply as “transposition.” The atrial cham-
bers are joined to their appropriate ventricles, but the ventricles give
rise to morphologically inappropriate arterial trunks. As shown, the
segmental combination can be found with the usual arrangement
of the organs, but also in the mirror-image variant. MRV, MLV,
morphologically right and left ventricles, respectively.
223
FIGURE 9.46. A so-called congenitally corrected variant of trans-
position. The essence of the lesion is discordant connections across
both the atrioventricular and ventriculoarterial junctions. As with
the “regular” variant of transposition, the congenitally corrected
pattern can be found with either usually arranged or mirror-image
atrial chambers. (Abbreviations as for Fig. 9.45.)
coronary arteries during infancy means that many of these
patients may develop coronary arterial disease in later life,
although thus far there is no evidence to indicate that this
is happening. Concerns have been raised, however, with
regard to dilation of the initial subpulmonary outflow tract,
which could potentially lead to aortic regurgitation after the
arterial switch procedure.
Congenitally Corrected Transposition
Because of the presence of discordancies at both the atrio-
ventricular and ventriculoarterial junctions, which is the
essence of this lesion, the circulations are congenitally cor-
rected (Fig. 9.46). The atrial chambers are typically in their
anticipated location but, because of the discordance at the
atrioventricular junctions, the ventricles are arranged in
mirror-image fashion, so-called left-handed topology. In
essence, the ventricles are on the “wrong sides” of the heart.
The segmental combination with double discordance, none-
theless, can sometimes be found when the atrial chambers
are mirror-image, so-called situs inversus, but the ventricles
are normally positioned, with so-called right-handed topol-
ogy (Fig. 9.46).
As a result of the two sets of discordant connections, the
circulations of blood are physiologically normal if there are
no associated septal defects or obstructive lesions within the
heart. Patients with uncomplicated corrected transposition,
therefore, may live a normal life, despite the fact that the
morphologically right ventricle is called upon to pump the
blood into the systemic circulation. Some patients with this
condition have first been recognized at autopsy in the eighth
decade of life.44 It is rare, nonetheless, for congenitally cor-
rected transposition to be without associated anomalies.45
When present, it is the associated lesions that determine the
circulatory effect of the condition. These include a ventric-
ular septal defect, obstruction to the outflow tract from
the morphologically left ventricle to the pulmonary trunk,
incompetence of the left-sided morphologically tricuspid
valve, which frequently demonstrates Ebstein’s malforma-
tion, and congenitally complete heart block.
224 chapter 9

Anomalous Pulmonary Venous Connections

The pulmonary veins may be anomalously connected to a
site other than the left atrium in total or partial fashion.
Totally anomalous pulmonary venous connection, if seen in
uncorrected fashion in the adult, is typically of the type in
which the anomalous termination lies above the diaphragm.
The common connections are with the superior caval venous
system or the coronary sinus (Fig. 9.47). As far as we know,
a totally anomalous infradiaphragmatic connection, which
is almost always to the portal venous system, has not been
reported in adults unless they have undergone surgical cor-
rection during childhood.
A partially anomalous pulmonary venous connection, in
contrast, is by no means rare in adults, although it may not
always be discovered.46 Partially anomalous connection may
either be a random event or part of a syndrome. If only a FIGURE 9.48. The anomalous connection of the right upper pul-
solitary vein is involved, then the anomalous connections do monary veins to the superior caval vein (SCV).
not always introduce a significant cardiovascular burden.
Random connections are exemplified by isolated cases in
which a left or a right upper pulmonary vein joins the left right lung, which has an anomalous arterial supply through
brachiocephalic vein or the superior caval vein (Fig. 9.48). a systemic-to-pulmonary collateral artery. Bronchial anoma-
Partially anomalous connection of a right pulmonary vein lies are also common.50
or veins in association with the sinus venosus type of inter- The so-called polysplenic syndrome,50 now known to be
atrial communication forms a recognized syndrome, the due to isomerism of the organs usually formed on the left
anomalous vein or veins terminating in the superior caval side of the body (Fig. 9.49), including the left atrial appendage,
vein close to its junction with the right atrium (Fig. 9.34). is usually characterized by fewer severe cardiovascular
Indeed, it is the anomalous venous connection that creates anomalies than the asplenic syndrome which is associated
the interatrial communication, which is outside the confines with right isomerism (Fig. 9.50).51 Survival to adulthood,
of the oval fossa.47 therefore, is more common in the former, although now even
There is one other syndrome involving a partially anoma- patients with right isomerism are undergoing conversion to
lous pulmonary venous connection that may first be mani- the Fontan circulation, and will likely present as adults to
fest in adulthood. This is when a vein from the right lung the cardiologist. Among the anomalies that may occur in the
terminates in the inferior caval vein, either above or below setting of left isomerism is connection of pulmonary veins
the diaphragm. The venous anomaly may be the sole condi- to the right-sided atrium, which possesses a morphologically
tion, or part of the so-called scimitar syndrome.49 The syn- left appendage. This may involve all of the pulmonary veins,
drome also typically involves sequestration of part of the or only the right veins.

Supracardiac connection
• to superior caval vein
• via azygos vein

Cardiac connection
• to LSCV & coronary sinus
• direct to right atrium

Infradiaphragmatic &
infracardiac
connection
• to portal venous system
FIGURE 9.49. The essential features of the syndrome often
• to inferior caval vein described as “polysplenia.” In reality, there is duplication of the
FIGURE 9.47. The options for drainage of totally anomalous pul- structures usually found on the left side of the body, in other words,
monary venous connections. LSCV, left superior caval vein. left isomerism.
 nor m a l a n d a bnor m a l a natom y 225

Anomalous Systemic Venous Connection

Major anomalous connections of the systemic veins may
involve the superior caval venous system, the inferior caval
venous system, or both.

INFERIOR CAVAL VENOUS SYSTEM

Congenital union of the inferior caval vein has been reported
with the left atrium, but is usually due to persistence of a
large eustachian valve, which directs the blood across a
patent oval foramen (Fig. 9.51). This can give the impression
that the atrial septum is intact should the eustachian valve
become attached to the margins of the fossa. This situation
is replicated should a surgeon closing a defect in the oval
fossa inadvertently suture the eustachian valve to the
margins of the oval fossa, a mistake that can happen in even
the best regulated of operating rooms.

SUPERIOR CAVAL VENOUS SYSTEM

Persistence of a left-sided superior caval vein is a relatively
common condition. In this condition, there are usually two
superior caval veins. The right-sided vein joins the right
atrium in its usual position, whereas the left-sided vein
drains to the right atrium through an enlarged coronary
sinus.52 In about three fifths of patients with this arrange-
ment, there is a bridging brachiocephalic vein between the
two superior caval veins.
Among the variations of this condition is that in which
the right-sided caval vein fails to join the right atrium, with
the right-sided brachiocephalic vein terminating in a left-
sided caval vein that drains through the coronary sinus.
Much more rarely, a left-sided caval vein can join the left
atrium directly, terminating near the base of the left atrial
appendage. This condition is part of the syndrome that
FIGURE 9.51. The arrangement in which a prominent eustachian
valve directs the return from the inferior caval vein to the left
atrium through a deficient oval fossa.
involves “unroofing” of the coronary sinus, with the mouth
of the coronary sinus then functioning as an interatrial com-
munication (Fig. 9.35).53
INFERIOR AND SUPERIOR CAVAL VEINS
The most common condition involving both caval venous
systems is when the inferior caval vein is interrupted within
the abdomen, the abdominal venous return then reaching
the heart through the azygos system of veins and the superior
caval venous channels, either on the right or the left sides of
the body. This arrangement is typically seen in the setting
of left isomerism, or polysplenia,54 but can also be found as
an isolated anomaly (Fig. 9.52).

Arteriovenous Fistulas
Congenital arteriovenous fistulas may involve either the sys-
temic or the pulmonary vascular bed.

PULMONARY A RTERIOVENOUS FISTULAS

FIGURE 9.50. The counterpart to left isomerism, often described
as “asplenia.” The essential feature of this syndrome is right
isomerism.
Congenital pulmonary arteriovenous fistulas may be either
solitary or multiple. In the latter instance, the condition may
involve one or more than one lobe of a lung. The individual
lesion is usually characterized by a plexus of intercommuni-
cating arteries and veins within the lung. Because the con-
dition allows desaturated pulmonary arterial blood to be
delivered to the pulmonary venous system, cyanosis and
clubbing of digits may be evident, depending on the volume
of shunt. The condition has a strong hereditary associa-
tion.55,56 The familial Rendu-Osler-Weber syndrome, with
telangiectasia involving various organs and mucous mem-
branes, is found in about one third of cases.57,58 Cerebral
abscess is a potential complication. Uncommonly, infection
may occur at the site of the fistula.
226
Azygos vein
Superior caval vein
Morph. right
appendage
Hepatic veins
FIGURE 9.52. In this heart, with the usual arrangement of the
atrial appendages, the veins traversing the diaphragm from the
abdomen carry only the hepatic venous return. The systemic venous
return is to the superior caval vein via the azygos system of veins,
with interruption of the abdominal course of the inferior caval
vein.
SYSTEMIC A RTERIOVENOUS FISTULAS
Congenital arteriovenous fistulas involving the coronary
arterial system have been discussed previously. Extracardiac
systemic arteriovenous fistulas may occur in any part of the
systemic circulation. Those involving the cerebral circula-
tion are usually covered in treatises concerned with intra-
cranial conditions, but the so-called aneurysm of the vein of
Galen is particularly important in the setting of cardiac
disease. Other congenital systemic arteriovenous fistulas
may involve any part of the body. Multiple arteries com-
monly supply the area of arterial and venous connections.
The main arterial trunks are dilated. When a limb is involved,
the greater length of that limb is characteristic. Infectious
endophlebitis is a recognized complication.
Combinations of Anomalies
Almost any combination of anomalies is possible. The
random association of some anomalies with others has been
discussed previously. In this section, we consider primarily
the combination of an interventricular communication with
pulmonary stenosis or atresia. The majority of these condi-
tions are associated with biventricular origin of the aorta and
right ventricular hypertrophy, this combination producing
the well-known tetralogy of Fallot. In each case, at some
level or levels between the right ventricle and the pulmonary
chapter 9
arterial system, there is obstruction to pulmonary flow,
either atresia or stenosis. When there is atresia at the pulmo-
nary outflow tract, then the pulmonary arteries are typically
hypoplastic, represented by atretic cords, or absent in extreme
cases. There is then major variation in the supply of blood to
the lung.
Tetralogy of Fallot
In the adult, tetralogy of Fallot displays the same range of
anatomic detail as in the infant or child (Fig. 9.53). The origin
of the aorta from the ventricles varies, as does the degree of
pulmonary stenosis. When the aorta takes its origin primar-
ily from the right ventricle, then the ventriculoarterial con-
nection is such as to make the combination part of the entity
known as double outlet right ventricle.
In terms of the degree of pulmonary stenosis, this also
shows a spectrum, with atresia at some level of the pulmo-
nary arterial channels representing the most severe form
(Fig. 9.54). Survival is not directly related to the width of the
pulmonary arterial channel, but rather to the degree of col-
lateral flow, so that many patients can survive for long
periods with major degrees of pulmonary obstruction.
Solitary Arterial Trunk
An extreme in the level of pulmonary arterial obstruction is
that in which is there not only atresia of the right ventricular
outlet, but also complete absence of the intrapericardial pul-
monary arteries, including the pulmonary trunk. In this
setting, a solitary arterial trunk takes its origin from both
ventricles, overriding the crest of the muscular ventricular
septum (Fig. 9.55). In this setting, the pulmonary arterial
supply is derived from systemic-to-pulmonary collateral
arteries. These usually arise from the aorta, principally the
descending aorta, and proceed to the pulmonary hila,
although one lung may initially have been supplied through
a patent arterial duct that has become ligamentous (Fig.
9.56).
Outlet septum
TSM
SMT
VSD & overriding aorta
FIGURE 9.53. In this heart, the subpulmonary outflow tract has
been bisected, showing a narrowed infundibulum (bracket), along
with the leaflets of the aortic valve overriding the crest of a deficient
ventricular septum (VSD). This is the tetralogy of Fallot. TSM, sep-
tomarginal trabeculation; SPT, septoparietal trabeculation. (See
also Figure 9.12.)
 nor m a l a n d a bnor m a l a natom y 227

Pulmonary arteries

Aorta

Muscular atresia

FIGURE 9.56. These are the pulmonary hila of the heart shown in
Fig. 9.55. The right lung is supplied through systemic-to-pulmonary
collateral arteries. The left lung was initially fed by an arterial duct,
which has become ligamentous.

Abnormal Aortic and Arterial Branching

Deviated outlet septum
This section discusses variations in branching or origin of
major arteries, including the coronary arteries and the
FIGURE 9.54. In this heart with tetralogy of Fallot, there is mus-
cular atresia of the subpulmonary infundibulum.
aorta.

Coronary Arteries
The anomalies of the coronary arteries59 considered here
include ectopic or anomalous origin of a coronary artery
from the aorta, coronary arterial dominance, and anomalous
origin of a coronary artery from a pulmonary artery, usually
the pulmonary trunk.

ECTOPIC OR A NOMALOUS ORIGIN FROM THE AORTA

In ectopic origin of a coronary artery from the aorta, the
artery typically arises from an inappropriate aortic sinus of
Valsalva, or may arise from an unusually high position, or
Solitary trunk may have an unusually acute angle of origin from the aorta.
In each of these situations, the ectopically arising artery can
run intramurally as it exits from the aorta. This creates a
situation in which the coronary arterial lumen can become
constricted during diastole. Sudden death, especially during
exercise, has occurred in some individuals with such ectopic
coronary arterial origin from the aorta.60 The commonest
pattern is when the circumflex coronary artery arises either
from the proximal segment of the right coronary artery, or
from the right aortic sinus posterior to the normally situated
origin of the right coronary artery. In this pattern, the anom-
alous artery courses behind the aorta to reach the left atrio-
ventricular groove (Fig. 9.57). In other patterns, the anomalous
artery runs between the subpulmonary infundibulum and
the aortic sinuses. This position increases the risk of con-
VSD striction, and poses a significant threat of sudden death.

CORONARY A RTERIAL DOMINANCE

FIGURE 9.55. In this heart, there is complete absence of the intra-
pericardial pulmonary arteries, along with failure of formation of
any subpulmonary infundibular structures. The trunk overriding
the ventricular septal defect (VSD) is best described as a solitary
arterial trunk.
The artery that gives rise to the inferior interventricular
artery is usually designated as the dominant coronary artery.
In about nine tenths of the general population, this is the
right coronary artery.
228 chapter 9

coronary artery; anastomoses between the two coronary

Retro-aortic arterial systems; subendocardial myocardial fibrosis (Fig.
circumflex 9.58), including fibrosis of papillary muscles; and large sinu-
artery soids that communicate with the left ventricle in the area of
the distribution of the anomalously arising left coronary
Aorta
artery.

Aortic Arch
The anomalies or variations of the aortic arch system seen
in the adult may occur with either a left arch or a right
arch.
Right
coronary
L EFT AORTIC A RCH
artery
Individuals with left aortic arch have variations from the
classic branching pattern. Among these is a common origin
for the brachiocephalic and left common carotid arteries.
A relatively common variation, seen in up to one tenth of
the population is origin of the left vertebral artery from the
aortic arch. Such an artery arises just proximal to the origin
of the left subclavian artery, and the two arteries commonly
share the same adventitial covering.
Potentially more significant is the arrangement in which
the right subclavian artery arises anomalously from the
distal aortic arch (Fig. 9.59). In this setting, the artery arises
FIGURE 9.57. In this heart, the circumflex artery arises from the
right coronary artery, and then runs behind the aorta to reach the as the fourth branch of the arch, and then runs behind the
left atrioventricular groove. esophagus. Such a vessel occurs in approximately 0.5% of
the population, and can cause problems during swallowing,
although this is not always the case.
In the setting of a congenitally bicuspid aortic valve,
R IGHT AORTIC A RCH
however, about one third of involved persons have domi-
When a right aortic arch is present, it may be either the only
nance of the circumflex artery.
aortic arch or part of a double arch. The double arch is char-
acterized by bifurcation of the ascending aorta into right and
ORIGIN OF A CORONARY A RTERY FROM THE
left arches (Fig. 9.60). Each arch passes over its appropriate
PULMONARY T RUNK
It is usually the left coronary artery that arises from the
pulmonary trunk,61,62 although very uncommonly both coro-
nary arteries can arise from the pulmonary trunk. This situ-
ation leads irrevocably to death in early infancy, unless there
is an associated condition characterized by pulmonary
hypertension.
Usually, the pulmonary arterial segment from which the
coronary artery arises is the pulmonary trunk, although
rarely a coronary artery may arise from one or another pul-
monary artery. Origin of the right coronary artery from the
pulmonary artery is less common than similar anomalous
origin of the left coronary artery. When the right coronary
artery is affected, however, some patients exhibit no evi-
dence of disease. There are reported cases, nonetheless, of
middle-aged persons in whom unexpected sudden death was
associated with anomalous origin of the right coronary artery
from the pulmonary trunk.
If it is the left coronary artery that arises from the pul-
monary trunk, and the condition is left untreated, the major-
ity of individuals die in infancy or childhood. The minority
who survive to adulthood manifest major flow from the nor-
mally arising right artery through the myocardium and then
into the left coronary artery, with the arteriovenous-like flow
FIGURE 9.58. This is the left ventricle of a heart in which the left
terminating in the pulmonary trunk. Some of these patients coronary artery arose from the pulmonary trunk rather than
can die suddenly as adults. In this setting, there are several the aorta. Note the long-standing ischemic changes in the
features in common. These include a large, tortuous, right myocardium.
 nor m a l a n d a bnor m a l a natom y 229

LCCA

RCCA
RSCA LSCA

Arterial
duct
FIGURE 9.59. A picture, from behind, of the aortic arch, in which
the terminal branch is the right subclavian artery (RSCA). Note its Right arch
retroesophageal course. Note also that its origin from the aorta is
dilated—the so-called diverticulum of Kommerell.

bronchus, joining posteriorly to the esophagus to form the Left brachiocephalic

descending aorta. When the arch is right-sided, it may also artery
be associated with a retroesophageal segment. In those Pulmonary trunk
examples lacking a retroesophageal segment, the pattern of
branching, from before it goes backward, is for the arch to
give rise to the left brachiocephalic artery, which divides into
left common carotid and left subclavian arteries, and then
the right common carotid and subclavian arteries (Fig. 9.61).
FIGURE 9.61. In this heart with a right-sided aortic arch, there is
When there is a retroesophageal component, it is the left mirror-image branching of the brachiocephalic arteries [RSCA, right
subclavian artery that is the final branch from the arch, with common carotid artery (RCCA), LCCA, LSCA]. Note the left-sided
the artery passing in a leftward direction behind the esopha- arterial duct, which takes its origin from the left subclavian
gus. This is the mirror image of the arrangement giving ret- artery.
roesophageal origin of the right subclavian artery (Fig. 9.62).
The left subclavian artery, when taking a retroesophageal
course, also usually arises from a diverticulum of the arch,
the so-called diverticulum of Kommerel. It is important to

FIGURE 9.62. The retroesophageal origin of the right subclavian

FIGURE 9.60. The essence of the perfect double aortic arch. All
known “vascular rings” can be explained on the basis of this
“perfect” arrangement.
artery (see Fig. 9.60) is explained on the basis of absorption of the
segment of the double arch (star) between the right subclavian artery
(RSCA) and the RCCA. This pattern, in mirror-image format,
explains retroesophageal origin of the left subclavian artery from a
right aortic arch.
230 chapter
note that a double aortic arch, as shown in Figure 9.60, can
exist with an atretic segment between the left common carotid
and subclavian arteries, and can be mistaken for a simple right
aortic arch with a retroesophageal segment (Fig. 9.63).
When the right arch is found in the absence of any retro-
esophageal segment, then this is typically associated with
intracardiac malformations, typically tetralogy of Fallot or
common arterial trunk. When found in this setting, then
usually there is mirror-image branching of the brachioce-
phalic arteries, although aberrant origin of the left subcla-
vian artery or isolation of the left subclavian artery (Fig. 9.64)
can also be found.
Abdominal Aorta
Uncommonly, there can be multiple collateral arteries that
arise from the abdominal aorta, or from the nearby lower
thoracic aorta, and lead to a lung, usually the right. This
pattern is typically seen in the setting of pulmonary seques-
tration, as for example, in the so-called scimitar syndrome.
Syndromes with Cardiac Disease
Congenital malformations of the heart are part of many
syndromes. We discuss only the more common associations
in this section.
One recognized association of anomalies is that of aortic
coarctation and the congenitally bifoliate aortic valve, the
latter lesion being found in up to half of the patients with
coarctation.
Patency of the arterial duct is found in up to one eighth
of those with a ventricular septal defect. The combination of
tetralogy of Fallot with atrioventricular septal defect and
common atrioventricular junction was, in the past, recog-
Ligamentous remnant
Retroesophageal LSCA
Arterial
ligament
FIGURE 9.63. The retroesophageal origin of the left subclavian
artery (LSCA) from a right aortic arch. There is persistence in the
ligamentous form of the segment that initially joined the artery to
the left arch, along with a ligamentous arterial duct.
9
FIGURE 9.64. In this heart, which is associated with a right aortic
arch, the left subclavian artery (LSCA) arises from the left pulmo-
nary artery, being fed though a persistent left arterial duct, but is
isolated because of resorption of the segments of an initially double
arch, specifically between the left common carotid artery (LCCA)
and the subclavian artery, and between the subclavian artery and
the descending aorta (stars).
nized as allowing patients to reach adulthood, but the com-
bination is now almost always recognized and treated
surgically during the first year of life.
Familial Cardiomyopathy
At least two forms of familial myopathy are well recognized
in the adult: the dilated and hypertrophic variants. To these,
we now need to add the increasingly well-recognized vari-
ants of so-called arrhythmogenic right ventricular cardiomy-
opathy. The familial dilated variant is similar in terms of its
pathology to apparently acquired congestive cardiomyopa-
thy. The heart is enlarged, with hypertrophied and dilated
ventricles. There are differing amounts, usually small, of
myocardial fibrosis. Congestive failure and sudden major
arrhythmias are common.
Arachnodactyly, or Marfan Syndrome
The laxity of the connective tissues that characterizes
Marfan syndrome commonly affects the cardiovascular
system. The elastic arteries show foci within their medial
walls of mucoid, cystlike deposits, shown as cystic medial
necrosis, associated with corresponding interruption and
retraction of fibers. In the aorta, the changes are most com-
monly located in the ascending portion. This leads to general
dilation of the ascending aorta, including the aortic sinuses.
The process of cystic medial necrosis, however, is less evident
beyond the arch than proximally. Aortic valvar regurgitation
and aortic dissection, each with its classic consequences, are
typical complications. Simple aortic regurgitation may result
from dilation of the aorta and coexisting myxomatous
changes in the aortic valvar leaflets. Cystic medial necrosis
may also involve the pulmonary trunk, producing so-called
idiopathic dilation.63 The leaflets of the atrioventricular
valves may also be involved in the myxomatous process,
this producing prolapse and valvar incompetence. Rarely,
myxomatous foci can be found in the intimal lining of the
 nor m a l a n d a bnor m a l a natom y
coronary arteries, and may be responsible for significant
obstruction.
Holt-Oram Syndrome
This syndrome is also known as the heart–hand syndrome,
or the heart–upper limb syndrome. As the names suggest,
the syndrome involves the heart and the arms. The usual
cardiac anomaly is an interatrial communication within
the oval fossa. Skeletal malformations of the arm are
characteristic.64
Down Syndrome
This syndrome, produced by trisomy of the 21st chromo-
some, is accompanied by congenital cardiac malformations
in two fifths of afflicted patients. The lesions typically
involve the septal structures, with a ventricular septal defect
being most common, followed by an atrioventricular septal
defect with common atrioventricular junction, although
afflicted individuals may simply exhibit an enlarged mem-
branous septum, or an isolated cleft of the aortic leaflet of
the mitral valve.65 Some patients have isolated persistent
patency of the arterial duct.
Turner Syndrome
Turner syndrome is commonly associated with coarctation
of the aorta.66 Pulmonary valvar stenosis, or deficiency of the
ventricular septum, occur less frequently.67
Summary
In this chapter, we have described the salient anatomy of the
normally formed and congenitally malformed heart.
Acknowledgments
This chapter was based on the chapter in the previous edition
by Jack L. Titus and Jesse C. Edwards.
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 1 Pathophysiology, Clinical
0 Recognition, and
Treatment of Congenital
Heart Disease
Steven R. Neish and Jeffrey A. Towbin
Left-to-Right Shunt Lesions . . . . . . . . . . . . . . . . . . . . . . .
Congenital Valve Abnormalities . . . . . . . . . . . . . . . . . . .
Complex Congenital Heart Disease. . . . . . . . . . . . . . . . .
Great Vein Malpositions . . . . . . . . . . . . . . . . . . . . . . . . . .
Key Points
• Atrial level communications include any of the follow-
ing: (1) ostium secundum atrial septal defect (ASD), (2)
ostium primum atrial septal defect, (3) sinus venosus
atrial septal defect, and (4) coronary sinus atrial septal
defect. The common ASD among these are the ostium
secundum ASD representing approximately 70% of all
ASDs. With all of the ASDs, significant pulmonary hyper-
tension rarely occurs before the third to fourth decade.
• Fifty percent or more of ventricular septal defects (VSDs)
close spontaneously in early childhood, even as late as
adolescence. The VSDs with large left-to-right shunts
may lead to severe pulmonary hypertension with bidirec-
tional or right-to-left shunting and cyanosis in the
adult.
• Patent ductus arteriosus leads to a continuous systolic
diastolic murmur under the left clavicle and places the
patient at risk for infection at the ductus site, and when
it leads to a large left-to-right shunt, may cause severe
pulmonary hypertension.
• Aortic valve stenosis in the child and early in adulthood
is usually caused by a bicuspid or a unicuspid valve.
• Supravalvular aortic stenosis occurs in two settings.
Williams syndrome is a dysmorphic syndrome caused
by a mutation of the elastin gene or chromosome 7, often
associated with hypercalcemia in infancy. The second
group of patients with supravalvular aortic stenosis have
a familial form without hypercalcemia, dysmorphic fea-
tures, or behavioral abnormalities.
235 Coronary Artery Anomalies . . . . . . . . . . . . . . . . . . . . . . . 269
247 Aneurysms of the Sinus of Valsalva. . . . . . . . . . . . . . . . . 269
256 Pregnancy and Congenital Heart Disease. . . . . . . . . . . . 270
268
• Subvalvular aortic stenosis has three types: membranous
subaortic stenosis, a fibromuscular tunnel type, and an
idiopathic hypertrophic subaortic stenosis type.
• Pulmonary stenosis may be valvular, supravalvular, or
subvalvular.
• Congenital mitral stenosis in adults is uncommon. Shone
syndrome describes the occurrence of multiple levels of
obstruction to blood flow into and out of the left ventricle
and in the aorta. The classic picture includes mitral ste-
nosis with a parachute mitral valve (single papillary
muscle), subaortic stenosis, a bicuspid aortic valve, and
coarctation of the aorta.
• Tricuspid stenosis is generally acquired rather than
congenital and causes include rheumatic heart disease,
carcinoid syndrome, and right atrial myxoma.
• Ebstein’s anomaly consists of downward displacement
of the tricuspid valve “atrializing” the inflow tract of
the right ventricle. Tricuspid insufficiency, right-to-left
shunts at the atrial level, and supraventricular arrhyth-
mias often coexist.
• Coarctation of the aorta as manifested in the adult is
almost always at or just distal to the ligamentum arterio-
sum and the take-off of the left subclavian artery. This
often leads to hypertension in the arms and reduced pres-
sures and pulses in the lower extremities sometimes
with some growth retardation in the legs.
• Tetralogy of Fallot consists of a large VSD, pulmonary
stenosis, either valvular or infundibular or both, right
ventricular hypertrophy, and overriding of the ventricu-
lar septum by a dilated aorta.
233
234 chapter
• Transposition of the great arteries in the adult exists as
D-transposition, L-transposition, and double-outlet RV.
• Truncus arteriosus exists as three types. Type I has a
common trunk, but this gives rise to separate ascending
aorta and pulmonary trunk. In type II, the truncus
extends up to the right and left pulmonary artery bifurca-
tions. In type III, there is no separate pulmonary trunk.
In 1897, Maude Abbott wrote her first paper on heart
murmurs. The following year she was made curator of the
McGill University medical museum in Montreal. She began
a formal study of congenital heart disease by studying patho-
logic specimens, encouraged by Sir William Osler. In 1908,
Osler included Abbott’s chapter on congenital heart disease
in his text called Modern Medicine.1 That chapter was the
definitive statement on congenital heart disease in the early
20th century. In 1936, Abbott published her classic text,
Atlas of Congenital Cardiac Disease,2 in which she described
hundreds of pathologic specimens and provided the frame-
work that allowed congenital heart disease to move past
being a curiosity.
In 1930, early in her career, Helen Taussig was appointed
to head the cardiac clinic at the Harriet Lane home at Johns
Hopkins Hospital in Baltimore. In a revolutionary way, she
began to understand the patterns that differentiated children
born with various forms of congenital heart disease. She
recognized that the degree of pulmonary blood flow pro-
foundly affected the long-term course of many children with
more severe congenital heart disease. She began to look for
a way to apply this observation. In 1941, Alfred Blalock
moved from Vanderbilt University to Johns Hopkins Hospi-
tal and, shortly after Blalock’s move, Taussig approached
Blalock and proposed that he attempt to attach the subcla-
vian artery to the pulmonary artery to augment pulmonary
blood flow in children with critically restricted pulmonary
blood flow. In 1944, the first operation was performed that
came to be known as the Blalock-Taussig operation. The first
three applications of this “B-T shunt” were described in 1945
and the door to real therapy for children with congenital
heart disease was opened.3
Successful open-heart surgery to correct septal defects in
humans was ushered in by the pioneering work of C. Walton
Lillehei,4 who closed a ventricular septal defect in a 4-year-
old boy, using the boy’s father for cross-circulation in 1954.
In the early days of open-heart surgery, the results of surgery
frequently were uncertain. Also, there were many adults
with congenital heart disease who had grown up before the
development of heart surgery. Congenital heart disease
clinics were filled with patients with unoperated congenital
heart disease, some of whom had survived into adulthood.
Today, most children with significant congenital heart
disease have palliative or corrective surgery in infancy or
childhood. Some of these operations are “reparative” while
others are best described as complex palliations. Today, the
cardiologist with an interest in congenital heart disease in
adults sees a combination of patients whose course is often
characterized by when and where they were born.5 There are
still patients with Eisenmenger’s syndrome (pulmonary
hypertension with severe cyanosis due to unrepaired con-
genital heart disease associated with chronic shunts), surviv-
ing into adulthood, who would have avoided that tragic
10
complication through reparative surgery if they had been
born a decade later.6 Others have been surgically corrected
but may have sequelae related to either their native disease
or some complication of therapy. Some remain with signifi-
cant cardiovascular disease because their defect was too
complex to repair. And finally, there are patients with condi-
tions that escape detection during routine physical examina-
tion, such as atrial septal defect and bicuspid aortic valve.
It has become increasingly apparent that patients who
have undergone surgical correction of congenital heart
disease frequently have complications later in adulthood.
The ligation and division of a patent ductus arteriosus perhaps
comes closest to a complete cure. Even patients with closed
atrial septal defects occasionally are plagued in later life by
supraventricular tachyarrhythmias, especially atrial fibrilla-
tion and atrial flutter. Therefore, most patients seen by car-
diologists interested in adult congenital heart disease are
those with previously “corrected” congenital heart disease
who have sequelae later in life. However, a significant minor-
ity consists of those with hitherto undiagnosed congenital
heart disease, inoperative heart disease, or congenital heart
disease for which the patient has refused surgery. Significant
advances in therapy, including surgery, pacemakers, better
treatment modalities for heart failure, and improved man-
agement of hyperviscosity syndromes, have increased the
life expectancy of such patients.
In earlier eras of congenital heart disease care, the physi-
cian who cared for adults could ignore some of the more
common defects, such as hypoplastic left heart syndrome
(HLHS), as children with HLHS and some of the other
complex defects never survived to adulthood. Some defects,
such as bicuspid aortic valve or ventricular septal defect are
much more common, and survival into adulthood has been
the rule for decades. This chapter concentrates on both the
most common congenital heart defects, as well as some of
the rarer defects that have the potential to present on a
regular basis to adult cardiology clinics.
The incidence of congenital heart disease varies with the
population studied and the age of the patients in the study.
In general, though, the order of frequency for the 10 most
common congenital heart defects is as follows:
1. Ventricular septal defect (VSD)
2. Atrial septal defect (ASD)
3. Aortic stenosis (AS)
4. Pulmonic stenosis (PS)
5. Coarctation of the aorta (COA)
6. Patent ductus arteriosus (PDA)
7. Tetralogy of Fallot (TOF)
8. Transposition of the great arteries (TGA)
9. Atrioventricular septal defect (AVSD)
10. Hypoplastic left heart syndrome (HLHS)
Congenital anomalies of the aortic valve actually are more
common than is represented by the above list, but many, if
not most, patients with a functionally bicuspid aortic valve
are not diagnosed until adulthood.7
The cardiologist treating adults should still be able to
diagnose congenital heart disease, or at least to narrow down
the diagnostic possibilities by both clinical and laboratory
methods.8 This is equally true in the long-term follow-up of
such patients, especially if they have undergone surgery,
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e
because the natural history of the disease will have been
altered by the operation itself. This demands thorough
knowledge of the operative techniques used at the time of
surgical intervention—many of which have changed consid-
erably in recent years.8
Left-to-Right Shunt Lesions
The most frequent physiologic abnormality caused by con-
genital heart disease is left-to-right shunting, resulting in
pulmonary overcirculation.9 The term left-to-right shunt
refers to blood in the systemic circulation (i.e., pulmonary
veins, left atrium, left ventricle, or aorta) shunting into the
circulation somewhere after the blood leaves the systemic
capillary bed and before it reaches the pulmonary capillary
bed. Abnormal communications can exist at atrial or ven-
tricular levels, the shunting can be atrioventricular or aorto-
pulmonary, or the pulmonary veins can connect somewhere
other than the left atrium. Such communications result in
shunting of blood, the direction of flow being determined by
the pressure gradient or the difference in resistance between
pulmonic and systemic circulation. Typically, the dominant
direction of flow at these abnormal connections is from the
systemic circulation into the pulmonary circulation (i.e., left
to right) because the impedance of the pulmonary vascula-
ture is much lower than the impedance in the systemic
circulation.
A unique physiologic situation exists if the defect results
in formation of a common mixing chamber. For example, a
subset of complete atrioventricular (AV) canal defects con-
sists of complete absence of the atrial septum (common
atrium). In total anomalous pulmonary venous connection
(TAPVC), the right atrium (RA) serves as the common mixing
chamber. In both common atrium and TAPVC, the systemic
venous return and the pulmonary venous return mix com-
pletely at the atrial level, before entering the ventricles. A
functionally single or common ventricle in which the other
ventricle is rudimentary would constitute a mixing chamber.
Finally, the septum between the aorta and the pulmonary
artery and the outlet portion of the ventricles may be absent
(i.e., truncus arteriosus). In all four of these situations, there
will always be some degree of arterial desaturation, regard-
less of the pulmonary vascular resistance (PVR).
Atrial Septal Defect
Atrial level communications may include any of the
following 9–11:
1. Ostium secundum atrial septal defect, representing non-
closure of the foramen ovale
2. Ostium primum atrial septal defect, which is a subset of
AV septal defect or an endocardial cushion defect
3. Sinus venosus atrial septal defect, resulting from failure
of the proximal portion of the sinus venosus to be incor-
porated into the RA
4. Coronary sinus atrial septal defect, in which there is a
communication between the coronary sinus and the left
atrium (LA), resulting in flow from the LA to the RA via
the orifice of the coronary sinus.5
235
TABLE 10.1. Paradigm to left-to-right shunts at the atrial level
Electrocardiogram,
Cyanosis frontal plane axis
Atrial septal defect, 0 Normal
secundum type
Atrioventricular canal
Ostium primum 0 Left
Common atrium + Left
Complete + Left
Anomalous pulmonary
venous connection
Partial 0 Normal
Complete + Normal
In practice, the overwhelming majority of atrial septal
defects (ASDs) are ostium secundum ASDs, representing
about 70% of all atrial communications. Ostium primum
ASD is second in prevalence. Sinus venosus ASD is uncom-
mon, and coronary sinus ASD is extremely rare. Patients
with uncomplicated atrial communications frequently arrive
at adulthood undiagnosed (Table 10.1).
Atrial Septal Defect, Ostium Secundum Type
Atrial septal defect, ostium secundum type, is the most
common newly diagnosed congenital heart disease in the
adult, possibly matched only by the bicuspid aortic
valve.7,9,10,12,13 It is helpful here to review the circulatory phys-
iology in the fetus in order to describe how ASDs develop
and physiologically present during life. During fetal life, the
pressures in the pulmonary artery and the aorta are equal;
the fetal right ventricle (RV), being adapted for pressure, has
the same compliance as that of the left ventricle (LV). Blood
returning from the placenta (oxygenated blood) flows via the
umbilical vein through the ductus venosus and preferen-
tially shunts across the foramen ovale. Vestigial preferential
right-to-left streaming from the inferior vena cava can be
demonstrated in adults with atrial septal defects by echocar-
diography or by indicator dilution techniques; the clinical
counterpart is paradoxical embolization. At birth, with the
infant’s first breath, there is an immediate drop in PVR,
which gradually decreases to normal in the first few months
of life. At the same time, the RV undergoes regression of
myocardial hypertrophy, gradually changing from its cylin-
drical configuration and thick walls to that characteristic of
the adult, in which the cavity is more crescentic and the wall
thinner than that of the LV. Therefore, in the fetus, there is
virtually no left-to-right shunting across the defect. If the
defect persists, as the PVR falls and the compliance of the
RV increases, left-to-right shunting results and pulmonary
flow may be two to five times the systemic flow. With time,
both the RA and the RV enlarge.
Significant pulmonary hypertension seldom occurs
before the third or fourth decade.12–14 The mechanism by
which pulmonary hypertension develops is not well under-
stood. It may rarely start in childhood. Although high flow
is implicated, it takes many decades for pulmonary hyper-
tension to develop, and not all patients develop pulmonary
hypertension.15 Progressive right ventricular enlargement
and hypertrophy may lead to decreased compliance of the RV
236 chapter 10

compared with that of the LV, and therefore, the exclusive

left-to-right shunt also yields some right-to-left shunting.
Right-to-left shunting is not a direct effect of the relative
pressures of the pulmonary artery and of the aorta, but rather
of the compliance of the two ventricles. If left ventricular
compliance also decreases, the atrial pressures rise, and
classic signs of congestive heart failure (CHF) may be present.
The pulmonary artery pressure in atrial septal defects with
shunt reversal is almost always significantly lower than the
systemic pressure. This contrasts with ventricular septal and
aortopulmonary defects, in which shunt reversal and pres-
sure equalization go hand in hand.
Approximately 10% of patients with atrial septal defects
have one or more anomalously connected pulmonary veins.
Mitral insufficiency may coexist in 10% to 20% of these
patients.16 The mitral insufficiency may be due to prolapse
of the posterior leaflet of the mitral valve associated with
secundum ASD and significant right ventricular enlarge-
ment.16 An interesting syndrome has been described (Lutem-
bacher’s syndrome) in which an atrial septal defect coexists
with mitral stenosis;17 in this disorder, patients remain rela-
tively asymptomatic until pulmonary hypertension develops
because the atrial septal defect decompresses the LA, and
therefore the left atrial pressure is not elevated despite sig-
nificant mitral valve obstruction.17–19 Patients with ostium
secundum-type ASDs are seldom symptomatic until they
begin to experience pulmonary hypertension, usually after
the fourth decade,20 if it occurs. It may not occur, however. FIGURE 10.1. Posteroanterior (PA) radiograph in a female patient
Unlike the other atrial communications, there is a 2 : 1 female with a large atrial septal defect. The cardiac silhouette is markedly
to male preponderance in cases of secondary ASD and this enlarged, the pulmonary vasculature is increased, and the main
defect is sometimes familial.21 pulmonary artery is huge. The aorta is inconspicuous, and there is
prominence of the right atrial border.
There is usually a soft systolic flow murmur due to mark-
edly increased pulmonary blood flow. The clinically diagnos-
tic feature, however, is a wide splitting of the second heart
sound (S2), which does not noticeably change with the respi-
described as a “pruned tree” (Fig. 10.2). The ECG is character-
ratory cycle. This wide, fixed splitting of the S2 is variably
ized by an rSR’ in lead V1, usually with a normal QRS axis.
attributed to a variety of theoretical physiologic phenomena.
When pulmonary hypertension develops, electrocardio-
Most likely, it is caused by increased capacitance of the pul-
graphic evidence of right ventricular hypertrophy may
monary arterial circulation and corresponding decreased
become manifest in the form of a tall R wave in lead V1 and
impedance. This increased capacitance leads to a prolonged
a rightward QRS axis.
“hangout interval” at the end of systole. Respiration has a
The echocardiographic picture of ostium secundum atrial
minimal effect on capacitance in this setting, so the splitting
septal defects shows an enlarged RA and RV. The ventricular
of S2 is wide and fixed. The electrocardiogram (ECG) almost
septum moves paradoxically. The atrial septum can be seen
always shows an rSR’ configuration in lead V1. The R’ is
as a “dropout,” especially by transesophageal echocardiogra-
thought to be caused by late activation of the crista supra-
phy. Shunting is demonstrable by color-flow Doppler, and the
ventricularis. This may explain why, after successful closure
pulmonary artery pressure can be estimated if there is tri-
of the atrial septal defect, wide splitting of the second heart
cuspid insufficiency.
sound often persists. The development of pulmonary hyper-
Cardiac catheterization is no longer indicated to confirm
tension accentuates the pulmonary component of the second
the diagnosis of an atrial septal defect. However, it is appro-
heart sound, P2, and ultimately cyanosis appears, at least
priate in middle-aged patients to characterize the pulmonary
with exercise if not at rest.
hemodynamics and to evaluate coexisting coronary artery
disease (CAD) before surgical correction, and also to rule out
Laboratory Findings anomalous pulmonary veins, if they are not accounted for by
echocardiography, for consideration of surgical correction.
Radiographic evaluation of patients with ASDs (Fig. 10.1)
shows an enlarged heart caused by dilatation of the RA and
Prognosis
the RV. The central pulmonary arteries are usually large,
with radiographic evidence of increased pulmonary blood Patients with normal or mildly elevated PVR are usually
flow. When significant pulmonary hypertension develops, asymptomatic, even with vigorous physical activity. They
the radiologic evidence of increased pulmonary flow may have atrial arrhythmias and are at risk for paradoxical
decreases, and the central pulmonary arteries are often embolism. However, the development of significant pulmo-
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e
FIGURE 10.2. Interatrial septal defect with severe pulmonary
hypertension. Note the increased heart size and the huge central
pulmonary arteries with distal “pruning.”
nary hypertension causes functional impairment, heart
failure, and shortened life span, but severe pulmonary hyper-
tension develops only in a minority of patients (<15%).
However, there is substantial evidence that the persistence
of the larger left-to-right shunt in itself shortens life expec-
tancy, with survival beyond age 50 years of age being less
than 50%. Factors contributing to this include the develop-
ment of pulmonary hypertension, which overtaxes the
volume-overloaded RV. The decreased diastolic compliance
of the aging LV may further increase the left-to-right shunt-
ing, and supraventricular tachyarrhythmias and paradoxical
embolism further complicate the course.14,16,22
Treatment
Because the mortality risk of surgical closure of an un-
complicated secundum atrial septal defect is approximately
1% or less, and the adverse consequences (i.e., pulmonary
hypertension, paradoxical embolism, and shortened life
expectancy) have a higher risk, early closure should be rec-
ommended, even when patients are asymptomatic. However,
when there is severe pulmonary hypertension, especially
with right-to-left shunting, the pulmonary/systemic flow
ratio may be closer to 1, and closure would be contraindi-
cated since ASD closure would not be expected to improve
pulmonary hypertension. In such cases, lung transplantation
with closure of the defect or heart-lung transplantation could
be considered.23,24 Closure of the ASD should be recom-
mended, even if patients are asymptomatic; if there is sig-
nificant pulmonary overcirculation. If the Qp : Qs ratio is less
than 1.3–1.5 : 1, there may not be evidence to support defect
closure, either by surgery or by catheter-placed device.
2 37
However, small ASDs found in childhood may not need
closure. There is some evidence favoring waiting because
about half of such patients have spontaneous closure of the
defect (age 8.4 years).25
PERCUTANEOUS R EPAIR
Open-heart surgery for the closure of defects in the atrial
septum is currently the “gold standard” for treatment of such
patients. The mortality rate for this procedure is close to 0%
in most contemporary reports.26 However, open-heart surgery
is a major procedure, with its attendant morbidity, need for
intensive care, and significant hospitalization. The compli-
cation rates after surgical closure of atrial septal defects in
adult patients can be as high as 13%.27
The pioneering work of King and Mills28,29 resulted in the
development of a double-umbrella ASD device and estab-
lished the feasibility of occluding ASDs with percutaneous
devices. The need for a 23-French delivery sheath and the
cumbersome procedure led to its abandonment. Many other
devices were subsequently developed, including the Rash-
kind single-disk device,30 the Lock USCI “clamshell”
device,31–35 the “buttoned” device, 36–39 the ASDOS device,40–43
the Manodisk device,44 the Das Angel Wings, the Amplatzer
device, the Cardioseal, and a modification of the Cardioseal
called the Starflex, and the Helex device.45–52 Currently, the
most popular device is the Amplatzer (AGA Medical Corp.,
Golden Valley, MN). It is favored for its ease of insertion, low
profile during insertion, and potential for retrievability if the
implantation is unsatisfactory. Investigation of several
devices is ongoing and it is likely that “full-service” cathe-
terization services will eventually employ more than one
device, depending on the unique nature of an individual
ASD.53 The closure of hemodynamically significant ASDs in
adults is now becoming the standard of care54 and, when
compared with surgical closure, performs well from the
standpoint of outcome and cost.55
Late Complications
Occasionally, patients have arrhythmias late, following suc-
cessful surgical ASD repair or device closure56–60 (Fig. 10.3).
Sinus node dysfunction often precedes the onset of more
complicated arrhythmias. Sick sinus syndrome may develop
with alternating bradycardia and tachycardia. The tachyar-
rhythmias that are common are atrial flutter and atrial fibril-
lation. Endocarditis does not occur in cases of isolated ostium
secundum ASD.
In patients in whom closure of an ASD is contraindicated
by a high pulmonary vascular resistance, treatment is based
on symptomatic care. Adequate control of the ventricular
rate, especially with atrial arrhythmias, and judicious use of
oxygen are helpful. Anticoagulation with low-dose warfarin
(Coumadin) is advisable to minimize paradoxical embolism.
Endocarditis does not occur in patients with the secundum
type of defect per se, because flow across the large defect is
at a low pressure. However, if mitral valve prolapse coexists,
the considerations for infective endocarditis prophylaxis
would be those pertaining to isolated mitral valve prolapse.
Cardiopulmonary transplantation would be a consideration
in patients with advanced pulmonary vascular disease who
are disabled.
238 chapter
I II
aVR aVL
V1
V2
V4 V5
Ostium Primum Atrial Septal Defect
Ostium primum ASD is an endocardial cushion defect in
which the septum primum (i.e., the lower portion of the
atrial septum) fails to develop, as does the atrioventricular
septum. In this situation, the anterior leaflet of the mitral
valve is attached to the ventricular septum in a somewhat
lower position than normal and is therefore at the same level
as the tricuspid valve. The anterior leaflet is cleft and, because
of its lower position, has characteristic angiographic61 and
echocardiographic20 features. The mitral valve cleft is associ-
ated with various degrees of mitral regurgitation. Typically,
the hemodynamic disturbance of an ostium primum ASD is
more severe than an ostium secundum ASD. This is particu-
larly true if there is significant mitral valve insufficiency. It
is rare for a patient with an ostium primum ASD to reach
adulthood undiagnosed.
The clinical diagnosis of an ostium primum ASD has
many of the features of those associated with a secundum-
type ASD (i.e., hyperactive RV; wide, fixed splitting of the
second heart sound; and a pulmonary flow murmur).
However, there is usually an additional murmur of mitral
insufficiency. This does not necessarily radiate to the axilla,
because the regurgitant jet is directed more medially than
toward the free wall of the LA. If the mitral regurgitation is
severe or if pulmonary hypertension develops, decreased
exercise tolerance and exertional dyspnea can be expected.
Examination finding may also include a left ventricular
filling sound [the third heart sound (S3) of mitral insuffi-
ciency] and a fourth heart sound (S4). The chest x-ray result
10
III
aVF
V3
FIGURE 10.3. Electrocardiogram of a patient
with an ostium primum defect, severe pulmo-
nary hypertension, and mitral insufficiency
through a cleft anterior leaflet. Note the left-
axis deviation, right ventricular hypertrophy,
V6 and atrial flutter.
is very similar to that of a secundum-type ASD unless there
is severe mitral insufficiency, in which case there is evidence
of left atrial enlargement as well. The ECG has the charac-
teristic rSR’ in lead V1, but in addition, the frontal plane QRS
axis is always leftward, and there is often first-degree heart
block (Fig. 10.4). With pulmonary hypertension, the chest
leads show right ventricular hypertrophy (Fig. 10.5).
Until and unless pulmonary hypertension develops, the
atrial shunting is left to right, and there is no cyanosis. When
the mitral insufficiency is severe, there may not be a signifi-
cant elevation of atrial pressures, because the RA has high
capacitance and the RV is adapted for volume overload and
accepts the increased left-to-right shunt. However, with a
decrease in compliance of a failing RV due to chronic volume
overload or a hypertrophied RV because of pulmonary hyper-
tension, atrial pressures rise, and the pulmonary venous
pressure can be estimated from inspection of the neck
veins.
The natural history of ostium primum ASDs differs
significantly from that of a secundum-type ASD. Ostium
primum defects are susceptible to infective endocarditis of
the cleft mitral valve. If the mitral regurgitation is severe,
patients may have dyspnea and left ventricular dysfunction,
and if the right ventricular compliance is compromised,
there are signs of both right ventricular and left ventricular
failure.
Patients with complete AV canal seldom survive to late
adulthood without cardiac surgery. The ECG shows left axis
deviation, right ventricular hypertrophy, large P waves, and
various degrees of AV block (Fig. 10.6).
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 239

V1 V4
1 aVR

2 aVL
V2 V5

3 aVF
V3 V6
FIGURE 10.4. Electrocardiogram of a patient with an ostium primum. Note the left-axis deviation, incomplete right bundle branch block
in V2, and first- and second-degree atrioventricular block.

Laboratory Studies
The echocardiogram classically demonstrates a low-lying
ASD with no continuity between the anterior leaflet of the
mitral valve and the aortic valve, and a cleft in the anterior
leaflet of the mitral valve.20 The mitral and tricuspid valves
are at the same level. There is mitral insufficiency of varying
degree, an enlarged RV, paradoxical septal motion, and
enlarged atria. Angiographically, the left ventriculogram
reveals a “goose-neck” deformity (Fig. 10.7), related to the
unusual attachment of the anterior leaflet of the mitral valve,
and some degree of mitral insufficiency.61

V1

V2

V3
II

V4

III

V5

aVR aVL aVF

V6

FIGURE 10.5. Electrocardiogram of a patient with an atrial septal patient has slow flutter with varying atrioventricular conduction,
defect of secundum type with severe pulmonary hypertension. Note which resembles “paroxysmal atrial tachycardia with block” and
the right-axis deviation and right ventricular hypertrophy. This may be mistaken for digitalis intoxication.
240 chapter 10

V1 V4
1 aVR

2 aVL
V2 V5

3 aVF
V3 V6
FIGURE 10.6. Electrocardiogram of a patient with an ostium primum. Note the left-axis deviation, incomplete right bundle branch block
in V2, and first- and second-degree atrioventricular block.

Prognosis transcatheter closure, in contrast to the secundum type of

The large left-to-right shunt may eventually lead to pulmo-
nary hypertension. The cleft mitral leaflets result in increas-
ing mitral regurgitation and left ventricular dysfunction and
is susceptible to infective endocarditis. Finally, AV block
may develop as part of the natural history of endocardial
cushion defects.
Treatment
The definitive treatment for an ostium primum defect is
early surgical closure.62 The condition is not suitable for
septal defect, because the lower border of the defect is in
direct continuity with the anterior leaflet of the mitral valve.
Precautions during surgical closure include not encroaching
on or injuring the AV node and the bundle of His. Therefore,
patching rather than direct suturing is required. The treat-
ment of the cleft mitral valve depends on the degree of mitral
regurgitation. However, valvuloplasty is often feasible in
skillful hands. If closure of the cleft in the anterior leaflet of
the mitral valve is overly aggressive or if there is insufficient
native mitral valve tissue, mitral stenosis may occur. Should
the patient show evidence of advanced second- or third-

FIGURE 10.7. (A,B) Left ventriculogram of a 21-year-old woman detachment of the anterior leaflet of the mitral valve to the ven-
after surgery for closure of an ostium primum defect. Note the usual tricular septum so it is at the same level as the tricuspid valve,
“bite” out of the inferomedial portion of the left ventricle, giving whereas normally it is attached more superiorly.
rise to the so-called goose-neck deformity. This is due to the lower
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e
degree AV block, biventricular or dual chamber (DDD) pacing
would be advisable but only after the ASD has been closed,
because the electrodes are thrombogenic and paradoxical
embolization may occur.
Prognosis
The prognosis for ostium primum atrial septal defects that
have undergone surgical closure depends on the degree of
pulmonary vascular disease, complications associated with
mitral valve prostheses, and left ventricular function. If the
mitral insufficiency has been relatively severe and long-
standing, even mitral valve replacement may provide only a
short-term reprieve from eventual failure of the LV.
2 41
difficult in the hands of an experienced operator. The coro-
nary sinus yields a rather high oxygen saturation, in contrast
to the normally very low saturation. It may be difficult to
distinguish between a coronary sinus ASD and partial anom-
alous pulmonary venous connection to the coronary sinus.
However, the coronary sinus ASD is more proximal, and
sampling of the more distal blood in the coronary sinus
should yield a low saturation, whereas with an anomalous
pulmonary venous connection to the coronary sinus, there
is a higher saturation throughout the coronary sinus. This
entity is of some clinical importance because the coronary
sinus ostium can be rather large, and there have been rare
instances in which the coronary sinus ostium has been mis-
takenly closed for an atrial septal defect.

Common Atrium Partial Anomalous Pulmonary Venous Connection

Common atrium is a variant of AV canal defect. It is char-
acterized by a total absence of the atrial septum and a cleft
in the anterior leaflet of the mitral valve. The clinical profile
differs from classic AV canal in that these patients invari-
ably have right-to-left shunting at the atrial level. Frequently,
patients with a common atrium have some cyanosis, if not
at rest at least with exercise, because the common atrium
acts as an incomplete mixing chamber. The ECG is essen-
tially the same as with an ostium primum atrial septal
defect. The echocardiogram differs in that there is complete
absence of the atrial septum. Because of the pulmonary
overcirculation, these patients are symptomatic at an earlier
age than other atrial septal defects, and surgical creation
of an atrial septum is usually performed in the first year
of life.
The connection of one or more pulmonary veins to a struc-
ture other than the LA should be considered in patients with
clinical or radiographic evidence of left-to-right shunting at
the atrial level.66 Partial anomalous pulmonary venous con-
nection may occur with no atrial communication.67 It may
coexist in approximately 10% of secundum-type ASDs. The
insertion may be directly into the superior vena cava; into a
vertical vein that goes into the innominate vein and then
into the superior vena cava; into the RA directly; to the coro-
nary sinus68; or, rarely, into the inferior vena cava (scimitar
syndrome)69 (Fig. 10.8). If the cardiologist is alert to the pos-
sibility, the echocardiographer who is warned is usually able

Sinus Venosus Atrial Septal Defect

Sinus venosus ASD is an ASD located posteriorly subjacent
to the superior vena cava. It is almost always associated with
the anomalous insertion of at least one pulmonary vein adja-
cent to the superior vena cava. Clinically, it is indistinguish-
able from a secundum type of atrial septal defect. On
echocardiography, the defect is seen posteriorly rather than
in the area of the foramen ovale, and an anomalous pulmo-
nary vein can be identified. Successful surgical closure of
this defect is more difficult because of the presence of an
anomalous pulmonary vein adjacent to the superior vena
cava, and some degree of dehiscence of the patch near that
area is common. As long as the residual left-to-right shunt
is small, it should not cause difficulty.63,64

Coronary Sinus Atrial Septal Defect

A congenital defect may occur between the coronary sinus
and the LA, which results in a left-to-right shunt that physi-
ologically resembles an atrial septal defect.65 The cause of a
coronary sinus ASD is unroofing of the coronary sinus into
the left atrium. This entity can be suspected when echocar-
diography fails to identify an ASD in the presence of clinical
and radiographic evidence of a left-to-right shunt. Cardiac FIGURE 10.8. Posteroanterior radiograph of patient with partial
anomalous venous return to the inferior vena cava (scimitar syn-
catheterization yields an oximetry series that is consistent drome). The heart is normal in size, as is the pulmonary vascula-
with a shunt at the atrial level. A useful maneuver is to ture. The anomalous drainage through a large scimitar vein (arrows)
introduce the catheter into the coronary sinus, which is not is well demonstrated.
242 chapter
to identify these. They may also be identified through cardiac
catheterization techniques using selective pulmonary arte-
riography (including the levophase) or by means of selective
indicator dilution techniques. It is important to be alert to
these veins because the closure of an ostium secundum-type
ASD alone only partially decreases the left-to-right shunt if
several anomalous pulmonary veins coexist.
Ventricular Septal Defects
Isolated ventricular septal defects (VSDs) are infrequently
seen in adults.70 Fifty percent or more of VSDs close sponta-
neously in early childhood, even as late as adolescence.71,72 If
the VSD is small, these defects are associated with little or
no hemodynamic disturbance of the LV and result in only a
small left-to-right shunt and no pulmonary hypertension.
Large defects are associated with equalization of pressure in
the two ventricles and therefore in the pulmonary artery. In
a large VSD, the direction and the degree of shunting are
determined by the relative resistances of the pulmonary
and systemic circuits. The right-to-left and the left-to-right
shunts are more or less balanced if the resistances in the
systemic and pulmonary circulations are equal. This is the
classic Eisenmenger complex. Large defects with a low to
mildly elevated PVR have large left-to-right shunts with
severe volume overload of the LV. These are almost invari-
ably discovered by a pediatric cardiologist, and the defect is
closed.72 Therefore, in adults, the common forms of congeni-
tal ventricular septal defect are either large ones of the Eisen-
menger physiology or those in association with pulmonary
stenosis, in which the pulmonary circulation is “protected”
from the development of pulmonary vascular disease. Occa-
sionally, one may see patients who have a moderate-size
ventricular septal defect, a large left-to-right shunt, and an
enlarged LV and are symptomatic who present as adults
(often coming from areas of the world without sophisticated
medical care). Unless there are separate, serious comorbid
factors, and pulmonary vascular resistance is not severely
elevated, the defect should be closed.
The most common form of congenital isolated ventricu-
lar septal defect is of the so-called perimembranous type,
which is posterior and inferior to the crista supraventricu-
laris, involving what would be the membranous septum and
some of the adjacent muscular septum.73 This is situated just
under the septal leaflet of the tricuspid valve and is sub-
tended by the aortic valve. The bundle of His courses along
the posterior rim of this defect and therefore is not affected,
but it is vulnerable during surgical closure of the defect.
Single or multiple muscular septal defects may also occur as
isolated congenital lesions.73 In early infancy, up to 50% of
isolated VSDs are in the trabecular septum. Later, muscular
VSDs are present in about 10% of the cases of VSD. They are
generally multiple and small, so that even in the presence of
large shunts, there is seldom significant elevation of the right
ventricular or pulmonary artery pressure. Although many of
these defects close spontaneously, they may persist and are
difficult to close completely at the time of surgery because
of heavy trabeculation on the right ventricular aspect of the
ventricular septum. The seemingly logical left ventricular
approach to closure of the lesion would seriously compro-
mise the contractility of the LV.
10
The predominant type of congenital isolated VSD seen
in adults is that termed the Eisenmenger complex (i.e., a large
VSD with severe pulmonary vascular obstruction and bidi-
rectional shunting).74
Small Ventricular Septal Defect
(Maladie de Roger)
Patients with small VSDs are totally asymptomatic. The
volume overload of the LV is minimal to mild. The heart size
remains normal, and pulmonary hypertension does not
develop on the basis of this defect alone. The sole risk is that
of infective endocarditis.
Rarely, a moderate-size defect may be converted to a
smaller defect by adhesion of the septal leaflet of the tricus-
pid valve, aneurysm formation of the membranous septum,
or prolapse of an aortic cusp. This prolapsed cusp may in
time become adherent to the VSD, partly occluding it func-
tionally. The patient may then present with primarily aortic
regurgitation and a small VSD.
The diagnosis of a small VSD is made clinically by the
characteristic holosystolic murmur, starting with the first
heart sound. This holosystolic murmur should not be mis-
taken for mitral insufficiency. It is loudest at the left sternal
border but does not radiate to the neck. In mitral regurgita-
tion caused by a redundant anterior leaflet, the murmur is
transmitted to the axilla, whereas if it is associated with a
redundant posterior leaflet, it radiates medially and often is
transmitted to the neck. The chest x-ray study and ECG are
usually normal. The diagnosis is best confirmed echocardio-
graphically with the color-flow Doppler technique.75,76 It is
also readily visualized on the left ventriculogram (Fig. 10.9).
If this is truly a small VSD and not one that has been made
small by the prolapse of an aortic cusp, surgery is not indi-
cated unless there are other unrelated cardiac defects that
require surgical correction. The prognosis is good, and the
chief precaution is the need for prophylaxis against infective
endocarditis. If a “small” VSD is associated with significant
aortic regurgitation due to a prolapsed cusp, the major con-
sideration is that of the aortic regurgitation.
Large Ventricular Septal Defect
The rare patient who survives into adulthood with a large
VSD and a large left-to-right shunt but without severely ele-
vated pulmonary vascular resistance may exhibit symptoms
similar to those of patients with significant mitral insuffi-
ciency, both representing examples of left ventricular volume
overload. The chief manifestation is exertional dyspnea as
a consequence of elevated left ventricular filling pressure
causing elevated pulmonary venous pressure. Radiographic
studies show cardiomegaly, primarily of the LV, and enlarged
central pulmonary arteries with radiologic evidence of
increased pulmonary flow. The ECG may show tall voltages
in the chest leads associated with left ventricular volume
overload. Echocardiography is essential not only to confirm
the large left-to-right shunt but also to determine the type
and the location.77 Cardiac catheterization is helpful in defin-
ing the pulmonary hemodynamics for surgical risk assess-
ment and for ultimate prognosis. Left ventricular angiography
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 243

FIGURE 10.9. (A,B) Left ventriculogram of a small ventricular septal defect, best seen in the lateral view (B). Note the normal size of the
left ventricle.

in several views is very helpful. Some of these patients may
unexpectedly experience a systolic gradient between the RV
and the pulmonary artery (Gasul’s phenomenon) without
having true pulmonary stenosis.78
Surgical closure of VSDs is associated with conduction
abnormalities in as many as 15% of cases, consisting of right
bundle branch block and left-axis deviation79,80 (Fig. 10.10).
Rarely in the current era, damage to the conduction system
can result in complete AV block, necessitating placement of
a pacemaker. There are no extensive data on the late occur-
rence of complete AV block, but it appears to be uncommon.79
These conduction abnormalities are related to the close

6 Sec.

Lead 1 V1 V4

6 Sec.

Lead 2 V2 V5

6 Sec.

Lead 3 V3 V6

Trial rate P-R Interval Patient position

Entricular rate QRS Interval Electrical axis
Hythm Q-T Interval S-T Segment
Waves T Waves
Emarks

aVR aVL aVF

FIGURE 10.10. Electrocardiogram of a patient who underwent part of another entity, such as tetralogy of Fallot. This bifascicular
closure of a ventricular septal defect. Note the left-axis deviation block may uncommonly progress to complete atrioventricular
and right bundle branch block, which are commonly seen after block.
ventricular septal defect closure whether as an isolated defect or as
24 4 chapter 10

proximity of the bundle of His to the posterior wall of the

VSD. Currently, transcatheter device closure of certain VSDs,
particularly certain muscular VSDs and perimembranous
defects, are being used effectively.81–85

Eisenmenger’s Complex
Eisenmenger’s complex is by far the most common presen-
tation of a large VSD in adults.74 These patients exhibit
equalized pressures and resistances in the pulmonary and
systemic circuits from early childhood onward (Fig. 10.10).
At rest, the patients have a bidirectional shunt. With physi-
cal exertion and a decrease in systemic vascular resistance
(SVR), the right-to-left shunting increases, resulting in
increased arterial desaturation and fatigue. There is an
inability to increase pulmonary blood flow with exercise,
so the magnitude of right-to-left shunt increases as systemic
oxygen delivery demands increase with exercise and sys-
temic blood flow increases. Therefore, these patients are
self-restricting and seldom need to have physical restric-
tions arbitrarily imposed. The longevity of such patients is
variable. Causes of death include sudden cardiac death,
infective endocarditis, brain abscess, massive hemoptysis,
and hyperviscosity. By x-ray study, the heart size may
be normal, the central pulmonary arteries are markedly
dilated, and there is no evidence of increased pulmonary
flow (Fig. 10.11).
Echocardiography characteristically demonstrates the
location of a large VSD and bidirectional shunting.86 It can
also differentiate between an isolated VSD with normally
related great vessels from one associated with congenitally
corrected transposition with double-outlet RV.
Cardiac catheterization characterizes the hemodynamics
(i.e., a large VSD through which the venous catheter can be
manipulated into both the aorta and the pulmonary artery),
severe pulmonary hypertension with markedly elevated
PVR, and bidirectional shunting.87
Continued survival of such patients requires careful
follow-up and management.88 The erythrocytosis is a conse-
quence of arterial desaturation, and symptoms of hypervis-
cosity are peculiar to each patient. Most patients have
correlating symptoms, such as visual disturbances, light-
headedness, or a “funny feeling,” at which time it may be
appropriate to phlebotomize them, simultaneously replacing
the blood loss with intravenous saline. It is seldom necessary
to bring the hemoglobin to much below 20 g. The use of
phlebotomy is controversial; it is variably applied at different
adult congenital heart centers. The patients’ symptoms
appear to be a better guide than arbitrary numeric guides. FIGURE 10.11. (A–E) Eisenmenger’s complex (ventricular septal
A word of caution is necessary here, however. Repeated defect with severe pulmonary hypertension and equal resistances
in the pulmonary and systemic circuits). Patient at age 2 (A), at age
phlebotomies without iron supplementation result in an 10 (B), and at age 20 (E). The left ventriculogram (C and D) shows
iron-deficiency anemia that can worsen symptoms of the normally related great arteries and markedly dilated pulmonary
hypervisco-sity due to the effects of iron deficiency on red trunk and left pulmonary artery. Commonly, adults with Eisen-
cell function. In iron deficiency, the red blood cells are small menger’s complex have this physiology from early life.
and more rigid, which increases viscosity. Therefore, iron
supplementation may be necessary. Rapid erythrocyte turn-
over may also lead to folate deficiency, which may require Patients with Eisenmenger’s complex do not progress to
folic acid supplementation. These patients should also be CHF unless other factors supervene, such as ventricular
cautioned to maintain adequate fluid intake during hot dysfunction. The RV is adapted to pressure work, and there
weather and during exertion. is no volume overload. However, injudicious and excessive
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e
phlebotomies may render the patient relatively anemic, espe-
cially if associated with iron deficiency, and CHF may ensue.
In some patients, moderate pulmonary insufficiency may
develop, creating a volume overload situation that can also
lead to CHF. Treatment of CHF in Eisenmenger’s syndrome
is controversial. Historically, digoxin and cautious diuresis
were employed. There is some evidence to support judicious
use of afterload reduction, but this therapy has the risk of
increasing the right-to-left shunt and aggravating the cyano-
sis. If the patient has an iron-deficiency anemia, often owing
to repeated phlebotomies, cautious transfusion of packed red
blood cells is sometimes helpful, as is iron replacement.
Current treatment regimens include bosentan, sildenafil,
and iloprost, and outcomes appear to be improved.88
Many patients with Eisenmenger’s complex manage to
do reasonably well, holding down full-time jobs and perform-
ing many normal activities, although they are not capable of
performing strenuous exertion. Ultimately, increasing pul-
monary vascular disease with increasing right-to-left shunt-
ing and increasing erythrocytosis make existence difficult,
and such patients should be considered for heart-lung
transplantation.
Patent Ductus Arteriosus
The ductus arteriosus is the main fetal path through which
oxygenated umbilical cord blood perfuses distal to the aortic
arch of the fetus. With delivery and the baby’s first breath,
there is an immediate drop in PVR, resulting in a reversal of
the shunt through the ductus arteriosus. Usually, the ductus
arterious constricts and is functionally closed by 18 hours
after birth. Patency may persist for several weeks without
any consequences. The pathophysiologic consequences of
persistent patency of the ductus arteriosus depend on the size
of the ductus and, to a lesser extent, on the length.89 There
is a continuous left-to-right shunt during systole and diastole
through the ductus as long as the PVR is lower than the
systemic resistance. Predisposing factors for a patent ductus
arteriosus (PDA) are maternal rubella in the first trimester
of pregnancy, prematurity, and high altitude.
245
there may be a suggestion of increased pulmonary blood
flow.
The echocardiogram shows evidence of flow into the left
pulmonary artery because the ductus is usually between the
distal aortic arch and the proximal left pulmonary artery91
shortly after bifurcation. During cardiac catheterization, it
is usually possible to manipulate the venous catheter from
the proximal left pulmonary artery through the ductus into
the descending aorta. The pulmonary artery pressure should
be measured simultaneously with the systemic arterial
pressure.
PROGNOSIS
The prognosis for PDAs with small-to-moderate left-to-right
shunt is excellent, the chief risk being endocarditis. Over
time, though, the likelihood of endocarditis is significant.
Cardiac catheterization can help to determine the status of
the pulmonary vasculature.
Because the PDA is extracardiac, its ligation and division
do not require open-heart surgery, making the surgical risk
virtually the risk of anesthesia only. At present, however,
there are transcatheter techniques for closure of a patent
ductus, and these are quite suitable for most patients with a
PDA who have persistent patency after the first few months
of life.92
Large Patent Ductus
With normal or even moderately increased PVR, patients
with large PDAs have a large continuous left-to-right shunt
(Fig. 10.12). They are only rarely seen as adults because the

Restrictive Patent Ductus Arteriosus

Most patients with restrictive PDA are asymptomatic because
the left-to-right shunt is generally mild to moderate. The
pathophysiology is similar to that of aortic regurgitation, and
there is a rapid run-off with some degree of left ventricular
volume overload. The classic physical finding is the machin-
ery murmur of Gibson,90 heard best in the left subclavicular
region and continuous throughout the whole cardiac cycle.
This is not to be confused with long murmurs in systole and
diastole, such as may occur in combined aortic stenosis and
regurgitation, in which the directional shift in flow is marked
by a short hiatus between the systolic and the diastolic com-
ponents. The murmur is identical to that heard in an AV
fistula, which it in fact resembles physiologically. The radio-
graphic study in patients with a small PDA shows a normal
heart size with normal pulmonary vasculature. There is a FIGURE 10.12. Posteroanterior radiograph of patient with a large
patent ductus arteriosus. There is moderate cardiomegaly, with
tendency, however, for the aortic arch to be somewhat wider increased pulmonary vasculature and marked enlargement of the
than usual for the patient’s age. With a moderate left-to-right main pulmonary artery segment (arrow in prominence of the
shunt, the heart size may increase somewhat over time, and aorta).
24 6 chapter
volume overload of the LV and the resultant symptoms betray
the diagnosis in childhood, at which time the defect is cor-
rected. A large PDA seen in adulthood is almost always one
with a PVR slightly less than, equal to, or even greater than
the SVR, with either a small bidirectional shunt or an exclu-
sively right-to-left shunt. In many respects, this resembles
the Eisenmenger complex associated with a ventricular
septal defect (Fig. 10.13).93 The patients experience signifi-
cant exercise limitations because peripheral vasodilation
serves to increase right-to-left shunting and further arterial
desaturation. However, unlike the situation in the Eisen-
menger complex with a ventricular septal defect, the natural
history of a high-pressure, high-resistance PDA may lead to
right-sided CHF if the pulmonary artery dilation results in
significant pulmonary insufficiency. The resulting volume
overload of the RV with an intact ventricular septum can
lead to decompensation.
The clinical history is that of exercise limitation and
sometimes angina-like symptoms with exertion, associated
with definite cyanosis. Classically, the cyanosis should
involve the left hand and the feet and not so much the right
hand, although this is occasionally seen (Fig. 10.14). Far more
common, however, is cyanosis and clubbing of all four
extremities, possibly because of reversal of flow in the
ascending aorta during early diastole. Sometimes there is
hoarseness caused by compression of the recurrent laryngeal
nerve, especially if the PDA becomes aneurysmal. Hemop-
tysis may occur, presumably because of the pulmonary
hypertension.94
FIGURE 10.13. Posteroanterior radiograph of patient with patent
ductus arteriosus and severe pulmonary vascular disease, as indi-
cated by calcified plaque in the pulmonary arteries (curved white
arrow). The ductus arteriosus itself is also calcified (black arrow).
Pulmonary artery segment and aortic knob are markedly enlarged.
10
FIGURE 10.14. Differential clubbing in a 23-year-old patient with
reversing ductus arteriosus. Note the marked clubbing of the toes
and of the fingers of the left hand, with normal nails and fingers on
the right hand. Although classic, this is less common than cyanosis
and clubbing of all fingers and toes in reversing ductus arteriosus.
L ABORATORY STUDIES
The chest x-ray evaluation is characterized by a prominent
aortic arch and large central pulmonary arteries. If the PVR
is high, the peripheral pulmonary vasculature appears
“pruned,” as in the Eisenmenger complex. The heart is
usually of normal size. Examination of the heart may dis-
close only a systolic murmur or no murmur, prominent pal-
pable pulsation of the main pulmonary artery, and a loud P2.
Radiographically, it is possible to see the PDA as a slightly
oblique shadow between the distal portion of the aortic arch
and the pulmonary artery. This is especially evident when
there is calcification of the ductus (Fig. 10.13).
Echocardiographically, a high-pressure PDA is best seen
by the transesophageal technique. Cardiac catheterization is
used to define the pulmonary hemodynamics, and the PDA
can be visualized angiographically for the surgeon.
PROGNOSIS
In a large PDA in which there is still an appreciable left-to-
right shunt and in which the pulmonary/systemic flow ratio
is greater than 1.5 : 1, the ductus can still be divided and
ligated with the anticipation that the pulmonary artery pres-
sure will fall. However, the PVR will remain somewhat ele-
vated. When pulmonary flow and systemic flow are equal, as
are their respective resistances, closure of the PDA is contra-
indicated, and the only treatment would be heart-lung
transplantation.24,95
Endocardial Cushion Defects
The crux of the heart refers to the area where the atrial
septum, the ventricular septum, the mitral valve, and the
tricuspid valve all come together. The structures that make
up this part of the heart are formed by endocardial cushion
tissue during development as the common atrioventricular
canal is divided. Defects in this part of the heart have been
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e
variably referred to as endocardial cushion defects, atrioven-
tricular canal defects, and atrioventricular septal defects.
Each nomenclature has a group of passionate defendants. The
severity of disease caused by abnormal development and
division of the atrioventricular canal ranges from minor
abnormalities of the mitral valve such as a cleft in the ante-
rior leaflet to much more severe disturbances such as a
complete atrioventricular canal defect or complete atrioven-
tricular septal defect. The anterior leaflet of the mitral valve
is almost invariably cleft in this group of defects. Deficiency
of the primum atrial septum at the crux is referred to as an
ostium primum ASD. Alternatively, this abnormality has
been referred to as a partial atrioventricular canal defect. The
combination of an ostium primum ASD and a pressure-
restrictive VSD is conventionally referred to as a transitional
atrioventricular canal defect. A large ASD and a large inlet
VSD is referred to as a complete AV canal (septal) defect.
Typically, there is a large common AV valve that sits over
both ventricles. This common AV valve has four to six leaf-
lets, including an anterior bridging leaflet and posterior
bridging leaflet that “bridge” the ventricular septum. Defects
of the AV septum make up the most common type of defects
seen in Down syndrome.
Clinical Presentation
The clinical presentation of ostium primum ASD and its
close relative, common atrium, was discussed earlier.
Complete AV canal defect in adults may present in asso-
ciation with either pulmonary stenosis or pulmonary hyper-
tension. In the latter case, it has many of the characteristics
of the Eisenmenger syndrome. These patients have a high
incidence of cyanosis. The heart is enlarged, and there is a
loud P2. There is an absent P2 in cases with associated pul-
monary stenosis, and a loud ejection systolic murmur is
heard if pulmonary stenosis is present. Evidence of AV valve
regurgitation may be observed by evaluation of deep jugular
pulses.
Laboratory Studies
The chest x-ray shows an enlarged heart with a large pulmo-
nary arterial tree and, if there is no pulmonary stenosis,
evidence of increased pulmonary blood flow. Both ventricles
and both atria are enlarged. The ECG may be similar to that
of an ostium primum ASD (i.e., rSR’ in the anterior chest
leads, left-axis deviation, and often first-degree AV block).
Echocardiography visualizes the low-lying ASD, a corre-
sponding VSD, and the characteristic straddling AV valve.20
If there is pulmonary stenosis, this can be seen with color-
flow Doppler techniques, and the degree of stenosis can be
estimated. Measurements should be made of the pulmonary
hemodynamics with quantification of the left-to-right and
the right-to-left shunts and the respective resistances.
Because of the cyanosis, there is secondary erythrocytosis,
which must be carefully managed as discussed earlier.
Prognosis
Long-term survival with a complete atrioventricular septal
defect, without surgery, is uncommon, and such patients
rarely survive into adulthood.
2 47
Treatment
Treatment is surgical unless there is irreversible pulmonary
vascular disease. If there is severe pulmonary vascular
disease, heart-lung transplantation is the only option. In
earlier eras, patients with Down syndrome were often denied
surgical therapy. More recently, though, this has not been a
consideration, and children with Down syndrome routinely
do well following surgery. Over the long term, postoperative
morbidity is related to the adequacy of the mitral valve func-
tion. Repair of the cleft mitral valve in endocardial cushion
defects is challenging and patients are almost always left
with some degree of mitral insufficiency. This can be severe
enough to require a second operation to repair or replace the
mitral valve. Additionally, if the atrioventricular tissue is
inadequate or the cleft in the anterior leaflet is repaired
overaggressively, there can be concomitant mitral stenosis
following repair.
Congenital Valve Abnormalities
Aortic Stenosis
Congenital obstruction of the outflow tract of the left ven-
tricle in the adult is overwhelmingly due to valvar disease
and commonly results from the development of aortic steno-
sis because of a congenital bicuspid or unicuspid valve.96,97
The incidence of aortic valve disease is four to five times
higher in males than in females.98 Idiopathic hypertrophic
subaortic stenosis and asymmetric septal hypertrophy, now
known as hypertrophic cardiomyopathy (HCM), are different
disorders from valvular aortic stenosis and are discussed
separately.
Aortic Valve Stenosis
In nonelderly adults, aortic stenosis typically develops
because of a bicuspid (or unicuspid) aortic valve.99,100 This is
sometimes seen in association with coarctation of the
aorta.101 In general, the valve causes little or no hemody-
namic disturbance for the first several decades of life and, in
fact, may never cause any hemodynamic disturbance at all.
Progressive aortic regurgitation may develop, especially in
young adulthood. It appears that most valves with this abnor-
mality develop progressive thickening and fibrosis after the
third or fourth decade of life. Over time, increasing calcifica-
tion and progressively severe aortic stenosis (AS) develops.
The presence of mild AS may be associated with progres-
sively severe aortic regurgitation when inadequate coapta-
tion outweighs inadequate opening of the valve.101 Bacterial
endocarditis may also transform the pathophysiologic dis-
turbance from predominant stenosis to predominant
regurgitation.
The course of the disease, once stenosis begins, tends to
be relentless but has a highly variable timetable. In general,
the progression to severe AS may take decades, although on
rare occasion may be rapid. After significant AS develops, the
natural history is similar to that of acquired AS. The classic
ominous symptoms are syncope, angina, and CHF. Sudden
death is a threat even when mild symptoms are noted.98,102–104
However, evaluation for surgery should be undertaken if
24 8 chapter
there has been any subjective change in exercise tolerance or
in the patient’s general sense of well-being. Most patients
with predominant AS have well-preserved left ventricular
function if exertional syncope is the primary manifestation.
Although angina may occur in severe AS without concomi-
tant CAD, CAD is not uncommon in the presence of AS and
should always be evaluated when surgery on the aortic valve
is contemplated.105–107 The appearance of overt CHF is usually
of ominous prognostic consequences, although some patients
may recover virtually normal left ventricular function after
successful surgery. Approximately 5% of patients with a
bicuspid aortic valve (BAV) have associated cystic medial
disease of the aorta, which can become the basis of an aortic
dissection. Coarctation of the aorta is sometimes associated
with a BAV (it is far more common for coarctation of the
aorta to be associated with a BAV, rather than the reverse),
which has its own inherent natural history and complica-
tions.108 Before the aortic valve has become heavily calcified,
the presence of a BAV has classic physical examination find-
ings. The most characteristic feature of a BAV is a loud sys-
tolic ejection click, which coincides with the doming of the
aortic valve toward the end of isovolumetric contraction of
the LV.109 In a younger age group, this may be the only physi-
cal examination finding, although commonly there is an
aortic systolic murmur that starts after the ejection sound.
The ejection click is usually somewhat pronounced, and
it is likely that the doming of the aortic valve prolongs the
phase of isovolumetric contraction.109,110 The aortic systolic
murmur, if present, starts with the ejection click and may
be of variable intensity.98,111
The second heart sound characteristically preserves both
components (A 2 and P2) until significant AS develops, when
the second sound becomes single. There may or may not be
10
an early diastolic blowing murmur of aortic regurgitation.
The peripheral pulse contour characteristically shows an
anacrotic notch. In general, the more severe the stenosis, the
more delayed the upstroke and the lower the anacrotic notch
on the upstroke.98,112 Classically, the heart is not enlarged.113
If the aortic valve is heavily calcified, it can be visualized,
especially in the lateral view of the chest film, and can be
readily seen on fluoroscopy. A characteristic associated
finding is dilation of the ascending aorta (Fig. 10.15).114 This
dilation is asymmetric, anterior, and to the right and is
believed to be due to the direction of the abnormal flow
pattern across the bicuspid aortic valve. This “poststenotic
dilatation” can be observed even when there is no systolic
gradient across the aortic valve. The ECG may be unremark-
able throughout the course of the disease up to the time of
surgery, although it may demonstrate a characteristic “strain”
pattern of left ventricular hypertrophy in some patients.
DIAGNOSIS
The clinical diagnosis of aortic valve stenosis is made by
auscultating the characteristic ejection systolic murmur,
which is harsh, heard in the upper right sternal border and
suprasternal notch, and radiates to the neck.98 This murmur
may be mimicked by mitral insufficiency associated with an
“overshooting” of the posterior mitral valve leaflet directing
the regurgitant jet anteriorly and medially, giving rise to a
murmur best heard along the left sternal border and some-
times heard in the neck.115–117 Valvar pulmonary stenosis may
also be heard in the neck. An aortic ejection sound strongly
suggests the presence of a BAV. With that, many or most such
aortic valves become more stenotic.7,118–121 The ejection sound
may gradually disappear, and its absence is associated with
increasing fibrosis and calcification of the valve leaflets.122,123
FIGURE 10.15. Aortic stenosis on a
congenitally bicuspid aortic valve. Note
the eccentric poststenotic dilatation of
the ascending aorta, with a normal-sized
aortic ring. The ventriculogram illus-
trates the contraction of the severely
hypertrophied left ventricle to a very
small end-systolic volume.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 249
The first heart sound is characteristically soft, and the A 2 59-year-old man 12364016
component of S2 gradually diminishes as the stenosis becomes No aortic systolic gradient
progressively more severe. A soft diastolic murmur of aortic
insufficiency is not uncommon as the cusps become more
rigid. As the stenosis becomes more severe, an S4 becomes
prominent and may sometimes be mistaken for S1. The
peripheral pulses show an anacrotic notch and a somewhat
delayed upstroke. In general, the lower the notch, the more
severe the stenosis. The heart is usually not grossly enlarged
unless there is a significant degree of aortic insufficiency.
Radiographically, the heart is typically of normal size
unless there is significant concomitant regurgitation, possi-
bly with some calcification of the aortic valve and “postste-
notic” dilatation of the ascending aorta, as previously
described (Fig. 10.16). The ECG, even in cases of severe aortic
stenosis, may range from normal to that characteristic of left
ventricular hypertrophy with a “strain” pattern (Fig. 10.17) 67-year-old man 12364016
Severe aortic stenosis, symptomatic
and may not be helpful in the clinical evaluation of severity.
The echocardiogram shows a thickened aortic valve, which
becomes increasingly immobile as it becomes more calcified.
The LV exhibits concentric hypertrophy, and the systolic
gradient across the aortic valve can be estimated by the
velocity of the systolic jet.124,125 Similarly, aortic insufficiency
can be visualized.
On cardiac catheterization, the LV can be entered either
retrograde across the stenotic aortic valve or by transseptal
puncture from the femoral venous approach to the LA and
then the LV. Angiography shows the characteristic postste-
notic dilatation of the ascending aorta, which does not
involve the aortic ring or sinuses. Simultaneous pressures FIGURE 10.17. Electrocardiograms of a patient who developed
severe symptomatic aortic stenosis within less than 8 years. Tight
stenosis and angina were corrected by valve replacement. Note the
absence of significant electrocardiographic changes during this
interval.

across the aortic valve can be measured, and with simultane-

ous measurement of cardiac output, the valve area can be
calculated from the Gorlin formula,126,127 assuming inconse-
quential aortic regurgitation. If the patient has CHF, the
clinical picture must be modified to include left ventricular
dilation, decreased contractility, and a ventricular gallop
rhythm.

FIGURE 10.16. Posteroanterior radiograph of a patient with con-
genital aortic stenosis. The heart is slightly enlarged and has a left
ventricular configuration. The pulmonary vasculature is normal.
There is striking prominence of the ascending aorta (arrow) as a
result of poststenotic dilatation.
T REATMENT
There is no absolute aortic valve area that clearly dictates
intervention. In general, the patient who is normally active,
who has no symptoms, and in whom the clinical signs and
the echocardiogram do not suggest severe aortic stenosis can
be safely watched. Even when the evidence points to signifi-
cant aortic stenosis, the total absence of symptoms should
outweigh the objective measurements of valve orifice size in
continuing careful observation and follow-up.98 However,
with even mild changes in status that can be ascribed to the
heart, together with the physical signs of significant aortic
stenosis that are confirmed by echocardiography and cathe-
terization, surgical replacement of the aortic valve should be
seriously considered. These changes may involve merely a
subtle change in well-being or a slight decrease in exercise
tolerance.128 It is advisable to proceed with cardiac catheter-
ization when it is felt that surgery is imminent, both to
250 chapter
confirm the clinical and echocardiographic evidence and to
visualize the coronary arteries. It is not wise to wait until
major symptoms arise, because the incidence of sudden
death rises dramatically.129 In patients with AS and angina,
there is a significant incidence of coexisting CAD.105,106
Treatment involves surgical replacement of the calcified
valve130,131 by a prosthetic valve, and coronary artery bypass
grafting, if indicated. Even patients older than 80 years of
age may benefit from valve replacement; they have an opera-
tive mortality of 9.4% and a good outcome in 81% of cases
described. Porcine bioprosthesis is especially suitable in the
elderly, in whom the longevity of such prostheses is better
than when they are implanted in younger patients. Balloon
valvuloplasty has been useful in children but disappointing
(but improving) in adults, for whom the benefits are of
limited duration, especially with a stiff, calcified valve.132–135
More recently, innovations have occurred including percuta-
neous valve repair and replacement approaches, which appear
to have promise.135,136
Long-term follow-up on a large cohort of 462 patients
with congenital aortic stenosis (mostly children) showed that
with gradients of less than 50 mm Hg, medical follow-up is
appropriate, whereas with gradients of more than 80 mm Hg,
intervention is clearly indicated.130
Supravalvar Aortic Stenosis
Supravalvar aortic stenosis typically occurs in two set-
tings.137,138 Williams syndrome is a dysmorphic syndrome
caused by a mutation of the elastin gene on chromosome 7,139
most typically a deletion. Often, there is hypercalcemia in
infancy. Affected people have characteristic facies and char-
acteristic personality traits and limits in learning. As infants,
there is often pulmonary artery branch stenosis, which
regresses with time. At the time of diagnosis in infancy,
there may be no real supravalvar aortic obstruction, but over
time the aortic obstruction tends to be progressive. There is
also another group of patients with supravalvar aortic steno-
sis that is familial. These individuals appear to have autoso-
mal dominant transmission and do not have the findings of
dysmorphic features, hypercalcemia in infancy, or behav-
ioral abnormalities. On physical examination, there is
usually no ejection click, but there is a harsh ejection murmur
at the right upper sternal border that transmits prominently
into the carotid arteries. Additionally, there is a peculiar
physical examination finding, caused by the Coanda effect.
The Coanda effect causes the jet of blood passing through
the supravalvar narrowing to track along the greater curve
of the aorta and into the innominate artery and subsequently
into the right subclavian artery. This creates a higher systolic
blood pressure in the right arm than in the left arm or the
legs. While the pathophysiology seems similar to aortic valve
stenosis, there are some important differences. The coronary
artery origins are proximal to the obstruction. Since coro-
nary flow is most prominent in diastole, coronary blood flow
may be compromised in severe obstruction because blood
flow back from the aorta into the coronary arteries is com-
promised. Also, ostial stenosis is often present, causing even
more coronary compromise. As the obstruction tends to be
progressive, treatment typically consists of surgical repair
once there is more than mild stenosis.
10
Subaortic Stenosis
Subvalvar aortic stenosis has three types: membranous sub-
aortic stenosis,98,140 a fibromuscular tunnel type,98,141 and an
idiopathic hypertrophic subaortic stenosis type. Discrete
subaortic stenosis may be familial.98,142
Membranous subaortic stenosis or subaortic rings are
uncommon in adults. An aortic systolic murmur and often
an aortic diastolic murmur are present, the latter resulting
from aortic valvar regurgitation. This is postulated to be
related to damage to the aortic valve caused by the jet of
blood flowing through the obstructive membrane.143 In
patients who have a predominantly muscular ring, a charac-
teristic Brockenbrough’s sign may be observed after prema-
ture beats (i.e., a fall in the aortic systolic pressure and an
increase in the ventricular pressure after an extrasystole).
Treatment of this condition involves resection of the ring. At
surgery, the resection may be incomplete, to avoid damage
to the conduction system or the anterior leaflet of the mitral
valve.143,144
Idiopathic hypertrophic subaortic stenosis is an older
term for one of the findings in some patients with hypertro-
phic cardiomyopathy. This disorder is not discussed in this
chapter.
Pulmonary Stenosis
Pulmonary stenosis (PS) can be valvar, supravalvar, or sub-
valvar. Although pulmonary stenosis may occur as an iso-
lated anomaly, it is often associated with an ASD, VSD, or
transposition of the great arteries (TGA).
Pulmonary Valve Stenosis
Pulmonary valvar stenosis typically is caused by commis-
sural fusion and is associated with a dome-shaped valve.
Alternatively the valve may be dysplastic.145,146 The conse-
quent obstruction to right ventricular outflow results in
right ventricular hypertrophy and, when severe, an increase
in the right ventricular filling pressure. Patients with iso-
lated mild PS usually do well,147–149 whereas those with mod-
erate (peak-to-peak systolic gradient of 50 to 80 mm Hg) or
severe stenosis (systolic gradient >80 mm Hg) should be con-
sidered for intervention.150,151
Multiple peripheral PSs are rare in the adult (Fig. 10.18).
These are almost always associated with one of several clini-
cal syndromes, including the following:
1. Williams syndrome137–139
2. Noonan syndrome152,153
3. Congenital rubella syndrome154
In patients who have an associated patent foramen ovale,
right-to-left shunting at rest may occur during atrial systole
(during which the right atrial pressure exceeds that of the
LA) or during exercise or tachycardia, when the pressure in
the RA may exceed that of the LA throughout the cardiac
cycle, resulting in arterial desaturation. These elevated right
atrial pressures result from the decreased compliance of the
hypertrophied RV. The Valsalva maneuver at rest may cause
a transient increase in the right atrial pressure relative to
that of the LA during its release.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 2 51

FIGURE 10.18. Tracing the pulmonary artery pressure as the cath-

eter is being advanced distally. Note the sudden drop in pressure as
the catheter advances. This patient had the clinical pressure of
tetralogy of Fallot with a large ventricular septal defect. The obstruc-
tion to pulmonary flow was in the more distal pulmonary arteries
rather than at the pulmonary valve.

Mild PS (systolic gradient <50 mm Hg) is compatible with

a normal existence, the chief risk being infective endocardi-
tis.155 In increasingly severe degrees of PS, the degree of right
ventricular hypertrophy increases and may result in early
and significant right-to-left shunting at the atrial level if FIGURE 10.19. Posteroanterior radiograph of a patient with valvu-
there is an atrial communication, or right ventricular failure. lar pulmonary stenosis. The heart is normal in size, and there is
This is now an extremely rare eventuality when adequate striking enlargement of the main pulmonary artery (open arrow)
and the left pulmonary artery (solid arrow).
medical facilities are available and early intervention can be
instituted.

DIAGNOSIS
Pulmonary stenosis is always associated with a pulmonary
ejection systolic murmur.111 Pulmonary valve stenosis is
usually loudest at the left upper sternal border and has prom-
inent radiation to the lungs rather than the neck. On auscul-
tation, it may be difficult to distinguish from an aortic
systolic murmur because the pulmonic systolic murmur
may also be heard in the neck. Two subtle auscultatory fea-
tures help to confirm the diagnosis of PS versus AS. In PS,
the ejection systolic murmur should be heard throughout the
duration of right ventricular systole, and thus beyond A 2 and
ending with P2. Furthermore, the pulmonary systolic murmur
is better heard over the left side of the back as opposed to the
right. This phenomenon is related to the anatomy of the
pulmonary arteries; anatomically, the left pulmonary artery
is almost a direct continuation of the main pulmonary artery,
whereas the right pulmonary artery comes off at a right
angle. There is often a systolic ejection sound (click). The
ECG may be normal in mild pulmonary stenosis, but with
increasing severity, the ECG demonstrates an increasing
right ventricular hypertrophy in the chest leads and a ten-
dency to right axis deviation. The chest x-ray is characterized
by a normal heart size with a right ventricular configuration
and a left heart border showing prominence of the main and
left pulmonary arteries (Figs. 10.19 and 10.20). Calcification
of the pulmonary valve is very rare. Patients with only sub-
pulmonary stenosis do not exhibit pulmonary artery dilata-
tion. In patients whose stenosis is far advanced, increasing
cardiomegaly is present owing to enlargement of the RV and
RA. The skilled observer may suspect “decreased pulmonary FIGURE 10.20. Pulmonary stenosis with intact ventricular septum
in a middle-aged man. The cardiac shadow is unusual in that there
blood flow” by the vascular pattern on the chest film. is marked poststenotic dilatation of the main pulmonary artery. The
However, this is more reflective of the decreased pulse pres- cardiomegaly is of right ventricular configuration, typical of long-
sure in the pulmonary arteries than of decreased pulmonary standing significant pulmonary stenosis in this age group.
252 chapter
FIGURE 10.21. Electrocardiogram of a patient with severe pulmo-
nary stenosis. Note the right-axis deviation and severe right ven-
tricular hypertrophy.
flow because it is the same as the cardiac output. The echo-
cardiogram demonstrates a dome-shaped stenotic pulmonary
valve, the severity of which can be gauged by Doppler deter-
mination of the pressure gradient and assessment of coexist-
ing infundibular stenosis. Pulse oximetry can be useful to
detect an associated right-to-left atrial level shunt.
When stenosis is mild, the ECG is usually normal. With
moderate to more severe PS (systolic gradient >50 mm Hg),
right ventricular hypertrophy is seen in the chest leads, and
“P pulmonale” will be increasingly evident (Fig. 10.21).
Cardiac catheterization for direct measurement of the
systolic gradient across the pulmonic valve, combined with
simultaneous cardiac output measurements, permits calcu-
lation of valve orifice size by the Gorlin formula.126 The
catheter may cross a probe-patent foramen ovale, and, if so,
a comparison of the oxygen saturation of the pulmonary vein
and that of the systemic artery indicates whether a signifi-
cant right-to-left shunt is present. Angiography in the RV
visualizes the valve and right ventricular outflow tract
stenosis.
PROGNOSIS
In the modern era, the prognosis is usually good because the
striking murmur demands cardiac evaluation and, when
indicated, intervention. However, such patients are always at
risk for infective endocarditis.
T REATMENT
Treatment of isolated pulmonary valvar stenosis formerly
entailed surgical valvuloplasty, but increasingly, the treat-
ment of choice is percutaneous transvenous balloon valvu-
loplasty.156–159 This is the noninvasive analogue of the older
Brock procedure (pulmonary valvotomy)160 but with more
adequate dilatation of the valve. Treatment with balloon
valvuloplasty is highly successful and can be repeated if the
dilatation is inadequate or restenosis occurs.161–163 If there is
a coexisting probe-patent foramen ovale, consideration should
be given to its closure because late paradoxical embolism is
possible, but during balloon dilation, it may be protective.164
Several devices are now able to close atrial communications
by transcatheter techniques.28–51,165,166
10
Long-term follow-up of patients with PS shows that the
probability of survival is similar to that of the general popu-
lation after 25 years (95.7%) whether medically or, when
indicated, surgically/catheter treated. Survival is somewhat
shorter when associated cardiomegaly is present.145,167
Subpulmonary Stenosis
Subpulmonary stenosis is relatively uncommon as an iso-
lated lesion but is the more common type of pulmonary ste-
nosis associated with a ventricular septal defect (tetralogy of
Fallot).168 Pulmonary stenosis can be either membranous or
infundibular and may be clinically indistinguishable from
pulmonary valvar stenosis. However, pulmonary valvar ste-
nosis is associated with poststenotic dilatation of the main
pulmonary artery, which is readily seen on chest x-ray, and
the echocardiogram is definitive. When the condition is
severe, the treatment is surgical, with either resection of the
obstruction or roofing of the outflow tract by patching.169,170
On rare occasion, the “stenosis” may be caused by a tricuspid
valve aneurysm during systole.171
Mitral Stenosis
Congenital mitral stenosis (MS) in adults is uncommon.
Shone syndrome is the term used to describe the occurrence
of multiple levels of obstruction to blood flow at levels of
flow into and out of the left ventricle and in the aorta.172,173
The classic picture includes MS with a parachute mitral
valve (a single papillary muscle), subaortic stenosis, a bicus-
pid aortic valve, and coarctation of the aorta. These patients
typically require intervention in infancy and often repair
will be staged with different lesions requiring intervention
at different ages. In adulthood, the clinical picture may
resemble that of rheumatic mitral stenosis, in that there is a
long and initially asymptomatic history followed by gradu-
ally increasing exertional dyspnea and fatigability. Atrial
fibrillation may develop secondary to enlargement of the LA
as a consequence of the stenosis.
Cardiac examination does not identify the opening
snap characteristic of rheumatic mitral stenosis, and a dia-
stolic rumble may or may not be present. However, there may
be signs of pulmonary hypertension associated with a loud
P2 and an active RV. The definitive examination is echocar-
diography, both transthoracic and transesophageal. However,
hemodynamic studies at cardiac catheterization are impor-
tant for the characterization of pulmonary hemodynamics
and for the search for other features of the Shone
syndrome.
Treatment consists of excision of the mitral valve with
valve replacement, and removal of the supravalvar ring if this
is significantly stenotic.
Tricuspid Stenosis
Congenital tricuspid stenosis is extremely rare as an isolated
lesion.174,175 Most cases of adult tricuspid stenosis are acquired,
such as those associated with rheumatic fever, carcinoid syn-
drome, or right atrial myxoma.
Echocardiography provides a definitive diagnosis by dem-
onstrating a stenotic tricuspid valve with an enlarged RA.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 253
Cardiac catheterization is usually unnecessary unless the
coexistence of other anomalies cannot be entirely excluded
by echocardiography.

Atrioventricular Valvar Regurgitation

Atrioventricular (AV) valvar regurgitation, long held to always
be pathologic, is now seen as a phenomenon that may at
times be “normal” under certain conditions when it is
minimal. This has become clear with newer, highly sensitive
echocardiographic techniques. Near-instant closure of the
AV valves is dependent on normal sinus rhythm, an optimal
PR interval, and normal ventricular function. The swiftness
of AV valve closure is greatest when there is sinus rhythm
with a normal PR interval, resulting in a ventricular contrac-
tion that generates the steepest ventricular pressure rise as
a consequence of the presystolic atrial “boost.” Therefore, in
atrial fibrillation, mild valve regurgitation may occur in the
presence of a normal valve. Similarly, in marked first-degree
AV block, mild regurgitation may occur because atrial systole
is not timely. In AV dissociation or third-degree heart block,
mild AV valve regurgitation may be intermittent, depending
on the timing of atrial contraction in relation to ventricular
systole. Normally, one may see mild tricuspid regurgitation,
even with sinus rhythm. Thus, pathologic valvar regurgita- FIGURE 10.22. Posteroanterior radiograph of a patient with
tion entails more than trivial regurgitation in the presence Ebstein’s malformation of the tricuspid valve with right-to-left
of sinus rhythm and a normal PR interval. shunt. The cardiac silhouette is huge. There is prominence of the
right atrial border. The pulmonary artery segment and aorta are
inconspicuous. The pulmonary vasculature is frankly decreased.
Mitral Valve Regurgitation
Isolated congenital mitral regurgitation is rare. Rarely, an
isolated cleft in the anterior leaflet of the mitral valve can
In mild cases of Ebstein’s anomaly, there is little or no
lead to mitral regurgitation. A cleft in the anterior leaflet of
functional disturbance, and the condition is compatible with
the mitral valve usually is in the spectrum of AV canal or
a normal life expectancy. When the condition is severe, the
endocardial cushion defects.
entire inflow tract is functionally atrialized, and there is
little pump function of the RV. There is an associated atrial
Aortic Valve Regurgitation communication, with a patent foramen ovale or an ASD in
50% of patients. If right-to-left shunting occurs, cyanosis and
Congenital aortic valve insufficiency is extremely uncom-
fatigability ensue. The large “atrium” also predisposes to
mon. There have been rare reports of absence of the aortic
atrial fibrillation. The chest x-ray is characteristic and has
valve. These patients have severe aortic valve insufficiency
been described as a “pumpkin” heart (Fig. 10.22).
with severe consequences on cardiac output and ventricular
The diagnosis is made by echocardiography to delineate
function. Patients born with an absent aortic valve require
the tricuspid valve, assess right ventricular function, and
surgical valve replacement, most typically with a homograft
look for right-to-left shunting.177,179
valve, early in the neonatal period.
The ECG may show one of two patterns: Wolff-
Parkinson-White pattern180 or an unusual right bundle branch
Ebstein’s Anomaly block with a “splintered” QRS complex in V1 or V2 (Fig. 10.23).
These patients may have an accessory AV pathway that
Ebstein’s anomaly consists of downward displacement of the
predisposes to supraventricular tachyarrhythmias (SVTs).
tricuspid valve so that the septal and posterior leaflets are
adherent to the right ventricular wall, thus to a greater or
Treatment
lesser extent “atrializing” the inflow tract of the RV.176,177 The
tricuspid valve is deformed and may assume a cribriform No treatment is needed when the condition is mild.181 If there
appearance, and it is invariably associated with tricuspid is considerable atrialization of the RV and some function in
regurgitation. Some evidence has linked this anomaly to the remaining RV, tricuspid valve replacement or reconstruc-
maternal use of lithium.178 tion with closure of the ASD may be indicated.182 Electro-
The physical findings show a characteristic “quadruple physiologic studies are appropriate so that an accessory
cadence” consisting of S1, one or multiple clicks (“sail sound”) pathway can be interrupted at operation. When arrhythmias
produced by the upward motion of the billowing anterior are significant, they require treatment. These include atrial
leaflet, and wide splitting of S2 due to right bundle branch ectopic tachycardia, atrial flutter and fibrillation, atrial
block. reentry tachycardia, and ventricular tachycardia (VT).183
254 chapter 10

presurgical era was ominous with only 10% of patients sur-

viving to age 50 years. Coarctation of the aorta is the most
common congenital cardiovascular disease in Turner
syndrome.187,189

Diagnosis
There are seldom symptoms from hypertension alone.
Because blood flow distal to the coarctation is normal, lower
body development is normal, and claudication is not neces-
sarily a part of the clinical picture. In the adult, no symptoms
occur until one or more complications develop.190 The diag-
nosis is made clinically by the faint or absent pulses in the
FIGURE 10.23. Electrocardiogram of a 24-year-old man with femoral arteries in the presence of hypertension in the arms.
Ebstein’s anomaly. Note the right bundle branch block pattern, with In some instances, the femoral artery pulsations are good,
“splintering” of the QRS complex in the V2 (i.e., R’SS’S).
but simultaneous pressure measurements in the arms and
legs reveal the systolic pressure in the lower extremities to
be somewhat lower than in the arms. A bicuspid aortic valve
is present in more than half the cases.190,191 Sometimes, the
Therapy may include radiofrequency ablation.183 Severe cases
intercostal collaterals are palpable, and murmurs are audible.
of Ebstein’s anomaly, however, do not do well over the long
The chest x-ray study often shows a notch at the site of the
term. In some cases, cardiac transplantation is required.184
coarctation just distal to the aortic arch, the so-called “3”
sign (Fig. 10.24), caused by dilatation of the proximal aorta
Coarctation of the Aorta because of the hypertension and poststenotic dilatation distal
to the coarctation. There is frequently notching of the pos-
By far, the most common congenital aortic obstruction in
teroinferior border of the ribs after the second rib (Fig. 10.25).
adults is coarctation of the aorta (COA, which in adults is
These are not directly due to increased flow per se in the
almost always at or just distal to the ligamentum arteriosum
intercostal arteries but rather to the tortuosity and resulting
and the takeoff of the left subclavian artery. This anomaly
“knuckling” of the arteries from increased flow, the notches
is seen in adults who have hypertension in the arms and in
corresponding to the knuckling. Mild cases of COA are
whom there is a decrease in the pulse pressure of the femoral
sometimes found incidentally in the evaluation of a bicuspid
arteries. It is twice as common in men and is sometimes seen
aortic valve192 (Fig. 10.26).
in patients with Turner syndrome.185–187 Sometimes there is
Echocardiography is useful to assess the anatomy and
a discrepancy between the blood pressure in the two arms.
function of the aortic valve and the degree of left ventricular
This may occur because the coarctation is proximal to the
hypertrophy and to follow the diameter of the ascending
left subclavian artery stenosis or because there is an anoma-
aorta, especially after surgery. Transesophageal echocardiog-
lous origin of the right subclavian artery distal to the coarc-
raphy may or may not visualize the coarctation optimally.
tation or because the origin of the left subclavian artery is
involved in the coarctation and is stenotic.
Physiologically, there is hypertension of the arterial
system proximal to the coarctation and normal blood pres-
sure distal to the COA. Outside of infancy, the decreased or
absent pulses in the distal arteries are due not to low flow
but to a narrow pulse pressure. Invariably, in untreated
adults, the mean pressure in the distal arterial tree is normal.
Flow to the distal aorta is by a number of collaterals via arte-
rial anastomoses involving the internal mammary, intercos-
tal, and superior and inferior epigastric arteries. It has been
well demonstrated by Shepherd188 that flow distal to the
coarctation is normal at rest and in exercise. This is often
not appreciated if it is assumed that impalpable pulses are
associated with low flow. The difference in the systolic pres-
sure between the upper and the lower halves of the body is
determined by the degree of coarctation and by the caliber
and the number of the collateral vessels. Hypertension results
both from mechanical obstruction, and damping of pulsatile
flow distal to the coarctation may affect the renin-angioten-
sin system via the juxtaglomerular apparatus leading to a
high renin state.
FIGURE 10.24. Coarctation of the aorta in a 24-year-old man. Note
Mild COA initially may not be associated with hyperten- the “3” sign just beyond the aortic arch, where the indentation
sion. In general, though, the severity of obstruction is pro- (arrow) is the site of the coarctation with a dilated aortic arch proxi-
gressive and the natural history of unoperated COA in the mal to the coarctation because of the hypertension.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e
FIGURE 10.25. Posteroanterior radiograph of a patient with coarc-
tation of the aorta. The heart is not enlarged, and the pulmonary
vasculature is normal. The aortic arch is inconspicuous owing to
tubular hypoplasia of the distal segment. Rib notching (arrows) is
demonstrated.
Magnetic resonance imaging (MRI) has emerged as the most
valuable tool to completely outline the anatomy of the aortic
arch in coarctation.193,194 It can provide important informa-
tion that is helpful to direct surgical or interventional cath-
eterization procedures.195,196
Prognosis
The frequently associated congenital bicuspid aortic valve
discussed elsewhere influences prognosis separately if it pro-
gresses to significant aortic stenosis or reflux.96–98 There is
FIGURE 10.26. (A,B) Mild coarctation
found incidentally during evaluation of
aortic stenosis on a bicuspid aortic valve.
Note the characteristic poststenotic
dilatation.
255
an increased incidence of cystic medial changes in the
aorta,197 which may predispose to aortic dissection, the ini-
tiation of which may be just above the aortic valve or in the
aortic arch.198,199 Aortic rupture may occur as an infrequent
complication of dissection. Infective endocarditis may occur
at the site of coarctation or, more commonly, on the bicuspid
aortic valve. The presence of arterial hypertension from birth
predisposes to premature cerebrovascular disease and CAD
if the hypertension persists into adulthood.186,197 Cerebral
hemorrhage may occur in 20% of cases as a result of a fre-
quently associated berry aneurysm of the circle of Willis.200
In women, pregnancy increases the risk for aortic rupture,
ventricular dysfunction, and increased hypertension.201,202
Most patients who survive childhood reach adulthood
without having symptoms but hypertension, until one of the
complications supervenes.
Treatment
Treatment in adults should be undertaken as soon as the
diagnosis is made. Balloon dilatation is often performed in
the pediatric age group, but recurrence is common in native
coarctation and has limited enthusiasm.203,204 Currently,
stents have been used with better outcomes in adolescents
and adults.204 In adults, the most common form of coarcta-
tion is a discrete constriction, which is best resected with
end-to-end anastomosis.205,206 Sometimes significant resteno-
sis occurs, necessitating reintervention. Long tubular coarc-
tation is rare in adults. Cross-clamping of the aorta during
surgery does not usually cause ischemia of the kidneys or
spinal cord, because most of the distal aortic flow is via col-
laterals. Overall, most patients have been treated with
surgery over the years. There appears to be a place for balloon
angioplasty with stent placement as an alternative to surgery
is some patients. After successful correction in the adult,
hypertension often persists but is more readily controlled
medically, especially with repair in later adulthood. This
persistent hypertension appears to be related to barometer
resetting and activation of the renin-angiotensin system.
Patients must be followed clinically throughout their lives
because of the potential complications associated with
256 chapter
hypertension and the frequently associated bicuspid aortic
valve.
Complex Congenital Heart Disease
Complex congenital heart disease is a group of diseases in
which more than one cardiac abnormality is present, which
may or may not be associated with cyanosis.
Without Cyanosis
Congenital heart diseases without cyanosis have been alluded
to in separate categories. Their clinical presentation is a
composite of their individual pathophysiology. Such combi-
nations include atrial septal defects with one or more anoma-
lous pulmonary veins,66–69 Shone’s syndrome,172 Williams
syndrome (supravalvar aortic stenosis) and peripheral pulmo-
nary artery stenoses (with characteristic facies), aortic insuf-
ficiency and mitral insufficiency with Marfan syndrome,207
coarctation of the aorta or ventricular septal defect with
Turner syndrome,187 pulmonic stenosis or AV canal defect in
Noonan syndrome,153 and various degrees of AV block with
endocardial cushion defects, from first- to second- to third-
degree AV block.
With Cyanosis
These conditions involve TGA. Three categories of great
vessel transposition can be seen in the adult: D-
transposition, L-transposition, and double-outlet RV.
D-Transposition (Complete Transposition) of the
Great Arteries (D-TGA)
This form of transposition of the great arteries involves vir-
tually a direct switch between the two great arteries so that
the aorta arises anteriorly from the RV and the pulmonary
artery arises posteriorly from the LV208 (Figs. 10.27, 10.28,
10.29). It is evident that without intercommunication, these
would be two closed circuits that are incompatible with life.
Therefore, there must be a shunt at the atrial level (most
common) or at the ventricular level, or else a large PDA. In
patients with an ASD or VSD, pulmonary stenosis may be
present, which “protects” the pulmonary vasculature.209
Uncorrected D-TGA is compatible with survival into adult-
hood, but patients are invariably cyanotic. Because the dis-
ability is obvious in childhood, these patients now undergo
surgery before they reach adulthood. Echocardiography208,210
is the diagnostic modality of choice. Cardiac catheterization
is essential to characterize the pulmonary vasculature for
any consideration of surgery. Surgical treatment for this con-
dition has undergone considerable evolution, from “atrial
switching” (actually rerouting of venous blood to the appro-
priate ventricle) to present-day methods, including arterial
switching.208,211
Tetralogy of Fallot
Tetralogy of Fallot (TOF) consists of a large ventricular septal
defect in the usual position, together with pulmonary steno-
10
FIGURE 10.27. Posteroanterior radiograph of a patient with trans-
position of the great vessels, ventricular septal defect, and pulmo-
nary stenosis. The heart size is at the upper limits of normal, and
the pulmonary vasculature is slightly accentuated. The main pul-
monary artery segment is absent.
sis, either valvar or infundibular, or both.212 The large VSD
results in equal pressure in the two ventricles. The two other
features constituting the “tetralogy” are right ventricular
hypertrophy and overriding of the ventricular septum by the
dilated aorta. This malformation is compatible with surviv-
ing into adulthood.213,214 The more severe the PS, the greater
the degree of right-to-left shunting at the ventricular level
(Fig. 10.30). The more complete the arterial desaturation, the
greater the disability. Such patients not only are prone to the
usual complications of cyanotic heart disease (e.g., endocar-
ditis, brain abscess, and complications of marked erythrocy-
tosis) but may also experience sudden death, which has been
attributed to spasm of the infundibulum.215 Lesser degrees of
PS result in a lesser degree of right-to-left shunting, with a
modestly decreased exercise capacity but with the ability to
perform most normal activities. In some patients, the degree
of PS is such that the patient is not visibly cyanotic at rest
but only with exercise; such patients are said to have tardive
cyanosis.216
The usual clinical findings in the adult are cyanosis and
clubbing of the digits and a loud, harsh pulmonary ejection
murmur with spilling over A 2 to a very soft P2 of the second
heart sound, or P2 may even be absent. This murmur is often
well heard in the neck, and such radiation should not mislead
one into thinking that this is of aortic origin. Frequently,
there is a systolic ejection sound that arises in the dilated
ascending aorta. A faint blowing diastolic murmur of pul-
monary insufficiency is sometimes heard either starting
with P2 or, when P2 is inaudible, starting after a gap from
A 2.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 257

LPA
RPA
MPA

RV

A Complete transposition, VSD, hypoplasia LPA B

AO PA

Inf
FIGURE 10.28. (A–D) D-transposition
in a 28-year-old man. (D) The completely
switched position of the pulmonary
artery (PA) and the aorta (AO) is evident,
with the aortic valve anterior to the pul-
monary trunk and the pulmonary valve. RV
LPA, left PA; MPA, main PA; RPA, right C D
PA; RV, right ventricle.

FIGURE 10.29. (A,B) Double-outlet

right ventricle in a 25-year-old man with
a supracristal ventricular septal defect
with significant left-to-right shunting.
Note the kyphoscoliosis, which is not
uncommon in cyanotic congenital heart
disease.
258 chapter 10

FIGURE 10.30. This 22-year-old man

had origin of both great vessels from the
right ventricle with the ventricular
septal defect under the pulmonary valve.
(A) In this chest film note the unusual
left-sided heart border caused by the
markedly dilated pulmonary artery (PA).
(B) This ventriculogram shows both
great vessels arising from the right ven-
tricle. This patient had an Eisenmenger
physiology. AO, aorta.

T REATMENT
The first palliative operation for cyanotic congenital heart
The chest x-ray (Fig. 10.31) is characterized by a some- disease with pulmonic stenosis was the Blalock-Taussig
what globular heart of normal size, and on the lateral view anastomosis (B-T shunt), anastomosing the subclavian artery
a prominent RV can be seen “hugging” the sternum. There to the pulmonary artery, resulting in significant functional
may be a right-sided aortic arch, which deviates the esopha- improvement, with many patients reaching adulthood.218
gus and the sternum slightly to the left. If the pulmonary Surgical correction now consists of closure of the VSD and
stenosis is purely valvar and tricuspid, as occurs in about relief of the PS.169,170 If the PS is valvar, the entire procedure
20% of these cases, poststenotic dilation of the pulmonary can be performed transatrially for both the closure of the
trunk and left pulmonary artery occurs.217 With the much VSD and the pulmonary valvotomy. In patients in whom the
more common infundibular stenosis, the left heart border is
concave because the pulmonary trunk is relatively small.
This stenosis usually creates a “third chamber” just subja-
cent to the pulmonary valve.206,207 The ECG shows RV hyper-
trophy (RVH), often with a right bundle branch block pattern.
Echocardiography shows the large VSD, the overriding large
aorta, the pulmonary valvar or infundibular stenosis with
the systolic gradient by Doppler, and RVH. Cardiac catheter-
ization can quantify the pulmonary artery pressure and the
PVR and can measure the systolic gradient between the pul-
monary artery and the RV. By careful catheter withdrawal,
it is possible to quantify the systolic gradient across the valve
and also across the infundibulum, if both coexist. Right
ventriculography can indicate the size and the location of the
ventricular septal defect, and biplanar angiography demon-
strates the extent of the infundibular stenosis, if present (Fig.
10.32). Sometimes, unusual moderator bands can mimic
classic infundibular stenosis.

PROGNOSIS
Patients who reach adulthood with uncorrected tetralogy of
Fallot used to be common, but now the vast majority of such
patients are diagnosed in childhood and undergo surgery.169,170
Patients who have had a surgically placed Potts shunt or a
Waterston anastomosis may experience significant rise in
PVR,169,170 unlike those who have undergone the single
Blalock-Taussig anastomosis,218 in which pulmonary vascu-
FIGURE 10.31. Posteroanterior radiograph of a patient with tetral-
lar changes are exceedingly rare. However, a double Blalock- ogy of Fallot. The heart is normal size and boot shaped in configura-
Taussig anastomosis may result in volume overload of the tion. The pulmonary vasculature is decreased. The esophagus is
LV (Fig. 10.33). displaced toward the left by a right-sided aortic arch.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e
PA
P.V.
Inf
RV
PA
P.V.
Inf Inf
VSD
RV
RV
FIGURE 10.32. Right ventriculogram of a 40-year-old patient with
tetralogy of Fallot. In the upper panels are anteroposterior views
showing the normal relationship of the pulmonary trunk and the
ascending aorta (AO). The lower panels show an infundibular
PS is largely infundibular, it may be necessary to expand and
roof the outflow tract and the pulmonary trunk by incision
and patching. In general, the postoperative results of such
surgery have been extremely gratifying, with restoration of
full functional capacity.169,170,219,220 However, late sequelae
may include recurrent supraventricular tachyarrhythmias
related to the atriotomy, ventricular tachycardias related to
ventriculotomy, and mild right-sided CHF resulting from
ventriculotomy and pulmonary regurgitation.169,170,219,220 Such
CHF is uncommon, but when it exists, it occurs mostly in
patients who have undergone ventriculotomy, either to close
the VSD or to open up the infundibular stenosis rather than
using the transatrial approach.
Many patients with TOF have a mild degree of aortic
insufficiency, which is related more to the dilatation of aortic
root than to intrinsic valvar disease. This is almost never of
clinical significance. Over the long term, many problems
remain in patients who have undergone “total correction”:
impaired right heart function, decreased exercise intoler-
ance, and especially rhythm disorders.169,170,219–222
259
PA
Inf PA
AO Inf
RV
PA
PA
Im.V.
Inf
VSD
LV
LV RV
chamber just under the pulmonary valve (Pulm. V.) and also show
contrast from the right ventricle (RV) passing through a high ven-
tricular septal defect (VSD) into the left ventricle (LV). The ventricu-
lar septum can be clearly seen.
Pulmonary Atresia with Ventricular Septal
Defect (Pseudotruncus Arteriosus)
Pulmonary atresia may be associated with a large VSD and
is sometimes considered the extreme version of the tetralogy
of Fallot.168 A more uncommon situation exists when the
pulmonary atresia is seen with an intact ventricular septum
(PA-IVS) and a small RV that is drained by large coronary
sinusoids. The latter is almost never seen by cardiologists
treating adults.223
Pulmonary atresia associated with a VSD (PS-VSD) is
more usefully thought of clinically as an entity apart from
the tetralogy of Fallot.168 The clinical manifestations and the
surgical considerations are quite different. The pulmonary
circulation is derived entirely from large anomalous arteries
that arise from the descending aorta, often called bronchial
arteries224 (Fig. 10.34). At the junction of these arteries with
the pulmonary arteries, it is common to observe significant
stenosis, so that the distal pulmonary arteries may be of
relatively normal pressure. Pulmonary atresia can range
260 chapter 10

FIGURE 10.33. Tetralogy of Fallot in a

20-year-old woman. (A) A globular and
bulky heart with somewhat increased
pulmonary vasculature after a Blalock-
Taussig anastomosis. (B) Some decrease
in pulmonary flow is due to decreasing
shunt through the anastomosis. (C)
Striking cardiomegaly after a left-sided
Blalock-Taussig anastomosis, demon-
strating the adverse effect of marked
volume overload on the heart. (D)
Decreased heart size after spontaneous
closure of the first anastomosis.

FIGURE 10.34. (A–D) Angiogram of a 30-year-old man with pseudotruncus arteriosus. There is a rather dilated ascending aorta, no pulmo-
nary trunk is seen, and the pulmonary vasculature fills from “bronchial” arteries that arise from the descending aorta.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e
from mere atresia of the pulmonary valve, which is uncom-
mon, to atresia of the pulmonary trunk and often atresia of
the proximal left and right pulmonary arteries. These patients
are markedly cyanotic. A characteristic feature on clinical
examination is the presence of a continuous murmur
throughout the chest, arising from the stenoses of the bron-
chopulmonary anastomoses. The chest x-ray demonstrates a
large ascending aorta and aortic arch, and absence of the
pulmonary trunk and the left and right pulmonary arteries
(Fig. 10.35). There are bronchial arteries arising from the
descending aorta. Echocardiography can identify the absence
of a pulmonary artery in the presence of a large ventricular
septal defect. Cardiac catheterization is essential for the
measurement of pressures in the distal pulmonary arteries.
This is a very difficult procedure, which involves cannulat-
ing the bronchial arteries arising from the descending aorta
and threading the catheter into the distal arteries beyond the
stenoses. All the arteries arising from the descending aorta
that are supplying the pulmonary vasculature should be thus
cannulated.
Arteriography of each of these vessels is also important
to define the anatomy. If the anatomy is suitable and the PVR
acceptable, some of these patients can be considered for
staged open-heart surgery to establish continuity between
the RV and the pulmonary arteries.223 This can be performed
only in highly selected individuals and carries a significant
surgical risk.
Hypoplastic Left Heart Syndrome
Hypoplastic left heart syndrome is an unusual lesion in adult
congenital cardiology clinics. Until the 1980s, this complex
was almost universally fatal in the first year of life.225 In
1982, Norwood reported his initial experience with a complex
palliation that has subsequently become known as the
Norwood procedure.226 Classic hypoplastic left heart syn-
drome (HLHS) consists of mitral atresia or severe mitral ste-
nosis, aortic atresia or severe aortic stenosis, left ventricular
hypoplasia which is usually severe, and hypoplasia of the
FIGURE 10.35. (A,B) Pseudotruncus
arteriosus in a 24-year-old man. Note
the large ascending aorta and aortic arch
and marked concavity of the left heart
border owing to the absence of the
central pulmonary arteries.
2 61
ascending aorta. Over the past two decades, the Norwood
procedure has become standard therapy in most centers, and
in the future a cadre of these patients will survive into
adulthood.227–229
Double-Outlet Right Ventricle
A double-outlet RV (DORV) is rarely seen in the adult. Both
the aorta and the pulmonary artery arise from the RV.230 The
relationship of the great arteries is more or less usual. There
is an obligatory VSD.230 When the VSD is under the aortic
valve (Taussig-Bing anomaly), cyanosis is minimal or mild,
with left ventricular blood flowing preferentially into the
aorta and pulmonary flow coming chiefly from the RV. Right
ventricular blood goes to both great vessels but primarily to
the pulmonary artery. When the VSD is subjacent to the
pulmonary valve, the situation physiologically resembles
that of D-transposition of the great vessels with ventricular
septal defect. Diagnostic confirmation is by echocardiogra-
phy230 and by cardiac catheterization and angiography230 for
consideration of surgical correction.231,232
Tricuspid Atresia
Tricuspid atresia233 is unusual but is compatible with sur-
vival to adulthood, providing that there is a coexisting
VSD.233,234 This anomaly never occurs alone because live
birth obligates patency of the foramen ovale or, more com-
monly, a secundum type of ASD. In patients who survive to
adulthood, coexisting PS or subpulmonary stenosis is virtu-
ally always present. About one fourth of the patients also
will have transposition of the great arteries, with the aorta
arising from a hypoplastic right ventricle. Patients with tri-
cuspid atresia are invariably cyanotic because there is mixing
at both the atrial and at the ventricular level. The degree of
disability largely depends on the degree of arterial desatura-
tion. This, in turn, depends on the magnitude of pulmonary
blood flow. Patients with a large VSD and mild PS will have
the most pulmonary blood flow and be the least cyanotic
262 chapter
FIGURE 10.36. Tricuspid atresia in a 16-year-old girl. Note that
there is unusual cardiomegaly due to the greatly dilated “right
atrium,” which is actually composed of the true right atrium and
the thin-walled, atrialized right ventricle.
initially. Over time, though, there will be high pulmonary
blood flow and pulmonary vascular disease will develop. If
pulmonary vascular disease develops, standard single ven-
tricle palliations such as the Fontan procedure will be
impossible.235
Clinically, there is always marked cyanosis with club-
bing. The characteristic murmur of pulmonary stenosis can
be heard. There is some degree of cardiomegaly. On chest x-
ray study, the enlarged heart is somewhat bottle shaped, with
normal or somewhat decreased pulmonary vasculature (Fig.
10.36). There may be associated skeletal anomalies, such as
pectus excavatum and kyphoscoliosis.
The ECG shows left axis deviation in patients with nor-
mally related great arteries and normal axis in patients with
I aVR V1
II aVL V2
III aVF V3
RHY THM STRIP: II
25 mm/sec; I cm/mV
LOC 50000-0006
10
FIGURE 10.37. A 34-year-old man with tricuspid atresia and nor-
mally related great vessels. Note the left-axis deviation and the
unusual P waves.
D-TGA. The P waves are often large and bizarre (Figs. 10.37
and 10.38). Atrial arrhythmias are common, especially atrial
fibrillation and atrial flutter (Fig. 10.39). In some patients,
preexcitation or Wolff-Parkinson-White (WPW) syndrome is
notable on the ECG.236
The echocardiogram demonstrates an absence of the
inflow portion of the right ventricle. There is an ASD with
obligate right-to-left shunting, a functionally single ventricle
communicating with a rudimentary ventricle via a VSD, and
often PS. There may be transposition of the great arteries.
Cardiac catheterization provides important information
if a Fontan procedure is contemplated.235 The PVR must be
carefully quantified and adequacy of ventricular function
determined. These can be accurately obtained only with
direct measurements of pressures in the pulmonary artery
and the two atria and measurement of simultaneous flow by
the Fick method. Measurement of pulmonary artery pressure
is needed to calculate the PVR. Because even a mild elevation
of PVR greatly decreased the success of the Fontan proce-
dure,237 direct measurement is vital.
V4
V5
V6
FIGURE 10.38. A 25-year-old
man with tricuspid atresia. Note
the marked right-axis deviation
in the frontal plane. This patient
had L-transposition of the great
15569 arteries.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e
V.P. # 844 379
Tricuspid atresia
I
II
III
aVR
FIGURE 10.39. Electrocardiogram of a
young woman with tricuspid atresia and
chronic atrial flutter.
T REATMENT OF T RICUSPID ATRESIA WITH
PULMONARY STENOSIS
Earlier treatment modalities were directed toward increasing
pulmonary blood flow by creating systemic artery to pulmo-
nary artery shunts.238–242 The earliest treatment was the
Blalock-Taussig anastomosis, originally devised for tetralogy
of Fallot.218 In the Blalock-Taussig operation, a significant
portion of the partially oxygenated arterial blood is recycled
into the pulmonary vasculature for more complete oxygen-
ation. The Glenn procedure (anastomosis of the superior
vena cava to the right pulmonary artery) is another palliative
modality.243 In the Glenn procedure, no true shunt is involved,
because the operation allows the superior vena cava to bypass
the right heart and empty directly into the pulmonary artery.
However, blood from the inferior vena cava continues to
shunt from right to left, so that although there is some clini-
cal improvement, the increasing desaturation of the inferior
vena cava blood associated with work by the lower extremi-
ties, such as walking and running, results in shunting of
increasingly desaturated blood and therefore a considerable
limitation of exercise capacity.
In 1971, Fontan and colleagues237 devised an ingenious
procedure to separate the pulmonary and systemic circula-
tions. The original procedure entailed closing the ASD,
closing the stenotic pulmonary valve, and anastomosing the
RA to the pulmonary artery by means of a conduit. A modi-
fication in which the communication between the RA and
the pulmonary artery is achieved by anastomosing the right
atrial appendage to the pulmonary artery avoids the use of
prosthetic material.244 In this arrangement, flow proceeds
from the venous system to the LA entirely by the pressure
gradient between the RA and the LA. Two obligatory condi-
263
V1
17
V2.5
V3.5
V4
V5
aVL aVF
V6
V4R
tions must be met for this to succeed: a virtually passive
pulmonary vascular bed (i.e., an unequivocally normal PVR)
and a completely normal left ventricular filling pressure.245
When these conditions are rigidly met, this operation is sur-
prisingly successful and the patients are able to live relatively
normal lives with normally saturated arterial blood. However,
the cardiac output response to exercise is somewhat limited
and, therefore, so is the maximal exercise capacity.245 The
long-term results are uncertain but it appears that a signifi-
cant portion of this increasingly large patient population will
require cardiac transplantation.246–249 In adulthood, palliative
shunts should be performed only when the physiologic condi-
tions preclude a Fontan procedure and the degree of cyanosis
is severe.
Truncus Arteriosus
Truncus arteriosus is an incomplete septation of the ascend-
ing aorta and the pulmonary trunk.250,251 The semilunar
valve is a single truncus valve, which in most cases consists
of three cusps but may be either quadricuspid or bicuspid. It
is commonly insufficient, sometimes markedly so, and strad-
dles a VSD.250 Truncus defects are divided into three types.250
Type I has a common trunk, but this gives rise distally to
recognizably separate ascending aorta and pulmonary trunk
(Fig. 10.40). In type II, the truncus extends up to the right
and left pulmonary artery bifurcations, there being no sepa-
rate pulmonary trunk (Fig. 10.41). In type III, the left and
right pulmonary arteries arise from either side of the truncus.
In adults, the most common type is a type I truncus.252 Such
patients have a regurgitant truncal valve, a common mixing
chamber, and Eisenmenger’s physiology. In the very young
264 chapter
patient, the PVR may be somewhat less than the SVR, so that
surgical correction can be attempted. By adulthood, the PVR
is markedly elevated, and few if any of these patients are
candidates for corrective surgery. The remaining possible
treatment is heart-lung transplantation. When patients are
operated on in childhood, the results are promising for sur-
vival to adulthood.253
The clinical examination classically reveals cyanosis and
clubbing.251 There is usually no systolic murmur, but occa-
sionally one may be heard. The early diastolic blowing
murmur of truncal valve insufficiency is characteristic.
Depending on the degree of truncal valve insufficiency, the
heart may or may not be enlarged. Chest radiography is char-
acterized by a cardiac silhouette with a wide waist, which is
the markedly dilated truncus arteriosus. The pulmonary vas-
culature is similar to that in Eisenmenger’s complex (i.e.,
large central pulmonary arteries and no evidence of increased
10
FIGURE 10.40. Truncus arteriosus in
an adolescent. (A,B) Note the rather
characteristic wide waist of a heart with
a somewhat unusual shape but not
enlarged. The shape is in part influenced
by the presence of pectus excavatum,
which is not infrequently seen in
patients with congenital heart disease.
(C,D) The heart and great vessels, with
injection into the right ventricle. The
truncus artery is clearly seen in both
anteroposterior and lateral views, with
the truncus dividing into a separate
aorta and pulmonary artery. The ven-
tricular septal defect can be seen (D),
where the anterior right ventricle and
the posterior left ventricle are separated
by the ventricular septum.
pulmonary flow).251 Echocardiography readily visualizes the
truncal arteriosus and the truncus valve and can distinguish
the truncus subtype. Cardiac catheterization is important in
characterizing the pulmonary vasculature, especially if there
is any consideration of repair, because the PVR would need
to be significantly less than the SVR.
Note should be made of a commonly used term, pseudo-
truncus arteriosus, which is really pulmonary atresia with
VSD. Despite the single arterial outflow from the two ven-
tricles, this is really not a variant of truncus arteriosus,
because the single outflow is the ascending aorta and not a
truncus, and the valve is a competent tricuspid aortic valve
rather than a truncal valve. Pulmonary blood flow in this
lesion is via bronchopulmonary anastomoses, as described
earlier.
Aortopulmonary window or aortopulmonary septal
defect is a separate entity, different from truncus arterio-
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e
FIGURE 10.41. Posteroanterior radiograph of a patient with truncus
arteriosus type II. The heart is markedly enlarged, and no main
pulmonary artery segment is demonstrated. The right and left pul-
monary arteries are prominent, as is the aorta. The left pulmonary
artery is in an abnormally high position (arrow).
sus.254 In this condition, there is a “window” in the septum
between the aorta and the pulmonary trunk. The aorta and
the pulmonary trunk have separate semilunar valves, and
the window does not go down to and involve the semilunar
valves. If the window is large, the adult patient presents with
Eisenmenger’s syndrome (Fig. 10.42). Smaller windows may
protect the pulmonary vasculature and allow closure of the
defect.
Congenitally Corrected Transposition
Numerous attempts at standardizing the nomenclature of
this anomaly have been attempted but none has ever been
completely satisfactory. These include L-transposition of the
great arteries (L-TGA), corrected transposition (CC-TGA),
congenitally corrected transposition, and ventricular inver-
sion. The most precise description is atrioventricular discor-
dance or ventricular inversion. This “inversion” involves
both the AV valves and the semilunar valves, so that the
venous ventricle is the anatomic LV, the arterial ventricle is
the anatomic RV, and the crista supraventricularis is on the
left, as is the tricuspid valve, whereas the mitral valve is the
right AV valve. The AV conduction system goes down the left
side of the heart. The atria are not involved, and therefore
the venous return to both atria and the coronary sinus is in
the normal position. However, the aortic root and the pul-
monary trunk do not have an anteroposterior relationship
but rather a side-by-side relationship, so that the aortic root
forms the left heart border and the pulmonary trunk arises
medially. Were there no other abnormalities, this would be
a functionally “normal” heart and therefore would not belong
265
under the rubric of cyanotic congenital heart disease.255
However, such normal hearts are uncommon, and in such
cases, two common features in the natural history make it
unlikely that these patients will have a normal heart for the
rest of their natural lives. These patients are prone to develop
AV block, which may progress to third-degree block with a
narrow QRS.255,256 Although they may have Adams-Stokes
attacks, this is a less common manifestation, but exercise
tolerance may become limited because of the inadequate
chronotropic response to exercise. Furthermore, the left-
sided AV valve (i.e., the tricuspid valve) is prone to dysplasia
or to Ebstein’s anomaly.254 If the patient survives into adult-
hood, this Ebstein’s anomaly is not apt to be severe, but the
valve becomes insufficient because of systemic pressure in
the arterial ventricle. This may therefore necessitate subse-
quent valve replacement.255,256
In the vast majority of patients who reach adulthood,
there is communication at the ventricular level associated
with pulmonary stenosis. A ventricular septal defect or
sometimes even a functionally common ventricle may be
present. Such patients are always cyanotic but have a pulmo-
nary vasculature that is “protected” against the development
of pulmonary hypertension. The physical examination find-
ings are those of severe PS, together with cyanosis and club-
bing. The chest x-ray shows a normal heart size, very often
with a straight left heart border, this being the ascending
aorta (Figs. 10.43 and 10.44). The heart may have an unusual
contour if the inverted RV is prominent (Fig. 10.45). The ECG
FIGURE 10.42. Posteroanterior radiograph of a patient with
ventricular septal defect and severe pulmonary vascular disease
(Eisenmenger’s syndrome). The heart is moderately enlarged, and
the central pulmonary artery is distinctly enlarged, whereas the
peripheral pulmonary vasculature is normal. The main pulmonary
artery is huge (arrow) as a result of long-standing pulmonary
hypertension.
266 chapter
FIGURE 10.43. Congenitally corrected transposition in a 35-year-
old man with ventricular septal defect and no pulmonary stenosis.
Note the straight left-sided heart border, which is formed by the L-
transposed ascending aorta and the inverted right ventricle.
10
shows evidence of right ventricular hypertrophy and first-,
second-, or third-degree AV block (Figs. 10.46 and 10.47).
The echocardiogram is characteristic.255 The inversion of
the ventricles can be identified by the presence of the crista
supraventricularis in the arterial ventricle, the clearly
switched AV valves, and the unusual position of the two
semilunar valves. Because the aorta and the tricuspid valve
are now on the same side, the aortic valve and the left-sided
(tricuspid) AV valve are not in continuity, as would be the
relationship between the aortic and the mitral valves in the
normal heart. Ebstein’s anomaly of the left-sided AV valve
can also be visualized if present. The VSD and PS can be
further identified. For purposes of possible surgical treat-
ment, one needs to know whether the ventricular communi-
cation is a functionally common ventricle or a large VSD.
Cardiac catheterization is important for characterizing
the hemodynamics, including ventricular function, the
degree of pulmonary stenosis, and the PVR. These data are
especially important in patients who have a common ven-
tricle, with the possibility of a modified Fontan procedure as
a therapeutic option. Angiography can quantify the degree of
left AV valve insufficiency and the respective positions of the
two great arteries. The pulmonary stenosis can be confirmed
as being either valvar or subvalvar. Angiography also helps
FIGURE 10.44. (A–D) An 18-year-old
woman with congenitally corrected
transposition of the great vessels and a
common ventricle. (A,B) The anteropos-
terior views show that the ascending
aorta forms the left-sided heart border
and the pulmonary trunk arises more
medially. (C,D) The lateral views show
that the semilunar valves are more side-
to-side than anteroposterior to each
other.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 2 67

38EC 38EC
R

I aVR
Au
.5

II aVL
3 0.5
F

III aVF
V1 M
1.0

1.0
V1 V4
V2 0.5 1.0

V2 V5
V3 .5 1.0
FIGURE 10.45. Posteroanterior radiograph of a patient with cor-
rected transposition, ventricular septal defect, and pulmonary ste-
nosis. The heart is slightly enlarged, and the pulmonary vasculature
is within normal limits. There is a prominent bulge at the left heart
contour (arrows), representing the inverted right ventricle. The pul- V3 V6
monary segment is absent because the main pulmonary artery lies
centrally within the mediastinum and is no longer border 1.0 1.0
forming.

V1
FIGURE 10.46. Electrocardiogram of a 43-year-old patient with
to detail the anatomy of the coronary arteries, which undergo congenitally corrected transposition with pulmonary stenosis and
a curious “rotation.” ventricular septal defect. Note the absence of Q wave in the lateral
Patients who start out in life with a “normal” heart chest leads. This is because of the ventricular inversion, with the
usually have trouble eventually with the supervention of septum depolarizing from right to left rather than from left to
right.
various degrees of heart block and with insufficiency of the
left-sided AV valve. The prognosis for patients who have VSD
with PS has improved considerably with modern surgical
therapy. However, these patients are still susceptible to infec-
tive endocarditis. Even with correction of the left-sided AV
valve insufficiency, the anatomic RV may not perform opti-
mally over the years.257,258

T REATMENT
The treatment of this lesion is surgical.255,258 Because the
clinical profile of such patients closely resembles that of
tetralogy of Fallot, many of them have undergone a Blalock-
Taussig shunt anastomosis with marked improvement in
functional capacity and arrive at adulthood only mildly cya-
notic.259 Although they may not be functional class I, they
may still be quite functional but receptive to future surgical
procedures.260,261
For patients who have an ventricular septal defect and
FIGURE 10.47. Electrocardiogram of a 54-year-old woman with a
pulmonary stenosis, closure of the VSD and pulmonary val- third-degree heart block. She did well over the years, but eventually,
votomy would seem reasonable. The approach to the defect the inadequate chronotropic response to exercise necessitated a
from the right side in this lesion, however, is technically pacemaker.
268 chapter 10

difficult. Patients with a common ventricle and pulmonary

stenosis may be eligible for a modified Fontan proce-
dure,235,237,244 provided that the PVR and ventricular filling
pressure are normal. This can be accomplished by converting
the heart into one with tricuspid atresia by closing the tri-
cuspid valve and placing a conduit between the RA and the
pulmonary artery.

Great Vein Malpositions

Partial Anomalous Pulmonary Venous

Return (Connection)
Partial anomalous pulmonary venous return (PAPVR) is
physiologically similar to left-to-right shunting at the atrial
level.262 There may be one, two, or three pulmonary veins
that are anomalously connected, and they may drain together
or separately into the innominate–superior vena cava system,
coronary sinus, RA, or inferior vena cava. These constitute
pure left-to-right shunts. When all four pulmonary veins
connect anomalously (i.e., total anomalous pulmonary
venous connection, TAPVC) and drain eventually into the
RA, there is an obligatory ASD, the RA becoming a mixing
FIGURE 10.48. Posteroanterior radiograph of a patient with total
chamber, with right-to-left shunting at the atrial level.
anomalous venous return to the left superior vena cava. The heart
is mildly enlarged, the pulmonary vasculature is increased, and the
dilated left and right portions of the superior vena cava are clearly
Total Anomalous Pulmonary Venous Connection demonstrated (arrows); snowman heart.
Total anomalous pulmonary venous connection is uncom-
mon in the adult.262 The most common form is type I, in
which the pulmonary veins drain via a large ascending verti-
cal vein into the left innominate vein and then to the supe-
rior vena cava. Less common is type II, in which the veins
drain into a left superior vena cava and then into the coro-
or “figure-eight” configuration of the heart and great vessels
nary sinus. In type III, the pulmonary veins join to form a
(Fig. 10.48). The echocardiogram can identify the drainage
long anomalous vein into the inferior vena cava or even into
site of most or all of the pulmonary veins if the echocardiog-
the portal vein. Type III is not seen in adults and, if not cor-
rapher is compulsive in identifying all pulmonary veins or
rected during the first few weeks of life, is usually fatal. One
alerted beforehand to the diagnosis. Sometimes a transesoph-
may also see a combination of connections, with the veins
ageal echocardiogram may be required. Cardiac catheteriza-
draining separately but ultimately into the RA.262
tion is helpful in obtaining the oxygen saturations in all
In all situations, the oxygen saturation in all four cham-
cardiac chambers and in the pulmonary artery and aorta to
bers should in theory be identical, but in fact, this is not
give one a clue as to the likely connections. The anomalous
necessarily so. Drainage into the inferior vena caval system
connections can be individually cannulated, and angiograms
causes the relatively more oxygenated blood to stream pref-
of these anomalous veins and the exact anatomy are
erentially through the ASD so that the left heart chambers
extremely helpful to the surgeon, especially if they drain to
are somewhat more saturated than the right heart chambers.
different sites (Fig. 10.49). It may be necessary to explore the
When the connections are by the superior vena caval system,
superior vena cava and innominate vein, the coronary sinus,
there is apt to be more nearly equal saturation in all four
and the inferior vena cava. Selective indicator dilution curves
chambers. If all four veins drain to the coronary sinus, the
in the four pulmonary arteries or selective angiography of
right ventricle and the pulmonary artery may have a higher
these vessels can help identify the connections if the anoma-
oxygen content than the left side of the heart.
lous veins are not draining together. Today, computed tomog-
Clinically, patients may exhibit cyanosis and clubbing,
raphy (CT) and MRI are increasingly used to identify the
but the cardiac findings are similar to those of the secundum
pulmonary venous anatomy.263
type of ASD, with a wide, fixed splitting of the second heart
sound and a hyperactive LV. The ECG is also similar, with
Treatment
incomplete right bundle branch block with rSR´ in lead V1
and a normal frontal plane QRS axis. The chest x-ray is most The treatment is surgical. The type of connection that is
striking if all four pulmonary veins drain into a venous most readily amenable to surgery is anomalous pulmonary
sinus, then into a common vertical vein and into the innomi- venous connection of the snowman type, by a side-to-side
nate vein, and then to the superior vena cava. The marked anastomosis of the common venous sinus to the LA and liga-
dilatation of this system gives rise to the so-called “snowman” tion of the vertical vein.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e
FIGURE 10.49. This 35-year-old patient
had total anomalous pulmonary venous
connection via a large vertical vein to
the superior vena cava. (A) Chest x-ray
shows the characteristic “snowman” or
figure-eight configuration. (B) Angio-
gram shows the large horizontal vein,
being the confluence of the pulmonary
veins, which drains by a vertical vein
into the innominate vein and thence
into a greatly dilated superior vena
cava.
Coronary Artery Anomalies
Coronary artery anomalies can be divided into four
types.265–267 The first is anomalous origin of the right coro-
nary artery from the left coronary artery, or a branch of the
left coronary artery from the right coronary artery, or if the
left anterior descending coronary artery and the circumflex
artery have separate ostia. These patients are asymptomatic
and do well unless they acquire coronary atherosclerosis.
A second type is an ectopic course of the left coronary
artery, so that instead of coursing anterior to the pulmonary
artery, it goes between the aorta and the pulmonary artery.266
Sudden deaths have been reported with this anomaly. It is
likely that the pathophysiology is not compression of the
coronary artery between the aorta and the pulmonary artery,
as has been suggested, because the pulmonary artery is
essentially a low-pressure vessel. Rather, the course of the
coronary artery shortly after its origin from the aorta is at a
somewhat acute angle, which, during vigorous exercise, may
become more acute, with resultant myocardial ischemia.
The other anomaly in this group is myocardial bridging, in
which the epicardial coronary artery dives under the myo-
cardium and then reemerges. During systole, the vessel
undergoes compression. Most such cases are asymptomatic,
but an occasional patient has angina and a positive stress test
result that is relieved when the bridging is unroofed.268,269
A third anomaly involves fistulas between the coronary
arteries and the ventricular cavity.270 A coronary artery may
empty distally directly into a cardiac chamber. This more
commonly involves the right coronary artery, which drains
into the RV. More often, the coronary artery drains into a
telangiectatic structure, which then empties into the RV.
Clinically, such patients are usually asymptomatic, but the
physical examination may reveal a soft, continuous murmur
over the precordium, more commonly near the left sternal
border if the right coronary artery is involved. If the shunt
is large, there may be a “steal” phenomenon, which may
rarely cause angina. The treatment may be either surgical or
selective embolization of the distal telangiectatic lesion.
Angiographically, this lesion is seen at the terminus of a
269
greatly enlarged coronary artery as a “puddle” from which
contrast enters the RV. Fistulas of small coronary arterial
branches are sometimes seen in routine angiograms and are
of no hemodynamic significance.
If coronary artery fistulas are asymptomatic, it seems
that they can be safely watched. Although the details of the
lifelong mortality risk of such an anomaly are not entirely
known, the evidence that exists suggests that the mortality
risk of such fistulas is extremely small and would not neces-
sarily warrant surgical intervention.271
Finally, there may be an anomalous origin of a coronary
artery from a pulmonary artery.272 In this situation, the effect
is that of a large coronary artery steal because the pulmonary
artery is under low pressure. Therefore, anomalous origin of
the left coronary artery from the pulmonary artery is seen
less commonly in adults because it is usually symptomatic
or fatal in childhood unless it is treated. Formerly, the recom-
mended treatment was ligation of the anomalous artery, but
current treatment involves both ligation of the anomalous
coronary artery at its takeoff from the pulmonary artery and
bypass grafting. In the adult, anomalous origin of the right
coronary artery from the pulmonary artery is somewhat
more common and is usually asymptomatic, although it has
been implicated in sudden death.
Aneurysms of the Sinus of Valsalva
Congenital aneurysm of the sinus of Valsalva is caused by a
weakness at the junction of the aortic media and annular
fibrosis of the aortic valve.273 By far the most commonly
involved sinus is the right aortic sinus. The aneurysm
usually protrudes into the outflow tract of the RV or, less
commonly, into the RA. Aneurysm of the posterior sinus is
much less common, and that of the left coronary sinus
is extremely rare. An aneurysm of the sinus of Valsalva is
asymptomatic until it ruptures, at which time a sudden
large left-to-right shunt develops into the RV or RA, with
dyspnea due to pulmonary congestion and even pulmonary
edema.274 The physical findings are those of an arteriovenous
270 chapter
fistula (i.e., a loud, continuous murmur over the precor-
dium). The diagnosis is made clinically by the history and
physical findings and is corroborated by echocardiography,
which can locate the fistula and visualize the shunt. This
can also be accomplished by aortic root angiography. The
treatment is surgical.
The sinus of Valsalva aneurysm itself is a potential site
for infective endocarditis and occasionally is the cause of
rupture.
Pregnancy and Congenital Heart Disease
During pregnancy, there is an increase in intravascular
volume starting in the second trimester, reaching a peak at
32 weeks, and declining slightly thereafter until term.201,220,275
There is a corresponding rise in cardiac output owing to the
increased volume and the vascularity of the gravid uterus.276,277
During the first stage of labor, the hemodynamic alterations
are intermittent and transient. The pulmonary artery wedge
pressure may rise with each uterine contraction and fall
promptly with relaxation, the rise in pulmonary wedge pres-
sure being due to a sudden increase in intravascular volume
by up to 500 mm Hg, caused by the contracting uterus.
During the second stage of labor, however, vigorous bearing
down constitutes a series of giant, prolonged Valsalva maneu-
vers. During the third stage, there is a loss of blood of about
500 mL and a transient rise in cardiac output without a sig-
nificant change in arterial blood pressure, which translates
into a lower SVR.277–279
Patients with noncyanotic heart disease with left-to-right
shunting and normal to moderately elevated PVRs usually
tolerate pregnancy well.280,281 Patients with ASD, PDAs,
small-to-moderate VSDs, and mild valvar stenosis or insuf-
ficiency can also be safely carried through pregnancy. Coarc-
tation of the aorta carries a higher risk during pregnancy
because of possible aortic dissection, aortic rupture, or sub-
arachnoid hemorrhage from a berry aneurysm, which is
sometimes associated with coarctation of the aorta.282 In all
of these situations, salt restriction to prevent a dispropor-
tionate rise in the intravascular volume is of great impor-
tance. It is especially important in coarctation of the aorta,
in which management of the intravascular volume should
coincide with control of hypertension, if present. Salt restric-
tion may also help to control hypertension. However, if drug
therapy becomes necessary, the inevitable question of fetal
toxicity arises. Verapamil has been used during pregnancy
to treat fetal tachycardias without documented fetal toxicity.
However, nifedipine has been associated with a high rate of
cesarean section and low-birth-weight infants. The beta-
blockers propranolol and atenolol have been associated with
low birth weight, tachycardia, and hypoglycemia. Metoprolol
has been well tolerated, as has labetalol. There have been rare
reports of adverse effects on the fetus with angiotensin-con-
verting enzyme (ACE) inhibitors. Diuretics have not been
shown to be directly deleterious to the fetus, although they
may decrease placental perfusion. The combination of thia-
zide diuretics and methyldopa has apparently been shown to
be safe and effective. There have been reports, however, that
thiazides, which cross the placental barrier, are associated
with neonatal thrombocytopenia and hyponatremia. Thus,
10
drugs should be reserved for pregnant women who have clear-
cut hypertension that cannot be controlled with salt restric-
tion alone.281
In patients who have mechanical cardiac prostheses280 or
who might have thromboembolic phenomena caused by
secondary erythrocytosis in cyanotic heart disease, use of
warfarin should be avoided because of its substantial terato-
genicity and fetal wastage. Heparin does not cross the pla-
cental barrier because of its molecular size and is the drug
of choice for anticoagulation.283 In the presence of erythro-
cytosis, self-administration of subcutaneous heparin is prac-
tical.284 For mechanical prostheses, however, more careful
monitoring of the activated partial thromboplastin time is
necessary, and intravenous administration of heparin via a
heparin lock may be necessary. It is precisely these consid-
erations that may make it advisable for women of childbear-
ing age who have severe congenital valve disease necessitating
valve replacement to opt for a bioprosthesis, if they wish to
bear children, with the full understanding that a second
operation will in all likelihood be necessary some years later,
after childbearing has been completed.
For cardiac arrhythmias, digoxin has a long history of
safety in pregnancy. Although by itself, it may not be espe-
cially effective, in combination with other drugs, it can be
useful.285 In general, quinidine has had a reasonable record
of safety, although rarely it causes damage to the eighth
cranial nerve of the fetus. Disopyramide, verapamil, meto-
prolol, and labetalol have a reasonable safety record.286,287 The
conduct of labor in patients with serious valve disease and
cyanotic heart disease optimally should include Swan-Ganz
catheterization for monitoring of the pulmonary artery
wedge and right atrial pressures, constant blood pressure
monitoring, and oximetry.288 Vaginal delivery, with shorten-
ing of the second stage of labor by forceps delivery, if neces-
sary, is feasible in most patients. However, intractable and
serious elevation of the pulmonary artery wedge pressure,
significant fall in arterial oxygen saturation, or intractable
hypertension or hypotension or fetal distress should raise a
serious consideration of cesarean section.
The first stage of labor usually does not cause serious
hemodynamic disturbances, except transiently during con-
tractions. However, the second stage should be shortened by
forceps if safely feasible, and anesthesia, which minimizes
vasodilatation, should be given. The third stage may be dan-
gerous in cyanotic patients, in whom the fall in SVR after
delivery, combined with blood loss, may suddenly increase
right-to-left shunting. The fall in blood pressure and arterial
desaturation may cause progressive deterioration, with a
fatal outcome. Therefore, every effort should be made to
replenish lost intravascular volume and to maintain blood
pressure and adequate oxygenation. Such patients should
have been typed and cross-matched, with blood available and
arterial vasoconstrictors on hand to maintain the blood pres-
sure and thus increase the SVR if necessary if sudden hypo-
tension occurs. Cesarean section itself is not without risk.
There is the risk posed by general anesthesia, the greater
blood loss, and the supine hypotension phenomenon of preg-
nancy (postulated to be due to compression of the inferior
vena cava by the gravid uterus). Therefore, cesarean section
is an option only when it appears that vaginal delivery is
posing an unacceptable risk.277,289
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e
Eisenmenger’s syndrome carries a high risk, as high as
38%, and causes considerable fetal wastage.281
Intrapartum open-heart surgery is almost never neces-
sary with careful medical management and is associated
with a high incidence of fetal wastage. Patients with tight
aortic or pulmonic valve stenosis may be considered for
balloon dilatation, preferably well after the first trimester
but before the intravascular volume has peaked.290
In general, with careful medical management, most
women with congenital heart disease can carry a pregnancy
safely to term, with the risk being somewhat higher in cya-
notic congenital heart disease. The risk is not only to the
mother but also to the fetus, because fetal wastage is higher
in cyanotic conditions. The causes are not entirely clear but
are probably multifactorial because fetal hemoglobin satu-
rates at relatively low oxygen tensions. The placental circula-
tion is probably adversely affected by low oxygen tension and
erythrocytosis.291 Women with repaired cyanotic heart
disease, such as transposition of the great arteries, may suc-
cessfully complete pregnancy292; however, maternal and fetal
complications, as well as genetic risks do play a role.
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 1 Echocardiography in the
1 Adult with Congenital
Heart Disease
Julie A. Kovach
Indications for Echocardiography in the Evaluation of
the Adult with Congenital Heart Disease . . . . . . . .
Indications and General Segmental Echocardiographic
Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abnormalities of Cardiac Septation. . . . . . . . . . . . . . . . .
Abnormalities of Venous Inflow. . . . . . . . . . . . . . . . . . . .
Abnormalities of Ventricular Inflow . . . . . . . . . . . . . . . .
Key Points
• Echocardiography, because of its excellent spatial
resolution and ability to assess both anatomy on two-
dimensional imaging and physiology by Doppler, is espe-
cially suited to the diagnosis and follow-up of adults with
congenital heart disease.
• Indications for echocardiography in this patient popula-
tion have been published.
• In the previously undiagnosed adult with suspected con-
genital heart disease, a careful segmental approach to
scanning is required to make a complete diagnosis.
• Echocardiography of adults with congenital heart defects
should be performed and interpreted by personnel trained
in the care of these patients.
• Echocardiography of adults with congenital heart disease
requires knowledge of the anatomy and natural history
of unoperated defects, awareness of the possible palliative
or corrective procedures for the defect, and awareness of
the potential complications, sequelae, and residua of the
repair.
Indications for Echocardiography in the
Evaluation of the Adult with Congenital
Heart Disease
Thanks to advances in antenatal and postnatal diagnostic
methods, rapid progress in surgical options and technique,
improvements in perioperative management, and meticulous
care by pediatric cardiac specialists, over 85% of children
born with cardiac anomalies survive well into adulthood.
The 32nd Bethesda Conference sponsored by the American
Abnormalities of Ventricular Number or
279 Morphology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
Conotruncal Abnormalities . . . . . . . . . . . . . . . . . . . . . . . 296
280 Obstruction to Ventricular Outflow . . . . . . . . . . . . . . . . 300
282 Miscellaneous Congenital Anomalies. . . . . . . . . . . . . . . 303
291 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
292
College of Cardiology estimated that over 800,000 adults
with congenital heart defects were living in the United States
as of the year 2000.1 Based on birth rates and disease inci-
dence, one group of investigators estimated that there are
currently up to 1.33 million U.S. survivors with congenital
heart disease born since 1940, 56% with simple lesions, 30%
with moderately complex lesions, and 14% with more severe
lesions.2 An additional 3 million Americans have bicuspid
aortic valves. Adults, most of whom have undergone some
operation to repair or palliate their defect, will soon outnum-
ber children with congenital cardiac defects. The long-term
clinical course of these patients will be determined by both
their congenital and acquired cardiovascular conditions,
which require accurate diagnosis, diligent ongoing follow-up,
and continued management.
Echocardiography plays an essential role in the diagnosis
and management of patients with congenital heart disease.
For an unselected cohort of children and adolescents referred
for evaluation of a cardiac murmur, echocardiography identi-
fied congenital cardiac lesions in 12% of subjects diagnosed
to have a functional murmur on history and physical exami-
nation performed by experienced congenital cardiologists.
For 152 individuals who underwent auscultation, the diag-
nosis by echocardiography was discordant in 19% of patients,
with a major discordance recorded in 6%.3 In many cases,
echocardiography supplants invasive diagnostic techniques
in patients who proceed to complete repair, palliation, or
reoperation without the need for cardiac catheterization.
Transthoracic echocardiography (TTE) with two-dimensional
(2D) imaging and color4 and spectral Doppler affords accurate
and complete characterization of cardiac anatomy and hemo-
dynamics in the majority of adults with congenital heart
disease. For patients with limited acoustic windows due to
279
280 chapter
prior operations, body habitus, coexistent lung disease, or
atypical cardiac location within the chest, or those with
structures not accessible to TTE, transesophageal echocar-
diography (TEE) provides direct visualization with excellent
resolution.5–8 In the operating room, TEE provides invaluable
assistance to the surgeon in determining the nature of the
surgery, assesses adequacy of repair, and rapidly identifies
any immediate complications, thus reducing operative mor-
bidity and mortality.9,10 Interventional cardiologists use TEE
or intracardiac catheter-based echocardiography for guidance
during transcatheter procedures, especially for placement of
closure devices for atrial septal defects (ASD) or patent
foramen ovale (PFO).11–17 Three-dimensional echocardiogra-
phy, a promising technique with rapidly improving image
quality and speed of image acquisition and rendering, has
added to the understanding of congenital heart disease,
including ASD closure, and facilitated the diagnosis of cor
triatriatum, an uncommon congenital defect.18–22 Diagnosis
of cardiac abnormalities in utero by fetal echocardiography
promotes better counseling and education of families. In
addition, fetal echocardiography facilitates earlier planning
of postnatal management by physicians and parents, includ-
ing possible surgery.23
Adults with previously undiagnosed congenital cardiac
defects, many with minimal hemodynamic consequences up
to that time, require a similar echocardiographic approach
to that called for in children. It is not unusual for a small
ASD without significant left-to-right shunt to be first diag-
nosed on routine TTE performed for other indications.
However, important differences exist between most adults
with previously diagnosed or repaired congenital heart
defects and their pediatric counterparts, and these differ-
ences necessitate additional considerations for the acquisi-
tion and interpretation of echocardiographic images in these
patients. Adults typically have more difficult acoustic
windows with less clear images than children owing to
larger body size, prior surgeries, and coexisting conditions
that can affect image quality such as lung disease. Echocar-
diographic contrast agents may improve diagnostic accuracy
for assessment of ventricular function and diagnosis of
certain anomalies such as apical hypertrophic cardiomyopa-
thy or noncompaction of the left ventricle in these patients.24
Age- and body habitus–associated changes in cardiac posi-
tion within the chest, cardiac malposition at baseline, or the
presence of conduits may require the use of multiple imaging
planes from varied ultrasound transducer positions on the
chest wall that differ from standard transducer locations.
“Adult” cardiovascular diseases like hypertension and ath-
erosclerotic coronary or peripheral arterial disease may alter
the “typical” physiology of a congenital defect; for example,
a small secundum ASD with no significant shunt when the
patient is 20 years of age may cause right ventricular volume
overload at age 50 when blood pressure is higher and ven-
tricular compliance is less. Patients with unoperated cardiac
lesions will exhibit expected complications of that defect as
determined by the underlying lesion. Importantly, adults
with congenital abnormalities that were “successfully”
repaired or palliated in childhood, including adults with
“cured” ASD and coarctation of the aorta, may have residua
or late complications of the repair or sequelae of unrepaired
components of the defect. The echocardiographer must have
11
knowledge of the echocardiographic features of the isolated
unrepaired defect, understand the potential repairs or correc-
tive operations for each defect (especially since the patient
may not know the nature of his operation), and examine for
potential complications, residua, or late sequelae of unoper-
ated defects or surgical repair or palliation. Thus, echocar-
diography in the adult with congenital heart disease demands
a thorough and careful systematic approach.
This chapter emphasizes the general approach to the
examination, outlines echocardiographic features of common
defects that may first appear in adulthood, briefly reviews
the echocardiographic characteristics of lesions that were
most likely diagnosed and operated in childhood, presents
the usual appearance of standard operative (and transcathe-
ter) procedures for congenital cardiac anomalies, and dem-
onstrates the echocardiographic findings of the most common
late complications or sequelae of palliation or correction.
Both 2D TTE and TEE have widespread use in these patients
and are presented in detail. M-mode echocardiography, which
at one time was utilized for the diagnosis of certain cardiac
defects, has minimal clinical application at present and is
not discussed. Like pediatric patients, adults with previously
undiagnosed congenital heart anomalies benefit from a
sequential, segmental approach for the determination cardiac
anatomy.
Indications and General Segmental
Echocardiographic Approach
The American College of Cardiology/American Heart Asso-
ciation Task Force on Practice Guidelines (Committee on
Clinical Applications of Echocardiography) noted the follow-
ing reasons for adult congenital patients to seek care from a
cardiologist and for which they might need an echocardio-
gram: (1) an initial diagnosis of congenital heart disease; (2)
a previously recognized congenital heart disease that is pres-
ently inoperable; (3) a progressive clinical deterioration, such
as ventricular dysfunction or arrhythmias due to the natural
history of their defect; (4) the patient becomes pregnant or
has other stresses such as noncardiac surgery or infection,
including infective endocarditis; (5) the patient has residual
defects after a palliative or corrective operation; (6) the patient
develops arrhythmias (including ventricular tachycardia,
atrial flutter, or atrial fibrillation) that may result in syncope
or sudden death; (7) a progressive deterioration of ventricular
function with congestive heart failure; (8) progressive hypox-
emia because of the inadequacy of a palliative shunt or the
development of pulmonary vascular disease; or (9) the patient
requires monitoring and prospective management to main-
tain ventricular or valvular function or to prevent arrhyth-
mic or thrombotic complications. The task force recommended
that cardiac sonographers and physicians who perform and
interpret echocardiograms for these patients have special
competency in congenital heart disease or refer the patient
to a cardiologist (either adult or pediatric) who is trained in
the care of adults with congenital heart disease. Based on
these considerations and the available literature, the task
force issued guidelines for indications for the performance of
2D and Doppler echocardiograms in the adult patient with
congenital heart disease (Table 11.1).25
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se 2 81
TABLE 11.1. Indications for echocardiography in the adult patient with congenital heart disease
Class I Patients with clinically suspected congenital heart disease, as evidenced by signs and symptoms
Patients with known congenital heart disease when there is a change in clinical findings
Patients with known congenital heart disease for whom there is uncertainty as to the original diagnosis or when the
precise nature of the defect is unclear
Periodic echocardiograms in patients with known congenital heart disease for whom ventricular function and
atrioventricular valve regurgitation must be followed
Patients with known congenital heart disease for whom pulmonary artery pressure is important
Periodic echocardiography in patients with surgically repaired or palliated congenital heart disease with the following:
change in clinical condition, clinical suspicion of residual defects, left or right ventricular function that must be
followed, the possibility of hemodynamic progression, or a history of pulmonary hypertension
To direct interventional catheter valvotomy (or other interventions as necessary) in the presence of complex cardiac
anatomy
Class IIb Annual or biennial follow-up Doppler echocardiographic study in patients with known hemodynamically significant
congenital heart disease and no evident change in clinical condition
Class III Multiple repeat Doppler examinations in a patient with repaired patent ductus arteriosus, atrial septal defect (ASD),
ventricular septal defect (VSD), coarctation of the aorta, or bicuspid aortic valve without change in clinical condition
Repeat Doppler examinations in patients with known hemodynamically significant congenital heart lesions

In general, the echocardiographic approach to the previ-
ously undiagnosed patient is anatomically sequential fol-
lowing the course of blood flow through a normal heart and
focusing on the presence or absence and location of cardiac
structures, with attention to morphology, relationships and
connections to one another. This approach is summarized
below. The sonographer must recognize that standard
imaging planes may not be helpful and adapt scanning as
necessary. “Unusual” transducer positions, including high
parasternal, laterally displaced apical, and even right-sided
or posterior thorax locations may be required to image
certain structures. Importantly, the ultrasound plane should
be purposefully aligned to visualize a specific structure of
interest. For previously operated patients, the cardiac sonog-
rapher must have knowledge of possible types of repairs for
a particular anatomic defect and use whatever clues are
available to examine the repair if the patient does not know
the nature of her surgery. For example, an adult with tetral-
ogy of Fallot who has an isolated scar on the right lateral
thorax and no right radial pulse may have been palliated in
childhood with a Blalock-Taussig shunt, and therefore might
need a right supraclavicular transducer position with
Doppler to evaluate for shunt obstruction and to estimate
pulmonary artery pressure. Finally, the examination must
include sufficient views to evaluate all intracardiac and
extracardiac structures, the normality or abnormality of
these structures, and the hemodynamic consequences of
anatomic alterations. The patient should not leave the labo-
ratory until every attempt has been made to answer all the
questions.
The first step of the examination, especially in the previ-
ously undiagnosed patient, is to determine visceral and atrial
situs and cardiac position within the chest (normal or levo-
cardia, dextrocardia, or mesocardia). This is most easily
accomplished from a subcostal transducer position and
transverse imaging plane in the upper abdomen. Since atrial
situs and visceral situs are usually concordant, a right-sided
liver and inferior vena cava and left-sided gastric bubble and
aorta are almost always associated with atrial situs solitus,
whereas a left-sided liver and right-sided gastric bubble indi-
cate atrial situs inversus. Since visceral-atrial discordance is
almost always accompanied by complex congenital defects,
it is usual that that diagnosis would already have been made
in childhood, so this is of little concern in the previously
undiagnosed adult. Additional clues to the determination of
atrial situs include the presence of the inferior vena cava
draining into an atrium (almost always the right atrium) and
atrial morphology. Some patients have an absent inferior
vena cava associated with anomalous drainage into the
azygous vein in the right chest, so the absence of the inferior
vena cava on ultrasound is not helpful in determining atrial
situs. The right atrium is broad-based and triangular (“puppy
dog’s ear” appearance) and is associated with a eustachian
valve while the left atrium is narrow-based, longer (“finger”
appearance), and is not associated with a eustachian valve.
In addition, the septal surface of the left atrium contains the
flap valve of the fossa ovalis. Rare patients have bilateral
right or left atria (isomerism) or have a common atrium with
no atrial septum.
Second, both systemic and pulmonary venous connec-
tions to the atria should be determined. In adults, only three
pulmonary veins are generally visualized on TTE (best seen
in the apical views). The right inferior pulmonary vein is
not seen. All pulmonary venous drainage into the left atrium
can be easily identified on transesophageal imaging. Third,
abnormalities of ventricular inflow such as tricuspid atresia
or cor triatriatum are assessed. Fourth, ventricular number,
morphology, relative size, position, and concordance with
the atria are determined. A ventricle is defined as a chamber
that receives at least 50% of the ventricular “inlet” or
fibrous ring of the atrioventricular (AV) valve. Neither AV
valve patency nor connection to an outlet is required. Cham-
bers that do not meet these criteria are termed rudimentary
chambers and may or may not have an outlet. The number
of ventricles is determined by the presence or absence of an
interventricular septum. If only one ventricle is present (e.g.,
double inlet left or right ventricle, possibly tricuspid atresia,
etc.), the morphology of the ventricle should be classified as
right, left, or indeterminate. Of note, the ventricle is almost
always concordant with the AV valve. That is, a tricuspid
282 chapter
valve (three leaflet with chordal attachments to three papil-
lary muscles) regulates flow into a right ventricle, and a
mitral valve (two leaflets with chordal attachments to two
papillary muscles) regulates flow into the left ventricle. The
septal leaflet of the tricuspid valve inserts more apically
than the anterior leaflet of the mitral valve. The right ven-
tricle is generally heavily trabeculated while the left ven-
tricular endocardial surface is smooth. The presence of a
moderator band defines a right ventricle. Fifth, abnormali-
ties of cardiac septation such as ASD, ventricular septal
defect (VSD), and AV septal defect (AV canal or endocardial
cushion defect), including direction and magnitude of shunt,
are assessed.
Sixth, ventriculoarterial concordance and great vessel
number and relationships are elucidated. Normally, the mor-
phologic right ventricle is anterior and to the right of the
morphologic left ventricle and gives rise to a pulmonary
artery that is anterior and to the left of the aorta. The mor-
phologic left ventricle gives rise to an aorta that is posterior
and to the right of the pulmonary artery. Since the great
arteries normally arise in orthogonal planes, their long axes
are perpendicular on echocardiogram. In the parasternal and
subcostal short axis views, the aorta and aortic valve appear
in short axis posterior and to the right of the pulmonary
artery and right ventricular outflow tract, which are visible
in long axis, the typical “circle and sausage” appearance. In
the two forms of ventriculoarterial discordance (transposi-
tion complexes), the great arteries arise in parallel; thus,
both appear as “circles” with varied anteroposterior and
lateral relationships in the parasternal short axis and in
longitudinal plane in the parasternal long axis views, respec-
tively. In d-transposition of the great arteries, the atria and
ventricles are concordant with normal anteroposterior
and right-left position of the ventricles, but the aorta arises
anteriorly from the right ventricle. The pulmonary artery
arises posteriorly and then bifurcates, an appearance readily
identified on echocardiogram and key to differentiating
the two great arteries. In l-(congenitally corrected) transposi-
tion, there is atrioventricular and ventriculoarterial discor-
dance, so that the morphologic right ventricle lies posterior
and to the left of the left ventricle and gives rise to an
aorta while the morphologic left ventricle lies anterior
and to the right and gives rise to a pulmonary artery. This
often is best thought of as “ventricular inversion” since
there is no mixture of deoxygenated and oxygenated blood
in the isolated form of this defect and patients are not
cyanotic.
Seventh, the right and left ventricular outflow tracts,
including subvalvular, valvular, supravalvular, and distal
great arteries must be evaluated for the presence of obstruc-
tive lesions such as pulmonary valve stenosis, branch pul-
monary artery stenosis, discrete subaortic membranes, and
even coarctation of the aorta. Finally, attention is turned to
the evaluation of native shunts (e.g., patent ductus arteriosus,
aortopulmonary windows, ruptured sinus of Valsalva aneu-
rysm, or systemic to pulmonary artery collaterals), and post-
operative structures (patches, conduits, surgically created
systemic to pulmonary shunts, Fontan circuits, etc.). In some
younger adults with excellent acoustic windows, origins of
coronary arteries can be identified in the parasternal short
axis view.
11
Abnormalities of Cardiac Septation
Atrial Septal Defect
The most commonly diagnosed congenital cardiac defect in
adulthood, aside from bicuspid aortic valve, is ASD, which
accounts for almost 30% of all first congenital cardiac diag-
noses in adults. It occurs due to failure or incomplete devel-
opment of portions of the interatrial septum and is classified
by the embryologic segment of the septum involved by the
defect. The ostium primum ASD, actually a type of endocar-
dial cushion defect often called a “partial” AV canal, is char-
acterized by the absence of the primum septum at the AV
junction or crux of the heart, is usually accompanied by
abnormalities of the anterior mitral valve leaflet in the form
of a cleft, and represents approximately 15% of ASD in adults.
Approximately 75% of ASDs are of the ostium secundum
type, which is caused by a defect in portions of the membra-
nous fossa ovalis (secundum septum). The atrial septal aneu-
rysm, which may be congenital or acquired, occurs when the
membranous flap of the fossa ovalis protrudes with a “wind-
sock”-like appearance into one or the other atrium and may
demonstrate mobility during the cardiac cycle. Atrial septal
aneurysms may have multiple small fenestrations that are
not visible on color Doppler. Occasionally, especially if a
PFO or multiple fenestrations are present with right-to-left
shunt, an aneurysmal atrial septum may be associated with
paradoxical embolization. Patent foramen ovale, persistence
of the normal embryologic state of an open flap valve of the
fossa ovalis, occurs in approximately 20% to 25% of all
adults, is not due to absence of atrial septal tissue, and should
not be confused with ASD. As noted previously, PFO, espe-
cially in patients with atrial septal aneurysm, may be associ-
ated with paradoxical thromboembolism. Sinus venosus
ASD, caused by absence of the basal segment of the inter-
atrial septum most commonly at the superior vena cava
(SVC) and rarely at the inferior vena cava (IVC) junction with
the atrium, accounts for 10% to 15% of ASD in adulthood.
Sinus venosus ASD is frequently associated with anomalous
drainage of one or more pulmonary veins usually into the
right atrium or SVC. The least common type of ASD is the
unroofed coronary sinus with direct communication between
the coronary sinus and the left atrium resulting in a left-to-
right shunt.
In the situation of a previously undiagnosed ASD in the
adult, an echocardiogram is typically ordered to evaluate
symptoms of dyspnea, effort intolerance, atrial arrhythmias,
or even neurologic symptoms suspicious for an embolic
event. Indirect echocardiographic evidence of enlargement
and volume overload of the right ventricle may first raise the
possibility of a significant left-to-right shunt from an ASD
and was one of the first characteristics of ASD described on
M-mode and 2D echocardiogram.26–31 In addition to findings
of dilation of the right ventricle, the interventricular septum
will be noted to move paradoxically (Fig. 11.1). Motion of the
interventricular septum is dependent on the relative pres-
sures of the right and left ventricles during systole and dias-
tole. In right ventricular volume overload due to significant
left-to-right shunting through an ASD, the relative pressures
in the ventricles equalize in diastole, resulting in character-
istic diastolic flattening of the septum. The left ventricular
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se
FIGURE 11.1. (A,B) Parasternal short axis view of the ventricles
demonstrating paradoxical septal motion of right ventricular volume
overload. In diastole (A), right ventricular pressure equals left ven-
tricular pressure, the interventricular septum is flat (arrow), and the
cavity assumes a D-shape in diastole as viewed from para-
sternal short axis view of the 2D echocardiogram. In systole,
left ventricular pressure exceeds right ventricular pressure
(the normal hemodynamic state) and the interventricular
septum resumes its normal circular geometry. In patients
with ASD and pulmonary hypertension, right ventricular
pressure will equal left ventricular pressure throughout the
cardiac cycle and the ventricular septum will remain flat-
tened in both diastole and systole, referred to as a right ven-
tricular pressure overload appearance.32,33 In children with
ASD, 2D and spectral Doppler have been used to quantitate
the pulmonary to systemic blood flow ratio (Qp/Qs) with
fairly good correlation with that determined by cardiac
catheterization.34,35 However, in adults, correlation between
echocardiographic methods of shunt quantification and cath-
eterization is poor; echocardiographic shunt quantification
is not of practical use in adults.36
Most ostium secundum and ostium primum ASDs are
accurately diagnosed with the combination of transthoracic
FIGURE 11.2. (A,B) Transesophageal echocardiogram of an ostium
secundum atrial septal defect (ASD) in the long axis plane. The
defect is in the region of the fossa ovalis with a rim of superior
283
left ventricle is D-shaped. In systole (B), left ventricular pressure is
greater than right ventricular pressure and the ventricle resumes its
normal circular geometry.
2D and Doppler echocardiography. In one study, ASD was
accurately diagnosed and categorized as primum, secundum,
or sinus venosus in 47 of 50 adults using 2D and color Doppler
imaging. Three of five sinus venosus defects proven at surgery
were missed on TTE.36 The presence of a secundum ASD
may be suggested on the apical four-chamber view by abrupt
dropout of echoes in the area of the fossa ovalis with bright
side lobe artifacts producing an inverted T-shape.37 Because
the interatrial septum is parallel to the ultrasound beam
when the transducer is in the apical position, attenuation of
the ultrasound beam and the relative thinness of the mem-
branous part of the septum compared to the muscular portion
may result in a false-positive diagnosis of secundum ASD by
2D TTE. The appearance of a color flow signal from the left
to right atrium in the apical view can assist in the diagnosis
of secundum defects. Transesophageal echocardiography is
excellent for localizing the defect (Fig. 11.2). When the ultra-
sound transducer is in the subcostal location with a trans-
verse imaging plane, the interatrial septum is perpendicular
limbus tissue between the superior vena cava (SVC) and the defect
(A). Color Doppler flow imaging (B) shows a large left-to-right shunt.
LA, left atrium; RA, right atrium.
284 chapter
FIGURE 11.3. (A,B) Transesophageal echocardiogram of an ostium
primum ASD. The defect is seen at the junction of the interatrial
septum and ventricular septum at the level of the atrioventricular
to the beam of the ultrasound and ASDs may be viewed more
directly. In 154 adults with documented ASD in whom ade-
quate subcostal views could be obtained, 89% of secundum,
100% of primum, and 44% of sinus venosus defects were
successfully visualized.38 Ostium primum defects are easily
identified on TTE in either the apical four-chamber or sub-
costal views and on TEE as echo dropout in the lower portion
of the interatrial septum at the level of the AV valves (Fig.
11.3). When a primum ASD is recognized, a cleft in the ante-
rior leaflet of the mitral valve may be seen on the parasternal
short axis view of the ventricle at valve level, and eccentric
mitral regurgitation is almost always present on color Doppler
imaging (Fig. 11.4). It is not unusual to visualize a small
aneurysm of the inlet portion of the interventricular septum
beneath the tricuspid valve that may be formed when some
of the septal leaflet of the valve has sealed over a ventricular
septal defect that was originally part of the endocardial
cushion defect.
Sinus venosus ASDs are frequently missed on 2D TTE
and color Doppler because of the posterior location of the
FIGURE 11.4. Color jet of mitral regurgitation in the left atrium on
apical four-chamber view in a patient with ostium primum ASD.
11
(AV) valves (A, arrow). Shunting is primarily left-to-right on color
Doppler with a zone of flow convergence seen on the left atrial side
of the septum (B).
defect and the distance of the defect from the ultrasound
beam; if seen at all, they are best visualized from the subcos-
tal view in adults. The existence of a sinus venosus ASD is
often suggested when no definite secundum or primum ASD
is seen on 2D or color Doppler but right ventricular enlarge-
ment with right ventricular volume overload motion of the
interventricular septum is present. The appearance of micro-
bubbles in the left atrium shortly after the appearance of
bubbles in the right atrium subsequent to injection of agitated
saline into a peripheral vein further suggests the diagnosis.
Saline contrast injections can be used to diagnose all
forms of ASD. A “positive” saline contrast study with appear-
ance of bubbles in the left atrium, however, documents only
the existence of a right-to-left shunt which could result from
intracardiac shunts other than ASD, including pulmonary
arteriovenous malformations or systemic to pulmonary
artery collaterals. The appearance of bubbles in the left
atrium occurring six or more cardiac cycles after appearance
in the right atrium should suggest an intrapulmonary right-
to-left shunt. The sensitivity of saline contrast study for the
diagnosis of ASD or PFO can be increased by asking the
patient to perform a Valsalva maneuver to transiently increase
right-sided intracardiac pressures and increase the shunt
during the contrast injection.39–42 More specific for the diag-
nosis of atrial septal defect is a “negative contrast” study in
which a “clear space” appears in the microbubble opacifica-
tion of the right atrium due to left-to-right shunting of
unopacified blood across the ASD (Fig. 11.5).43 False-positive
“negative contrast” effects can occur in the absence of ASD
due to unopacified blood flowing into the right atrium from
the inferior vena cava, coronary sinus, or anomalous pulmo-
nary veins. Both PFO and atrial septal aneurysm (Fig. 11.6)
with PFO can be associated with right-to-left or left-to-right
shunting on contrast study. For the diagnosis of right-to-left
shunt through a patent foramen ovale or atrial septal aneu-
rysm and the detection of a source of cardiac embolus in
patients with unexplained cerebral ischemia, TEE is superior
to TTE.44–52
Because of its close proximity to the interatrial septum
and obviation of most acoustic impediments, TEE generates
high-resolution images and is ideally suited for the diagnosis
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se
FIGURE 11.5. (A,B) Saline contrast injection in a patient with
ostium secundum ASD. (A) Microbubbles are seen crossing the
interatrial septum from the right into the left atrium (arrow). (B) A
and characterization of ASD. In studies of patients with
known secundum ASD, TEE was superior to TTE for the
diagnosis of ASD.53 Defect size measured by TEE showed
good correlation with defect size found at surgery.54 Because
TEE provides complete characterization of the interatrial
septum, it is the diagnostic procedure of choice for visualiz-
ing sinus venosus ASD to both the SVC (Fig. 11.7) and the
IVC (Fig. 11.8).55 The longitudinal esophageal plane is the
most useful for diagnosis of sinus venosus ASD on TEE. In
a study of 25 adults with sinus venosus ASD on TEE, only
three patients had defects that were clearly defined by TTE,
though another 11 had venosus ASD suspected on the basis
of color flow mapping, while another 10 adults were evalu-
ated to find the cause of unexplained right-heart enlargement
on TTE. The importance of TEE in these patients was further
emphasized by the finding of 37 anomalous pulmonary veins
FIGURE 11.6. Atrial septal aneurysm. In the parasternal short axis
view, a bulging of the interatrial septum with displacement of the
septum into the right atrium is noted (arrow). A displacement of
1 cm into either atrium is the typical criterion for the diagnosis of
ASA. The ASA may demonstrate mobility with the respiratory
cycle. RA, right atrium; LA, left atrium.
285
negative contrast effect is demonstrated when unopacified blood
from the left atrium passes into the right atrium (arrow), creating
an echocardiographic “clear space.”
preoperatively in 23 of 25 patients, requiring alterations in
operative approach.56 In the most common form of partial
anomalous pulmonary venous return, the right upper pulmo-
nary vein is seen entering the atrium at the junction of the
sinus venosus defect and the SVC with color flow directed
into the right atrium, but one or more pulmonary veins may
drain into the SVC directly, into the IVC, or into a hepatic
vein. Every attempt should be made to identify all pulmo-
nary venous connections in the patient undergoing TEE for
ASD. Occasionally, anomalous pulmonary veins occur in
patients with secundum ASD, so these should be sought in
all patients with secundum ASD. In the rare patient with the
unroofed coronary sinus defect, TEE may image the connec-
tion between the coronary sinus and the left atrium, and
left-to-right shunt may be seen on color flow mapping.
Like patients with ostium secundum and ostium primum
ASD, patients with sinus venosus ASD do not require routine
preoperative cardiac catheterization if pulmonary hyperten-
sion is not demonstrated.57,58 For adults with suspected
secundum ASD, TEE provides significant useful information
if transcatheter closure of the ASD is being considered.59
With appropriate experience, the size of the ASD on TEE can
be used to assist in device size selection.60 Closure devices
for ASD require that an adequate “rim” of septal tissue be
present on all edges of the defect to ensure adequate seating
of the device. This can be quantified by TEE or by intracar-
diac echocardiography. Three-dimensional reconstruction of
TEE images of the interatrial septum may provide additional
information to the interventional cardiologist for device
selection and assessment of deployment.61 Also, TEE can
identify multiple defects for which additional closure devices
might be necessary and identify anomalous pulmonary
venous drainage, which might necessitate a surgical rather
than transcatheter approach. Recently, intracardiac echocar-
diography has been used in the catheterization laboratory to
monitor percutaneous closure of ASD or PFO and may be less
expensive than TEE with equivalent success.62–64 On echo-
cardiography, the ASD occluder device appears as linear
bright echoes on either side of the interatrial septum (Fig.
11.9) and should be examined for security of its seating on
286 chapter 11

FIGURE 11.7. (A,B) Sinus venosus ASD to the superior vena cava (arrow) immediately beneath the superior vena cava (A). Color
on transesophageal echocardiography (TEE) in the long axis view. Doppler shows the left-to-right shunt (B). LA, left atrium; RA, right
The defect is visualized in the most superior portion of the septum atrium.

FIGURE 11.8. (A,B) Sinus venosus ASD to inferior vena cava. The defect (arrow) is seen in the inferior portion of the septum adjacent to
the coronary sinus (cs) in (A) with large left-to-right shunt demonstrated in (B). RA, right atrium; LA, left atrium.

FIGURE 11.9. (A,B) An ASD septal occluder device seated on the interatrial septum. The device is seen as parallel linear echoes on either
side of the septum (arrow) on the apical four-chamber view of TTE (A) and TEE (B).
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se
the septum and residual shunt on color Doppler flow mapping.
Although the frequency of serial follow-up in adults with
corrected ASD has not been established, these patients may
develop late atrial arrhythmias or pulmonary hypertension
and require continued monitoring.
Ventricular Septal Defect
The most common congenital cardiac defect diagnosed in
childhood, VSD is much less commonly diagnosed in adults,
in large part because 60% of small VSDs close spontaneously
before the teenage years. The remainder of VSDs have already
been repaired by adulthood or are large and associated with
fixed pulmonary vascular disease, absence of murmur, rever-
sal of the intracardiac shunt (Eisenmenger’s syndrome), and
cyanosis. A more common scenario is the adult with a loud
murmur and small, hemodynamically insignificant VSD.
Rarely, an adult may present with a moderately sized VSD
and symptoms of heart failure. Because small VSDs confer a
significant risk of endocarditis and larger VSDs are associ-
ated with a much higher risk of pulmonary hypertension
than ASDs, the echocardiographic recognition of VSD is
essential for these patients.
Defects of the ventricular septum are classified by ana-
tomic location as viewed from the right septal surface. The
most common type of VSD, making up 70% of all VSDs,
occurs in the membranous septum often with involvement
of adjacent muscular tissue beneath the crista supraventricu-
laris when viewed from the right ventricle and under the
aortic valve when viewed from the left. This defect is more
properly termed a perimembranous VSD but is also called a
subaortic VSD and is a type of outlet VSD. Defects in the
muscular portion of the septum are the next most common
accounting for 20% of VSD and may occur anywhere in the
septum from inlet to trabecular to outlet. Muscular VSDs
may be multiple in which case they are termed Swiss-cheese
defects and are the most difficult to identify echocardio-
graphically. Defects located beneath the pulmonic valve,
another form of outlet VSD, are referred to as supracristal,
doubly committed, or subpulmonic VSDs and represent
approximately 5% of all VSD. Because supracristal VSDs
FIGURE 11.10. (A,B) Perimembranous VSD. The defect in the
region of the membranous interventricular septum is not well seen
on the parasternal long axis view of the TTE (A, arrow). It is char-
287
undermine the aortic annulus, prolapse of an aortic cusp can
occur with the development of aortic insufficiency, which, if
more than mild, constitutes an indication for closure of even
small supracristal VSDs. Rarely occurring in isolation,
defects of the inlet septum occur beneath the septal leaflet
of the tricuspid valve and are often accompanied by defects
of the primum portion of the atrial septum as part of an AV
septal or endocardial cushion defect also known as an AV
canal.
Because of the complex, curved shape of the ventricular
septum, multiple transducer locations and imaging planes
with both 2D and color and spectral Doppler must be used
to interrogate the entire septum. The sensitivity and specific-
ity of echocardiography for the diagnosis of VSD are related
to the size and location of the defect. The best views of a
particular defect occur when the defect is perpendicular to
the ultrasound beam. Because a significant length of septum
is perpendicular to the ultrasound plane and axial resolution
is best when the transducer is the subcostal location, subcos-
tal views may be helpful, especially in thin adults.65 The
hallmark of VSD on 2D echocardiography is echo dropout of
the ventricular septum. The finding of a T-sign in the apical
views increases the specificity for the diagnosis of VSD in
the same fashion as for ASD.66–69 Frequently, the VSD is not
well visualized on 2D imaging, but high-velocity turbulent
flow in systole on color Doppler provides a definitive
diagnosis.70
Surface TTE is approximately 80% to 90% sensitive for
the diagnosis of perimembranous VSD. Perimembranous
defects are best visualized in the parasternal long axis and
parasternal short axis views. In the parasternal long axis
view, the defect appears immediately below the aortic valve.
In small, restrictive perimembranous VSDs, a turbulent sys-
tolic jet passes from the left ventricular outflow tract into
the right ventricle through the defect (Fig. 11.10). It is impor-
tant to remember that large VSDs with equalization of right
and left ventricular pressure may be seen as a sizable defect
with no turbulent systolic flow on color Doppler. In the
parasternal short axis view at the level of the aortic valve,
the turbulent jet is seen to the left of midline near the inser-
tion of the tricuspid valve at the 10 o’clock position if the
acterized by turbulent flow from the left to the right ventricle on
color flow Doppler (B).
288 chapter 11

FIGURE 11.12. Large inlet VSD. The defect in the interventricular

FIGURE 11.11. Color Doppler in the parasternal short axis view septum (arrow) is seen in the superior septum at the crux of the
showing a turbulent jet immediately inferior to the tricuspid valve heart in the apical four-chamber view.
seen at approximately the 10 o’clock position on the clock face of
the aortic valve (Ao).

aortic valve is considered to be a clock face (Fig. 11.11). Supra-
cristal VSDs are also best seen in the parasternal short axis
view at the base of the heart and appear as a systolic color
flow jet just beneath the pulmonic valve at the 2 o’clock
position on the aortic valve. Small supracristal VSDs may be
missed, especially if careful color Doppler imaging is not
performed. The highest sensitivity of echocardiography in
VSD is for inlet defects, which are best seen in the apical
four-chamber view (Fig. 11.12). For uncomplicated inlet VSD
without an atrial component, the septal leaflet of the tricus-
pid valve originates from its normal apically displaced posi-
tion relative to the mitral valve. In AV canal-type defects,
both AV valves are in the same plane and their chordal
attachments must be determined.
On occasion, the septal leaflet of the tricuspid valve may
partially close an inlet VSD, and a rare type of communica-
tion between the left ventricle and the right atrium called a
Gerbode defect may result.71 Muscular VSDs, when small,
are the most difficult to identify on TTE, with sensitivity as
low as 50% for their detection. Color Doppler must be per-
formed of the entire expanse of the ventricular septum in
multiple views including parasternal long axis, parasternal
short axis from apex to base, subcostal long and short axes,
and apical views if a muscular VSD is suspected. Some mus-
cular VSDs appear as narrow channels in the ventricular
septum with openings into the left and right ventricles at
different levels on the septum (Fig. 11.13). In adults, it is not
uncommon to find a ventricular septal aneurysm in the
region of the membranous septum, which appears as a thin
membrane that bulges into the right ventricle, rarely causing
right ventricular outflow tract obstruction, and may incor-
porate a portion of the septal leaflet of the tricuspid valve.72
The septal leaflet can completely or only partially seal the
perimembranous defect, and this can be best visualized by
color Doppler in the parasternal long axis view (Fig. 11.14).
Although 2D and color Doppler can identify the presence
and estimate the size of VSDs, continuous wave spectral
Doppler accurately quantitates the pressure gradient between
the left and right ventricles. By measuring systemic pressure
with a blood pressure cuff and subtracting the pressure gradi-
ent between the left and right ventricle, the right ventricular
systolic pressure can be estimated. In the absence of pulmo-

FIGURE 11.13. (A,B) Muscular VSD in the midportion of the trabecular septum (arrow) in the apical four-chamber view (A) with high-
velocity color jet from left to right (B). LV, left ventricle; LA, left atrium; RA, right atrium.
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se
FIGURE 11.14. Parasternal long axis view of ventricular septal
aneurysm. Parts of the septal leaflet of the tricuspid valve partially
seal over a perimembranous VSD. This is seen as a localized bulge
nary outflow obstruction, the pulmonary systolic pressure
can be inferred from the right ventricular systolic pressure.
With careful alignment of the Doppler cursor with the tur-
bulent jet on color flow imaging, the peak velocity of the VSD
jet can be measured (Fig. 11.15). Using the modified Bernoulli
equation in the usual fashion,
Peak gradient = 4 × V2 (peak velocity squared)
the peak gradient between the ventricles is calculated.73–75
Small restrictive VSDs will have high gradients, often in
excess of 100 mm Hg, whereas large, nonrestrictive VSDs
have low or no gradients, reflecting the fixed pulmonary
hypertension that is present in most adults with the defect.
The normal postoperative appearance of the septum after
surgical closure is typified by a bright linear echo on the
right ventricular side of the defect if a prosthetic patch was
used.76 Dehiscence of the patch may be visualized from mul-
tiple views by a turbulent systolic jet on color Doppler at the
margin of the patch (Fig. 11.16) or mobility of the echodense
patch into the right ventricle in systole.77 Echocardiography
FIGURE 11.15. Continuous wave Doppler of restrictive perimem-
branous VSD with peak velocity approximately 5.6 m/sec. The peak
pressure gradient between the left and right ventricle is calculated
to be 125 mm Hg by the modified Bernoulli equation.
289
of the membranous septum (arrow) into the right ventricle (A). Color
Doppler flow confirms the VSD (B).
is integral to the assessment of other complications of VSD
including evaluation of aortic insufficiency in patients with
supracristal VSD who have prolapse of a (usually right) coro-
nary cusp into the defect,78 pulmonary hypertension, or
endocarditis with vegetation79 typically of right heart struc-
tures at the site of jet impingement. Infrequently, an adult
may present who underwent banding of the pulmonary
artery (PA) in childhood to protect from fixed pulmonary
vascular disease, but never proceeded to closure of the defect.
An example of a PA band in an adult patient with a nonre-
strictive VSD and pulmonary hypertension is shown in
Figure 11.17. By measuring the systemic blood pressure by
cuff and subtracting the sum of the peak gradient across the
VSD and the peak gradient across the PA band, PA systolic
pressure can be estimated. A recent development is the
closure of perimembranous and muscular VSDs using trans-
catheter closure devices.80,81
Atrioventricular Septal Defects (Atrioventricular
Canal or Endocardial Cushion Defect)
Atrioventricular septal defects occur due to failure of fusion
of the inferior and superior endocardial cushions to varying
degrees, with abnormalities of the AV junction ranging from
isolated primum ASD with cleft mitral valve (MV) and
isolated inlet VSD (“partial” AV canal with separate AV
valves) to complete AV canal with a spectrum of abnormali-
ties of the AV valves. Echocardiography with color Doppler
can readily determine the size and extent of the septal defects,
the nature of the shunt, and the morphology of the AV valves.82
The extent of the atrial and ventricular components of the
defect is best gauged in the apical four-chamber or subcostal
views. In these views, the nature of the AV valve(s) and attach-
ments should be carefully explored. Some patients may have
a single (common) AV valve (Fig. 11.18). In the patient with
two AV valves in the same plane, chordal attachments of the
valves must be elucidated. The presence of a straddling AV
valve with chordal attachments crossing the septal defect to
insert into the opposite ventricle makes the surgical repair
more complex than does an overriding valve that overlies
the AV septal defect but has no chordal attachment to the
290 chapter 11

FIGURE 11.16. (A,B) Prosthetic VSD patch dehiscence. In the para- echo dropout of the defect (small arrow) (A). Flow across the defect
sternal short axis view, a bright linear echo is seen on the right is seen on color Doppler (B).
ventricular side of the inferior septum (large arrow) with associated

FIGURE 11.17. (A,B) In the high parasternal view, there is a band band (B) is 20 mm Hg, suggesting that there is insufficient protection
noted on the main pulmonary artery (arrow) just distal to the pul- of the distal pulmonary vascular bed from increased pulmonary
monic valve (A). The peak gradient across the pulmonary artery blood flow through the ventricular septal defect.

FIGURE 11.18. (A,B) Atrioventricular septal defect (AV canal or arrow) and the inferior portion of the ventricular septum (bottom
endocardial cushion defect). In the apical four-chamber view, a large large arrow) is seen (A). The common AV valve is seen in diastole
defect involving the superior portion of the atrial septum (top large (small arrows) in A and in systole (large arrow) in B.
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se
FIGURE 11.19. Color Doppler flow image of regurgitation of the AV
valve in a patient with AV septal defect.
opposite ventricle. In patients with a primum ASD, the asso-
ciated cleft anterior mitral valve leaflet is best directly visual-
ized in the parasternal short axis view, though the eccentric
mitral regurgitation may be appreciated in the apical views.
Although most patients present after having been repaired in
childhood, some adults, particularly patients with Down syn-
drome who were not operated, present with pulmonary
hypertension and cyanosis. Atrioventricular valve regurgita-
tion (Fig. 11.19) is common in these patients.
Abnormalities of Venous Inflow
The most frequent congenital anomaly of systemic venous
inflow is persistence of a left SVC, which is found in approxi-
mately 0.5% of the general population and up to 10% of
patients with other congenital heart defects. Embryologic
resorption of the right-sided SVC in utero is rare in these
patients, and an absent right SVC was seen in only three of
10 patients evaluated by magnetic resonance imaging.83 The
left SVC usually drains directly into the coronary sinus and
then to the right atrium with no physiologic consequences,
but on rare occasion will drain into the left atrium or pul-
FIGURE 11.20. (A,B) Persistent left superior vena cava. In the para-
sternal long axis view, a dilated coronary sinus (cs) is seen posterior
to the left atrium in the AV groove (A). When agitated saline is
2 91
FIGURE 11.21. Transesophageal echocardiogram of complete
eustachian valve. The eustachian valve is the flap valve of the infe-
rior vena cava (arrow). SVC, superior vena cava; RA, right atrium;
LA, left atrium.
monary vein. Most often, a persistent left SVC is suspected
when a dilated coronary sinus that appears as a large circular
structure in the posterior AV groove is noted on the paraster-
nal long axis view of the TTE. Persistence of the left SVC is
the most common cause of a dilated coronary sinus on TTE.
The coronary sinus can also be visualized with steep poste-
rior angulation in the apical four-chamber view as a longitu-
dinal structure behind the left atrium draining into the right
atrium. In adults, the actual left SVC is not often directly
visualized. Instead, the diagnosis is clinched by injection of
agitated saline into a peripheral vein in the left arm. In this
instance, bubbles will first be seen in the coronary sinus
followed by opacification of the right heart (Fig. 11.20).84–87
Injection of agitated saline into a vein in the right arm pro-
duces direct opacification of the right heart without opacifi-
cation of the coronary sinus. Although not an abnormality,
a prominent or “complete” eustachian valve at the junction
of the inferior cava extending to a varied degree to the ostium
of the coronary sinus warrants mention (Fig. 11.21) because
injected in a peripheral vein in the left arm, bubbles appear first in
the coronary sinus and then the right atrium and ventricle (B,
arrows). RV, right ventricle.
292 chapter
it can cause confusion and misdiagnosis as thrombus or
vegetation.
Anomalous pulmonary venous drainage in adults is most
frequently seen in association with a sinus venosus defect,
but may be an isolated abnormality with one or more pul-
monary veins draining into the SVC, IVC, right atrium, or
hepatic vein. Unrepaired total anomalous pulmonary venous
return is not seen in adults. In adults with normal pulmo-
nary vein anatomy, the right superior, and left superior and
inferior pulmonary veins may be identified draining into the
left atrium in the apical four-chamber view. The right infe-
rior pulmonary vein is not visualized in adults on TTE.
Often the only clue to the presence of isolated anomalous
pulmonary veins is enlargement of the right heart with no
right-to-left shunt on saline contrast injection. Preoperative
identification of abnormal pulmonary vein drainage in
patients with ASD is important for defining the approach to
these patients since a procedure to baffle flow from the vein
to the left atrium will be necessary in addition to repair of
the defect. For these patients, TEE is more accurate than TTE
for the diagnosis of anomalous pulmonary veins.88–92 Con-
genital stenosis of pulmonary veins is not seen in the adult
population. However, TEE has proved useful for arrhythmia
mapping in the pulmonary veins during radiofrequency abla-
tion of atrial fibrillation and diagnosing pulmonary vein
stenosis that can occur as a late complication of the
procedure.93,94
Abnormalities of Ventricular Inflow
The most common anomalies involving the inflow tract of
the right ventricle are tricuspid atresia or hypoplasia and
Ebstein’s anomaly. Patients with tricuspid atresia have an
obligate intraatrial communication and usually have associ-
ated hypoplasia of the right ventricle. Because these patients
are generally managed as patients with single ventricle physi-
ology, they will be considered in the section on single
ventricles.
Ebstein’s anomaly, an abnormality of tricuspid valve
development, is characterized by apical displacement of the
insertion of the septal (and sometimes posterior) leaflet of
the tricuspid valve and variable elongation of the anterior
leaflet, designated a “sail” leaflet owing to its resemblance
to the sail of a ship. There is a wide spectrum of tethering
of the anterior leaflet to the ventricle by multiple abnormal
short chords. This abnormality results in apical displace-
ment of the tricuspid valve coaptation point into the right
ventricle with “atrialization” of the inlet portion of the right
ventricle as a consequence. Ebstein’s anomaly, often accom-
panied by a secundum ASD or PFO, most often presents in
childhood with signs of right heart failure or cyanosis and
has a less favorable prognosis in this population. In many
instances, however, Ebstein’s does not present until adult-
hood, even in patients with severe apical displacement of
the tricuspid valve. In one study of 72 adults diagnosed
with Ebstein’s anomaly, the mean age at first diagnosis was
24 years.95 In general, suitability for tricuspid valve repair
versus replacement is determined by valve morphology, and
prognosis is related to the size of the functional right
ventricle.
11
The tricuspid valve morphology, chordal attachments,
and functional right ventricular size can be accurately
assessed using multiple views on TTE.96,97 The degree of
apical displacement of the septal leaflet is best estimated
from the apical four-chamber view. Because some degree of
apical displacement of the septal leaflet is present in the
normal heart and may be accentuated by right ventricular
enlargement from any cause, echocardiographic criteria have
been developed to make the diagnosis of Ebstein’s anomaly
in adults. In one study, an absolute value of 20-mm displace-
ment of the septal tricuspid leaflet relative to the insertion
point of the anterior leaflet of the mitral valve was used. In
other studies, a distance of 8 mm/m2 when normalized to
body surface area provided an accurate diagnosis of Ebstein’s.98
Tethering of the anterior leaflet should be evaluated in the
apical four-chamber view (Fig. 11.22). Assessment of tether-
ing of the anterior leaflet and functional right ventricular
size may also be performed in the right ventricular “inflow”
view obtained by anterior and medial angulation of the ultra-
sound beam from a left parasternal long axis transducer
position. A functional right ventricle area smaller than 35%
of the total ventricle and extensive tethering of the anterior
leaflet portend a less favorable surgical outcome.97 In unoper-
ated adults with Ebstein’s, the septal leaflet attachment ratio,
defined as the distance from the AV valve annulus to the
distal attachment of the septal leaflet divided by the total
ventricular septal length in the four-chamber view at end
diastole, did not correlate with the percent of atrialized area
of the right ventricle. However, a higher index (indicating
more severe apical displacement) was associated with worse
prognosis for survival.95 Both TTE97 and TEE99 can be used
to assess suitability for and adequacy of tricuspid valve
reconstruction. In Ebstein’s anomaly, there is usually severe
tricuspid regurgitation with the origin of the color Doppler
jet occurring at the coaptation point of the tricuspid valve,
close to the right ventricle apex (Fig. 11.23).
FIGURE 11.22. Apical four-chamber view of Ebstein’s anomaly.
The origin of the septal leaflet of the tricuspid valve (large arrow) is
displaced toward the right ventricle (RV) apex. The anterior “sail
leaflet” (small arrows) is elongated with multiple chordal attach-
ments to the anterior wall of the RV. There is a large area of atrial-
ized RV superior to the valve. RA, right atrium.
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se 293

FIGURE 11.24. Parasternal short axis view of the left atrium

FIGURE 11.23. Color Doppler flow image of Ebstein’s anomaly in showing the membrane of cor triatriatum (arrow). RA, right atrium;
the apical four-chamber view. The origin of the jet of tricuspid LA, left atrium.
regurgitation (arrow) is displaced far toward the right ventricular
apex.

Obstruction to inflow of the left ventricle can take the TEE can provide clear images of the membrane, its attach-
form of cor triatriatum, mitral supravalvular ring, congenital ment to the interatrial septum and lateral wall of the atrium
mitral stenosis, or mitral atresia (usually as part of complex above the atrial appendage, and the nature of the opening,103
left ventricular inflow and outflow obstructive lesions known thus guiding operative resection.103–106 A stenotic supravalvu-
as Shone complex). Shone complex is always diagnosed in lar mitral ring differs from cor triatriatum in that it occurs
infancy and childhood and therefore will not be dealt with at the level of or slightly superior to the mitral annulus, is
here. sometimes adherent to the base of the valve leaflets, but is
Cor triatriatum, caused embryologically by incomplete below the left atrial appendage. Small rings may be difficult
resorption of the floor of the common pulmonary vein as it to image with 2D echocardiography, but may be suggested
merges with the roof of the left atrium, is characterized by if color Doppler demonstrates turbulent inflow to the left
the presence of a perforated membrane that divides the left ventricle above the mitral valve leaflets. The echocardio-
atrium into a superior chamber that receives the pulmonary gram of a patient with a supravalvular ring is shown in
veins and an inferior chamber associated with the left atrial Figure 11.26.
appendage and the mitral valve. In most instances, the Congenital mitral stenosis, usually diagnosed in child-
opening in the membrane is restrictive. Patients present with hood, may be difficult to differentiate from rheumatic mitral
symptoms of left ventricular inflow obstruction with pulmo- stenosis on echocardiogram in adults. Congenital mitral
nary congestion. Asymptomatic adults with cor triatriatum
first identified as an incidental finding on TTE may have a
nonrestrictive membrane. Cor triatriatum is usually readily
identified on TTE.100,101 The membrane is often identified on
TTE in the parasternal views where it is seen in the left
atrium inserting anteriorly at the level of the posterior wall
of the aorta and coursing to the posterior left atrial wall (Fig.
11.24). However, the membrane is best visualized on TTE in
the apical view in the middle left atrium since it is perpen-
dicular to the ultrasound beam (Fig. 11.25). The left atrial
appendage may be identified in the lower chamber. Pulmo-
nary veins can be visualized draining into the superior
chamber and may be dilated if obstruction of the fenestration
is significant.
The site of obstruction in the membrane can be identified
by a turbulent color flow jet in the middle atrium that is
primarily diastolic, but can persist throughout the cardiac
cycle if stenosis is severe. The transmembrane gradient can
be calculated (reflecting severity of stenosis of the orifice)
using the modified Bernoulli equation from the peak velocity FIGURE 11.25. The membrane of cor triatriatum (arrow) is seen
obtained by pulsed or continuous wave Doppler in the apical coursing across the left atrium (LA) in the apical four-chamber
views.102 If the diagnosis is suggested but not clear on TTE, view.
294 chapter
FIGURE 11.26. (A,B) A supravalvular mitral ring is noted just supe-
rior to the mitral valve at the mitral annulus in A (two arrows) in
the parasternal long axis view. On color Doppler flow imaging in
stenosis is usually the result of abnormal insertion of chordae
tendineae into either a single papillary muscle, the “para-
chute” type of mitral valve, or into multiple small papillary
muscles, the “arcade” type. Both types of congenitally ste-
notic valves can be visualized in apical and short axis views
of the ventricle on TTE. An occasional adult will exhibit a
“double orifice” mitral valve, which has the hallmark of two
separate orifices seen on short axis cross-sectional views of
the ventricle at valve level. The degree of stenosis of these
valves is variable and dependent on insertion of the chords
(usually each orifice inserts into its own papillary muscle
making this, technically, a double parachute mitral valve)
and chordal fusion.107–109
Abnormalities of Ventricular Number
or Morphology
Single Ventricle Complexes
Many different congenital abnormalities may result in what
is physiologically a single pumping chamber in which oxy-
genated and deoxygenated blood mix before being pumped to
the body. In single ventricle hearts, a small outlet chamber
may exist with communication from the main ventricle
through a defect known as a bulboventricular foramen. The
rudimentary chamber does not have an inlet and is techni-
cally not a ventricle. Echocardiography permits extensive
evaluation of the wide spectrum of congenital abnormalities
resulting in a single ventricle.110 Often, the univentricular
heart can be classified morphologically as right, left, or inde-
terminate by its appearance on 2D TTE. The most common
type of univentricular heart is the morphologic left ventricle
and is referred to as a double-inlet left ventricle. Double-inlet
right ventricles also exist. If the single ventricle is a left
ventricle, a rudimentary outlet chamber with connection to
a pulmonary artery should be sought anterior and superior
to the ventricle. The rudimentary chamber in a morphologi-
cally right single ventricle is posterior and inferior to the
ventricle. Patency of the bulboventricular foramen can be
11
the apical four-chamber view (B), the convergence zone for mitral
inflow is above the level of the mitral valve signifying obstruction
at that level.
assessed on color Doppler flow imaging. Multiple complex
abnormalities are common in these patients. Ventriculoarte-
rial discordance with the aorta arising from the anterior
outlet chamber and the pulmonary artery arising from the
posterior chamber is especially common.
Tricuspid atresia results from failure of development of
the tricuspid valve. At birth, an ASD or PFO must be present
for survival. There is usually significant underdevelopment
or hypoplasia of the right ventricle with mixing of oxygen-
ated and deoxygenated blood in the left ventricle causing
cyanosis. Although the small right-sided chamber receives
the inlet of the tricuspid valve in the form of a fibrous ring,
and therefore is technically a ventricle, the physiology is
identical to that of other single ventricle complexes.
Patients with this group of defects who survive to adult-
hood have usually undergone an operation that establishes a
connection between the systemic veins or right atrium and
the pulmonary arteries to provide pulmonary blood flow and
improve oxygenation. In most adults, this connection is
created with one of several variations of a Fontan circuit. In
one common form of Fontan anastomosis, a connection is
made between the right atrial appendage and the PA either
by direct anastomosis (Fig. 11.27) or interposition of a conduit.
In other individuals, a conduit may be placed from the IVC
through the lateral right atrium and connected to the PA, the
so-called lateral tunnel Fontan, with connection of the SVC
to the PA in a total cavopulmonary connection. Especially
in individuals with elevated pulmonary vascular resistance
prior to surgery, holes or “fenestrations” may be deliberately
placed in the Fontan at the time of surgery to allow the
circuit to decompress, but at the cost of increased cyanosis.
These fenestrations may be closed using percutaneous inter-
ventional techniques at a later time. In other patients, the
conduit may be placed from the IVC external to the right
atrium to the pulmonary artery, the extracardiac Fontan
circuit.
Echocardiography plays a vital role in the understanding
and management of patients with univentricular hearts who
have undergone the Fontan operation. However, the Fontan
connection is often poorly visualized on TTE for many
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se
FIGURE 11.27. A classic Fontan anastomosis of the right atrial
appendage directly to the pulmonary artery is shown on trans-
esophageal echocardiogram. A layer of thrombus, a common finding
after Fontan operation in adults, is noted in the atrium (arrows). RA,
right atrium; PA, pulmonary artery.
reasons including multiple prior surgeries and scarring, mal-
position of the heart in the chest, and the location of most
connections behind the sternum. In some adults with direct
right atrial anastomosis to the pulmonary artery, the con-
nection may be visualized on high parasternal views on TTE
or on TEE. The lateral tunnel Fontan may be seen as a bright
circular prosthetic structure within the atrium. The Fontan
circuit should also be examined with color Doppler to assess
for obstruction and with spectral Doppler to establish flow
patterns within the circuit. In patients with low pulmonary
vascular resistance, the pattern of flow in the pulmonary
artery after Fontan is characterized as biphasic with the
largest peak due to atrial contraction in late diastole and a
smaller late systolic peak. Flow velocity typically increases
during inspiration. In patients with elevated pulmonary vas-
cular resistance or ventricular diastolic pressure, the Doppler
pattern may demonstrate a smaller peak in late diastole with
reduced respiratory variation, or absence of diastolic flow
altogether in extreme cases. Because of low-velocity flow and
enlargement of the right atrium, thrombus can develop
within the circuit, causing obstruction or pulmonary embo-
lism, especially in adults. Fontan thrombus may be identi-
fied on TTE,111 especially in symptomatic patients. However,
TEE is more likely to diagnose thrombus in these patients,112
an important finding since clinically silent pulmonary
embolism has been reported in up to 17% of Fontan patients
and anticoagulation is required (Fig. 11.28).113
Two congenital abnormalities of ventricular myocar-
dium, arrhythmogenic dysplasia of the right ventricle and
isolated noncompaction of the left ventricle, may be first
diagnosed in the adult. Arrhythmogenic right ventricular
dysplasia (ARVD) is a genetic condition, often with autoso-
mal dominant inheritance, characterized pathologically by
fibrofatty replacement of right ventricular myocardium. The
patient usually presents with ventricular arrhythmias of left
bundle branch block morphology. Since the extent of replace-
ment of ventricular myocardium with fibrofatty tissue is
295
variable, a wide spectrum of echocardiographic abnormali-
ties can be seen, ranging from normal right ventricular size
and function, to regional abnormalities with localized
“bulging” of the right ventricular free wall, to marked dila-
tion of the entire right ventricle, a condition termed Uhl’s
anomaly or “parchment” right ventricle. Because the right
ventricle has a complex, crescent shape, complete evaluation
requires the use of multiple ultrasound planes from subcos-
tal, apical four-chamber, and right ventricular inflow trans-
ducer positions. The right ventricle may be incompletely
visualized on TTE. The use of echocardiographic contrast
agents may improve the sensitivity for the diagnosis of ARVD
in these patients.114 The use of tissue Doppler velocity evalu-
ation may also increase the sensitivity for the diagnosis of
early disease.115
In isolated noncompaction of the left ventricle, the devel-
opment of ventricular myocardium is arrested prior to
condensation and compaction of the myocardium, and, as a
result, some or all of the myocardium has deep trabecular
recesses that communicate with the ventricular endocar-
dium. These adults typically present with heart failure or
ventricular arrhythmias. Transthoracic echocardiography
provides the diagnosis in the majority of patients. On 2D
echocardiography, the myocardium appears “spongy” with
deep sinusoids (Fig. 11.29). On color Doppler imaging, color
may be seen entering the sinusoids. With the use of peripher-
ally injected echocardiographic contrast agents, which may
be seen entering the sinusoids, noncompaction can be dif-
ferentiated from left ventricular thrombus and hypertrophic
cardiomyopathy. In one study with pathologic correlation,
four echocardiographic criteria were required to be diagnostic
for noncompaction: (1) absence of any other cardiac
abnormality; (2) echocardiographic appearance of a two-layer
structure to the myocardial wall, with a compacted thin
epicardial band and a much thicker noncompacted endocar-
dial stripe, and with deep endomyocardial spaces and a
maximal end-systolic ratio of noncompacted to compacted
layer >2; (3) predominant localization of abnormalities in the
midlateral, apical, and mid-inferior regions of the ventricle;
FIGURE 11.28. Transesophageal echocardiogram of right atrial
thrombus (arrow) in a patient after Fontan operation. RA, right
atrium.
296 chapter 11

FIGURE 11.29. (A,B) Apical four-chamber (A) and two-chamber (B) and inferior walls (arrow) of the left ventricle. LA, left atrium; RA,
views of noncompaction of the left ventricle. Areas of “spongy” right atrium.
appearing myocardium with deep sinusoids are seen in the lateral

and (4) color Doppler evidence of deep perfused intertrabecu- Doppler may suggest obstruction by the presence of a turbu-
lar recesses.116 lent jet at the site of the stenosis. Using continuous wave
Doppler through the obstruction, the total gradient may be
calculated, but obtaining individual gradients at each level
Conotruncal Abnormalities obstruction may not be possible. Though most patients with
unoperated tetralogy of Fallot have valvular pulmonic steno-
sis, an infrequent patient may have congenital absence of the
Tetralogy of Fallot
pulmonary valve with severe pulmonary insufficiency.120 In
The most common abnormality of conotruncal development the unoperated young adult who otherwise would not require
seen in adults is tetralogy of Fallot, a defect consisting of a cardiac catheterization, it is important to identify the origin
large subaortic/perimembranous VSD with malalignment of of the coronary arteries in the parasternal long axis view at
the infundibular septum; anterior and rightward displace- the level of the aortic valve.121 In some patients an aberrant
ment of the aortic root, such that the aortic valve “overrides” conus branch or left anterior descending artery can be identi-
the defect; obstruction to right ventricular outflow, which fied crossing the right ventricular outflow tract and could be
may occur at any level from subvalvular to the branch pul- transected if care is not taken during repair.
monary arteries; and right ventricular hypertrophy, resulting Adults with tetralogy of Fallot who present for care have
from the obstruction. The degree of aortic override from generally been repaired in late childhood or adolescence,
malalignment of the septum correlates with the severity of though some adults were palliated with a Blalock-Taussig
infundibular stenosis. The VSD with aortic override is the
most obvious echocardiographic finding in these patients
(Fig. 11.30) and is easily identified in the parasternal long axis
view on TTE.117 Another conotruncal abnormality, the
double-outlet right ventricle (DORV), can be confused with
tetralogy of Fallot on echocardiography if aortic override is
extreme. In DORV, both great arteries arise from the right
ventricle, and there is discontinuity between the posterior
wall of the aorta and the anterior leaflet of the mitral valve.
The diagnosis of DORV is made on TTE if more than 50%
of the aorta is seen to override the right ventricle and there
is aortic-mitral discontinuity, whereas the appropriate diag-
nosis is tetralogy of Fallot if more than 50% of the aorta
overrides the left ventricle and aortic-mitral continuity is
preserved.118,119 Right ventricular outflow obstruction can
occur at many levels, which must be evaluated in the patient
with tetralogy of Fallot.
Infundibular stenosis due to muscle bundle hypertrophy
and anterior displacement of the septum can be visualized
FIGURE 11.30. Parasternal long axis view of tetralogy of Fallot.
in the parasternal and subcostal short axis views at the base The aortic valve (AoV) overrides a large, subaortic VSD (arrow).
of the heart. Valvular stenosis and stenosis of the proximal There is marked hypertrophy of the right ventricle (RV). LV, left
pulmonary arteries can also be evaluated in this view. Color ventricle.
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se
FIGURE 11.31. Color Doppler flow image of the pulmonary valve
in the high parasternal short axis view. There is severe pulmonary
insufficiency.
shunt in childhood and never completed the repair. Serial
echocardiography is critical to the appropriate management
of the postoperative adult with tetralogy of Fallot. Most
of these patients, in whom repair included incisions across
the pulmonary annulus, many with transannular patches,
develop late severe, free-flowing pulmonary regurgitation as
a result (Fig. 11.31).122 Some patients develop aneurysmal dila-
tion of the prosthetic patch, which may be associated with
more severe pulmonary regurgitation. Continued volume
overload of the right ventricle produces systolic dysfunction
that is unlikely to improve if pulmonary valve replacement
is delayed until systolic dysfunction is symptomatic.123 Right
ventricular function, though difficult to precisely quantitate
echocardiographically, may be easily followed in a serial
fashion to monitor for the development of systolic dysfunc-
tion. Severe pulmonary insufficiency may beget right
ventricular dilation and tricuspid regurgitation, further com-
promising systolic function.124 In the patient with severe
valvular stenosis or pulmonary atresia who was repaired
with a right ventricle to pulmonary conduit, TTE and Doppler
may detect valve conduit stenosis due to pannus ingrowth
or valve calcification or conduit insufficiency. Echocardiog-
raphy also detects the sizable subset of adults with tetralogy
of Fallot repaired in childhood who now exhibit progressive
dilation of the aortic root with aortic regurgitation.125 Adults
who have been repaired uniformly exhibit a right ventricular
restrictive diastolic abnormality on spectral Doppler.126
Interestingly, this restrictive abnormality actually shortens
the duration of pulmonary regurgitation and is associated
with improved exercise performance in these patients.
D-Transposition of the Great Arteries
In patients with d-transposition of the great arteries (d-TGA),
there is both atrioventricular concordance and ventriculoar-
terial discordance, with the aorta arising from the anterior
right ventricle and the pulmonary artery originating from
the posterior left ventricle. The echocardiographic features
of the unoperated patient with d-TGA were outlined previ-
297
FIGURE 11.32. Transesophageal short axis view of the great vessels
in a patient with d-transposition of the great arteries. Both semilu-
nar valves appear in short axis. The pulmonary artery (PA) is seen
posterior and to the left of the aorta (Ao). In this transesophageal
image, the top of the sector corresponds to the transducer location
posterior to the heart in the esophagus.
ously and are shown in Figures 11.32 and 11.33. In d-TGA,
the aorta is usually anterior and to the right of the PA in
short axis views. Since the anomaly results in parallel cir-
cuits that would not be compatible with life, adult survivors
have necessarily undergone operations to restore the normal
flow pattern and allow oxygenation of systemic venous blood.
In the majority of adults, this procedure consisted of a com-
plete atrial septectomy with placement of either a pericardial
or prosthetic baffle in the atrium in the Mustard or Senning
operation, also known as the atrial switch procedure. The
interatrial baffle is saddle shaped and routes deoxygenated
blood from the vena cavae through the mitral valve into the
left ventricle and out to the pulmonary arteries. Oxygenated
blood returns from the pulmonary veins and is routed supe-
riorly over the baffle through the tricuspid valve to the right
ventricle and out the aorta. The interatrial baffle can be
FIGURE 11.33. Transesophageal long axis view of the great vessels
in a patient with d-transposition of the great arteries. The axes of
the pulmonary artery (PA) and aorta (Ao) are parallel rather than
orthogonal and the PA is posterior to the Ao.
298 chapter
FIGURE 11.34. Apical four-chamber view of a Mustard baffle in a
patient with d-transposition of the great arteries. Stenosis of the
pulmonary venous portion of the baffle is indicated by the narrow
color Doppler jet (arrow) from the pulmonary venous atrium (PVA)
toward the tricuspid valve. RV, right ventricle; LV, left ventricle.
directly visualized in the parasternal long axis view and in
the apical views on TTE as a linear echo within the left
atrium, and must be examined along its length for evidence
of leak or obstruction.127 Small leaks of the baffle are common,
and, if not seen on color Doppler imaging, may be revealed
by peripheral injection of saline contrast. The most common
site of baffle obstruction is within the systemic venous limb
at the SVC, but is unlikely to be visualized in adults by TTE.
Obstruction of the pulmonary venous limb of the baffle may
be suspected by a turbulent jet in the baffle on color Doppler
or by dilation of the pulmonary veins (Fig. 11.34). The gradi-
ent across the obstruction can be estimated from the dia-
stolic velocity obtained with spectral Doppler (Fig. 11.35). In
adults in whom acoustic windows and image quality are
poor, TEE clearly visualizes all limbs of the baffle (Fig. 11.36).
The systemic right ventricle with the usual curvature of the
right ventricular septum is seen in Figure 11.37.
FIGURE 11.36. (A,B) Transesophageal echocardiogram of a Mustard
baffle in the same patient with d-transposition of the great arteries
and obstruction of the pulmonary venous limb of the baffle (arrow,
11
FIGURE 11.35. Continuous-wave Doppler of the stenotic site in the
pulmonary venous limb of the Mustard baffle in the patient with
d-transposition of the great arteries shown in Figures 11.34 and
11.35. The mean gradient across the baffle stenosis is approximately
8 mm Hg.
Transesophageal echocardiography is also used to monitor
transcatheter interventions such as closure of baffle leaks
and stenting of SVC obstruction in these patients.128,129 Most
patients with d-TGA who have undergone the Mustard opera-
tion will exhibit systolic dysfunction of the systemic right
ventricle by early adulthood, though most remain asymp-
tomatic until the fourth decade. Transthoracic echocardiog-
raphy is used to follow systemic ventricular function and
monitor for AV valve regurgitation, another fairly common
problem in these patients.130 Patients with d-TGA may
develop subpulmonic obstruction that can be diagnosed by
Doppler. The arterial switch procedure for d-TGA involves
transection of the great arteries with reanastomosis to the
appropriate ventricle and reimplantation of the coronary
arteries. The operation restores normal flow direction, with
the left ventricle pumping to the systemic circulation and is
now the procedure of choice for patients with d-TGA. The
A). A convergence zone is seen on the pulmonary venous atrium
side of the baffle consistent with stenosis at that site (B).
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se 299

FIGURE 11.37. Parasternal short axis view of the ventricles in an

adult with d-transposition of the great arteries. The right ventricle
(RV) is dilated and the interventricular septum bulges into the left
ventricle (LV).

FIGURE 11.38. Apical four-chamber view of a patient with l-(con-

genitally corrected) transposition of the great arteries. The systemic
right ventricle (RV) with its moderator band (large arrow) and api-
cally placed septal leaflet of the tricuspid valve (small arrow) is to
first successful operation was performed in 1975, which the left of the left ventricle (LV).
means that these patients are now entering their 30s and 40s
and require continued echocardiographic monitoring for Persistent Truncus Arteriosus
supravalvular aortic and pulmonic stenosis and left ventricu-
lar dysfunction due to ostial stenosis of the coronary Persistent truncus arteriosus, an abnormality that results
buttons.131 from failure of partitioning of the conotruncal region of the
heart, is characterized by the presence of a single great vessel
positioned over a large outlet VSD (Fig. 11.40). The truncal
L-(Congenitally Corrected) Transposition valve has numerous, up to six, leaflets and, in adults, is
of the Great Arteries almost always regurgitant. Persistent truncus arteriosus is
In l-transposition of the great arteries (l-TGA), the ventric- classified by the origin of the pulmonary arteries. The pul-
ular loop forms to the left and results in inversion and mal- monary arteries may arise as a single vessel from the truncal
position of the ventricles with atrioventricular and
ventriculoarterial discordance. As in d-TGA, the great vessels
exit the ventricles in parallel, but in l-TGA the aortic valve
is usually anterior and to the left of the pulmonary valve in
short axis views at the base rather than to the right of the
pulmonary artery. Echocardiographically, the diagnosis is
established using multiple views to identify a rightward mor-
phologic left ventricle with smooth endocardium and basally
placed mitral valve and a leftward trabeculated right ventri-
cle with an apically displaced tricuspid valve and a moderator
band (Fig. 11.38). The great vessel exiting the morphologic
left ventricle is seen to course posteriorly and bifurcate into
a pulmonary artery while the aorta exits the anterior left-
sided right ventricle and extend anteriorly. Adult patients
usually have some degree of systolic dysfunction of the sys-
temic right ventricle that should be followed echocardio-
graphically, and most have regurgitation of the left-sided
tricuspid AV valve (Fig. 11.39).132 If a perimembranous VSD,
which occurs in 70% of patients with l-TGA, is not present,
the diagnosis may not be made until adulthood, when sys-
temic AV valve regurgitation and ventricular dysfunction
have already supervened. Because systemic AV valve regur-
FIGURE 11.39. Color Doppler image in the apical four-chamber
gitation is due primarily to morphologic abnormalities of the view of regurgitation of the systemic (tricuspid) atrioventricular
valve similar to Ebstein’s anomaly, operation is more likely valve in a patient with l-(congenitally corrected) transposition of the
to require replacement than repair. great arteries.
300 chapter 11

FIGURE 11.40. (A,B) Persistent truncus arteriosus (TA) is seen in the parasternal long axis view (A). There is a single great artery overriding
a large outlet VSD (arrow). A jet of truncal valve regurgitation is seen on color Doppler of the truncal valve (B).

artery, which then bifurcates, as separate vessels exiting artery pressure can be estimated by subtracting the gradient
from the posterior wall, as separate vessels from the sides of across the stenosis from the right ventricular systolic pressure.
the truncus, or discontinuous from the truncus and fed by After balloon pulmonary valvotomy, pulmonary regurgita-
collaterals from systemic arteries. tion or restenosis can occur and can be diagnosed on TTE.

Left Ventricular Outflow Obstruction

Obstruction to Ventricular Outflow
As with right ventricular outflow obstruction, obstruction of
flow from the left ventricle can occur at any level ranging
Right Ventricular Outflow Obstruction
from the outflow tract beneath the valve, to the valve itself,
Right ventricular outflow tract obstruction can occur at any to the supravalvular region of the ascending aorta or in the
level including the infundibulum, at the pulmonic valve, or descending thoracic aorta. The two least common types of
in the pulmonary arteries, all of which can be investigated outflow tract obstruction in adults are the subvalvular and
with 2D and Doppler TTE.133–137 Obstruction of outflow the supravalvular forms. Subvalvular stenosis in adults is
occurring below the pulmonary valve is a result of a fibro- usually a result of a discrete subaortic membrane or ridge just
muscular ridge or markedly hypertrophied muscle bundles in beneath the valve. Discrete subaortic stenosis may be seen
the infundibulum, an anomaly known as a double-
chambered right ventricle. A double-chambered right ventri-
cle can be difficult to differentiate from severe valvular
stenosis with secondary hypertrophy of the muscle bundles.
In double-chambered right ventricle, continuous-wave
Doppler through the infundibulum will reveal a velocity
spectrum characteristic of dynamic obstruction, with the
peak velocity occurring in late systole and a dagger-like
appearance similar to that seen in hypertrophic obstructive
cardiomyopathy involving the left ventricle. Stenosis of the
pulmonic valve is characterized by thickening and restricted
motion of the tips of the valve leaflets with systolic doming,
which is most clearly seen in the parasternal and subcostal
short axis views at the base of the heart (Fig. 11.41). The bifur-
cation of the main pulmonary artery can be identified from
a high parasternal transducer location to assess for narrowing
of the main pulmonary artery or the branches at their takeoff
from the main pulmonary artery. Stenosis of more distal
branch pulmonary vessels cannot be visualized echocardio-
graphically. The pressure gradient across the stenosis is esti-
mated using the modified Bernoulli equation from the peak
velocity obtained using continuous-wave Doppler (Fig.
11.42).138 In patients with tricuspid regurgitation, the right FIGURE 11.41. High parasternal view of the pulmonic valve (PV)
ventricular systolic pressure can be calculated from the peak in a patient with pulmonic stenosis. The leaflet tips have restricted
velocity of the tricuspid regurgitation jet. The pulmonary motion causing characteristic doming in systole (arrow).
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se
FIGURE 11.42. Continuous-wave Doppler across the pulmonic
valve with a peak pressure gradient of 52 mm Hg, consistent with
moderate pulmonic stenosis.
in isolation or after surgical repair of congenital heart defects
such as the AV canal. The membrane is identified on 2D TTE
in the parasternal long axis or apical views as a linear echo
originating from and perpendicular to the interventricular
septum (Fig. 11.43). If the membrane itself is not seen, a high-
velocity color jet in systole originating just below and directed
toward the valve may raise suspicion of its existence. Con-
tinuous-wave Doppler permits estimation of severity of ste-
nosis.139–141 Some degree of aortic regurgitation caused by
aortic leaflet trauma from the high-velocity stenotic jet is
seen in up to 80% of patients in one study of 134 adults with
the anomaly, but was more than mild in <20% of patients
and did not appear to progress during a follow-up of 4.8
years.142 This suggests that resection of mildly or moderately
FIGURE 11.43. (A,B) Apical five-chamber view in a patient with
discrete subaortic stenosis with aortic regurgitation. A bright linear
echo of the ridge of tissue is seen below the aortic valve (arrow, A).
A small jet of aortic insufficiency is noted in B.
3 01
obstructive membranes is not necessary in asymptomatic
patients as was previously recommended to prevent progres-
sion of aortic insufficiency. Two other forms of subvalvular
stenosis, the fibromuscular type and the tunnel type, are
infrequently seen in adults. Supravalvular stenosis may occur
as a discrete membrane typically located at the sinotubular
junction, as an hour-glass deformity of the ascending aorta
(the most common type) associated with “elfin” facies and
hypercalcemia as part of the Williams syndrome, or as diffuse
hypoplasia of the ascending aorta and arch. Two-dimensional
images from a high parasternal and suprasternal notch trans-
ducer locations may be necessary to view these defects.143
Continuous-wave Doppler can accurately estimate the pres-
sure gradient across discrete stenosis, but is unreliable if
serial obstruction exists at multiple levels and in the tunnel
form of supravalvular aortic stenosis.
Congenital aortic valve stenosis in adults is almost
always a result of a bicuspid aortic valve that was normal at
birth and became increasingly stenotic over time. Bicuspid
aortic valves are the most common congenital cardiac
anomaly occurring in 1% to 2% of the general population.
Restricted motion of the leaflet tips relative to the body of
the leaflet resulting in systolic doming of the valve in the
parasternal long axis view may first suggest a bicuspid aortic
valve. Valve morphology and leaflet number can be deter-
mined on 2D imaging from the parasternal short axis plane
in most adults.144,145 A true bicuspid aortic valve has two
cusps (though a raphe may give the illusion of a third cusp)
with two sinuses of Valsalva. Although a raphe may give the
appearance of three cusps in diastole, valve opening in systole
confirms the diagnosis when the two cusps are clearly seen.
This is visualized especially well on TEE (Fig. 11.44). As with
the other forms of left ventricular outflow obstruction, trans-
valvular pressure gradients derived from Doppler velocities
can be used to estimate the severity of valvular aortic steno-
sis. Aortic valve area can be calculated using the continuity
equation.146 A rare abnormality of aortic valve anatomy is the
quadricuspid aortic valve, which is more likely to be insuf-
ficient than stenotic (Fig. 11.45). The other two valve mor-
phologies associated with congenital aortic stenosis, the
FIGURE 11.44. Transesophageal echocardiogram of a bicuspid
aortic valve. There are two cusps and two sinuses of Valsalva in this
valve.
302 chapter 11

FIGURE 11.45. (A,B) A quadricuspid aortic valve is seen on a transesophageal echocardiogram short axis view in diastole (A) and systole (B).

acommissural valve and the unicuspid, unicommissural
valve, are seen in children and rarely in the adult. Aortic
stenosis in childhood is often treated by percutaneous balloon
valvotomy, which may result in early or late aortic regurgita-
tion and late restenosis that is readily diagnosed by 2D TTE.
Some children with severe aortic stenosis or insufficiency
undergo the Ross operation in which the diseased aortic
valve is excised, the native pulmonary valve is transected
and anastomosed to the aortic annulus, and a pulmonary
homograft is placed in the pulmonary position. These patients
should undergo serial echocardiographic surveillance
for development of autograft dilation and insufficiency
(Fig. 11.46).147
Coarctation of the aorta may take one of several forms,
but is most commonly caused by a discrete shelf of tissue in
the descending thoracic aorta just distal to the ostium of the
left subclavian artery near the insertion of the ligamentum
arteriosum. Approximately 80% to 85% of patients with
coarctation of the aorta have a bicuspid aortic valve, though
the opposite is not true. The coarct site is most likely to be
visualized by 2D TTE from a suprasternal notch transducer
position (Fig. 11.47) with a mosaic high velocity jet at the site
of the stenosis on color Doppler.148–150 However, the descend-
ing thoracic aorta distal to the coarctation may not be seen
clearly in adults, thus obscuring the diagnosis. Color-guided
continuous-wave Doppler provides an estimate of the gradi-
ent across the coarctation with certain caveats: (1) The gradi-
ent across the narrowing is flow dependent, so it may be
lower when the patient is at rest. Exercise such as treadmill
walking or leg lifts may increase the peak gradient across the
coarct, but may also cause flow to continue across the ste-
nosis into diastole, a sensitive indicator of more severe ste-
nosis. (2) The coexistence of a patent ductus arteriosus with
diversion of blood proximal to the coarct to the pulmonary
artery causes the Doppler to underestimate the true gradient
as will the presence of large or numerous collaterals around
the coarctation. (3) Severe aortic stenosis from a bicuspid
valve also results in falsely low gradient. A higher gradient
may be revealed after aortic valve replacement. An example
of continuous wave Doppler of severe coarctation is seen in
Figure 11.48. Operative coarct repair in childhood may have
been done by one of several methods, such as creation of a
subclavian flap as a patch, excision of the coarct with reanas-
tomosis of the proximal and distal aorta, or placement of an

FIGURE 11.46. (A,B) Two-dimensional (A) and color Doppler (B) transesophageal echocardiogram of aortic valve and proximal aorta in a
patient who has undergone the Ross operation. There is severe aortic insufficiency noted in the left ventricular outflow tract.
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se
FIGURE 11.47. Suprasternal notch view in a patient with coarcta-
tion of the aorta. There is marked narrowing just distal to the
takeoff of the left subclavian artery (arrow). The ascending aorta
(AAo) is aneurysmal.
interposition conduit. Knowledge of the type of repair is
important to adequately assess for late problems. Potential
late complications of coarct repair include restenosis of the
coarct site and aneurysm of the descending aorta proximal
to or just distal to the repair. In addition, aortic stenosis can
develop as can aneurysms of the ascending aorta related to
abnormalities of the media of the vessel wall. Transthoracic
echocardiography and TEE can be used to visualize each of
these complications or sequelae of coarctation of the aorta.
Miscellaneous Congenital Anomalies
Systemic to Pulmonary Artery Shunts
The most common native extracardiac left-to-right shunt
seen in adults is the patent ductus arteriosus (PDA). The
ductus arteriosus, which normally closes at birth, is a normal
structure of the fetal vascular circuit that diverts blood from
FIGURE 11.49. (A) A large patent ductus arteriosus (pda) is visualized connecting the descending thoracic aorta (Ao) and the pulmonary
artery (PA). (B) A low-velocity jet is seen on color Doppler.
303
FIGURE 11.48. Continuous-wave Doppler through the coarctation
site demonstrates a peak pressure gradient of 68 mm Hg.
the pulmonary artery directly to the descending aorta bypass-
ing the lungs. In certain individuals, particularly infants
with other congenital cardiac defects or who are premature,
the ductus may remain patent. The right-to-left shunt present
in utero will reverse as pulmonary vascular resistance drops
in the first week of life and a left-to-right shunt will ensue.
The size of the shunt is determined by the diameter of the
vascular connection and the pulmonary vascular resistance.
In patients with large left-to-right shunts, the development
of fixed pulmonary vascular disease will cause the shunt to
again reverse with resultant differential cyanosis of the lower
extremities. The ductal vessel is rarely seen directly in adults
on TTE, but may be visualized in children from the supra-
sternal or high parasternal transducer location in the short
axis view. It may be clearly seen on TEE (Fig. 11.49). In the
typical patient with small PDA, a narrow high-velocity con-
tinuous color jet may be identified entering the main pulmo-
nary artery adjacent to the left pulmonary artery directed
retrograde to the pulmonary valve (Fig. 11.50). This is best
304 chapter
FIGURE 11.50. Color Doppler of the pulmonary artery in the high
parasternal view shows a narrow jet (arrow) originating just proxi-
mal to the bifurcation of the pulmonary artery directed retrograde
to the pulmonic valve.
seen in the high parasternal imaging plane.151–153 Continuous-
wave Doppler of the descending aorta may reveal retrograde
diastolic flow indicating left-to-right shunting through the
ductus. Two-dimensional and Doppler TTE and TEE are also
ideal for monitoring PDA during and after percutaneous
closure (Fig. 11.51).154
Rarely, a sinus of Valsalva aneurysm, a result of localized
weakening of the media of the sinus, may occur. On TTE,
a sinus of Valsalva aneurysm is characterized by localized
bulging of the sinus, often into the right ventricle (Fig.
11.52).155 Color Doppler of unruptured aneurysms may dem-
onstrate aortic regurgitation due to abnormal geometry
of and failure of valve coaptation in diastole. The aneurysm
may rupture into any cardiac chamber; aneurysms of
the right coronary sinus typically rupture into the right
ventricle and those of the noncoronary cusp rupture into
the right atrium, resulting in a continuous left-to-right
shunt easily imaged by color Doppler.156–159 Transesophageal
FIGURE 11.52. (A,B) Transesophageal echocardiogram in the long
axis plane of a sinus of Valsalva aneurysm. The marked dilation of
the sinus in each patient is noted (arrow, A and B). The aneurysm
11
FIGURE 11.51. On transesophageal echocardiogram of the descend-
ing thoracic aorta (DAo) in the long axis plane, a bright circular
structure is identified (arrow), which represents the distal aspect of
a coil inserted into this patient’s patent ductus arteriosus.
echocardiography may visualize the defect more clearly
than TTE.160
The most common surgically constructed systemic-to-
pulmonary shunts seen in the adult population are the Glenn
anastomosis of the superior vena cava to the pulmonary
artery, and the Blalock-Taussig shunt from either subclavian
artery to the ipsilateral pulmonary artery. Generally, the
conduit itself is not visualized on 2D imaging in adults;
however, spectral Doppler can be used to assess the pressure
across the circuit, and thus estimate pulmonary artery
pressure.
Coronary Artery Abnormalities
Anomalous origin of coronary arteries occurs in approxi-
mately 1% of adults undergoing cardiac catheterization. The
most common type is origin of the left circumflex from the
right coronary sinus and is usually benign and discovered
has distorted the aortic annulus in the patient in B, who has signifi-
cant aortic insufficiency noted on color Doppler flow.
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se
incidentally on coronary angiography. The variants associ-
ated with myocardial ischemia and death are the origin of
the left main coronary artery from the right coronary artery
passing between the two great arteries and origin of the left
coronary artery from the pulmonary artery with reversal of
coronary flow. Both of these entities may cause myocardial
infarction and congestive heart failure. Transthoracic 2D
imaging in the basal short axis plane at the level of the aorta
may be useful for imaging coronary artery ostia in some
adults.161 In adults, TEE is far superior to TTE for localizing
coronary ostia.162–164 In some individuals, the proximal half
of the artery may be seen. Coronary arterial fistulas may
appear as turbulent jets on TEE or as hugely dilated vessels
seen on TEE.165–167
Summary
Transthoracic echocardiography and transesophageal echo-
cardiography are ideally suited for the initial diagnosis, man-
agement, and continued surveillance of adults with congenital
heart defects. Indications for echocardiography in these
patients have been established. The study should be per-
formed in a deliberate, segmental fashion.
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 1 Congenital Heart Disease
2 in the Adult:
Interventional Therapy
Charles E. Mullins
History and General Considerations . . . . . . . . . . . . . . . .
Valvular Stenoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Obstruction of the Great Vessels . . . . . . . . . . . . . . . . . . .
Intravascular Stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Coarctation of the Aorta . . . . . . . . . . . . . . . . . . . . . . . . . .
Systemic Veins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pulmonary Veins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Occlusion of Intracardiac Defects . . . . . . . . . . . . . . . . . .
Occlusion of the Patent Foramen Ovale . . . . . . . . . . . . .
Occlusion of Ventricular Septal Defects and Other
Abnormal Intracardiac Communications . . . . . . . . .
Key Points
• Balloon valvuloplasty and balloon angioplasty now are
applied effectively to all four cardiac valves and all major
blood vessels in children with cardiovascular diseases.
• Aortic valvuloplasty is done in children with valvular
aortic stenosis with a systolic gradient greater than or
equal to 50 mm Hg at rest, or a peak gradient of 40 to
50 mm Hg with symptoms or signs of ischemia.
• The most typical form of congenital mitral stenosis con-
sists of thickened leaflets and shortened chordae tendin-
eae with decreased interchordal spaces. Other forms
include supravalve mitral membrane and a parachute
mitral valve.
• The techniques for relieving congenital or surgically
acquired vascular lesions by balloon angioplasty and
stents now are routine and employed with variable
success for stenoses anywhere within the great vessels.
• The discrete, shelf-like coarctation of the aorta represents
the ideal lesion for successful dilation.
• Obstruction to systemic veins in patients with congeni-
tal heart disease usually is iatrogenic.
• Congenital pulmonary vein stenosis is very rare and
usually occurs with other congenital heart lesions with
or without associated surgical intervention.
• The final suitability of an atrial septal defect for trans-
catheter closure is determined by transesophageal
echocardiography (TEE) and confirmed during cardiac
311 Device Occlusion of Miscellaneous Intracardiac
312 Communications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
317 Occlusion of Extracardiac Intravascular
317 Communications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
320 Occlusion of the Other Abnormal Extracardiac
321 Vascular Communications . . . . . . . . . . . . . . . . . . . . . 332
322 Miscellaneous Therapeutic Catheter Procedures . . . . . . 333
322 Catheter Removal of Foreign Bodies . . . . . . . . . . . . . . . . 335
326 Collaborative (Hybrid) Therapeutic Catheterization
and Surgical Procedures . . . . . . . . . . . . . . . . . . . . . . . 336
327 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
catheterization with an accurate balloon sizing of the
defect.
• The major indications for closing a patent foramen ovale
(PFO) are significant right to left shunting through it, and
a documented central nervous system (CNS) embolic
event in the presence of a PFO.
• Interventional cardiologists have been occluding the
patent ductus arteriosus (PDA) nonsurgically for almost
four decades.
History and General Considerations
As cardiovascular surgeons have become more technically
adept at performing surgery for congenital heart disease in
smaller, sicker, and bluer patients, they have expected and
required better diagnostic information about those same
patients. The same surgical interventions for these patients
stimulated not only the requirement for better angiography
and diagnostic cardiac catheterization in these patients
by the catheterizing cardiologists but also intensified the
desire to perform these treatments in the catheterization
laboratory. To accomplish these goals, pediatric interven-
tionalists have been at the forefront of development of
new catheterization techniques and better imaging systems.
Along with better diagnoses and imaging, there has been
an explosion of new therapeutic catheters, devices, and
procedures for use in the pediatric as well as the growing
311
312 chapter
population of surviving adults with congenital heart
disease.
Historically, pediatric cardiac catheterization began
moving from strictly diagnostic to therapeutic catheteriza-
tions in 1966 when Rashkind and Miller1 introduced balloon
atrial septostomy for babies with transposition of the great
arteries. This procedure was lifesaving for a very limited
number of patients, but of equal importance, it demonstrated
that transcatheter intracardiac procedures could be per-
formed relatively safely in small babies with excellent long-
term results.
During the same time period, the development of diag-
nostic cardiac catheterization was advanced by the introduc-
tion of transseptal left heart catheterization by Cope2 and
Ross et al.3 and Roveti et al.4 This procedure became widely
used in pediatric cardiology when Duff and Mullins5 intro-
duced the long transseptal sheath in 1978. The long trans-
septal sheath encouraged the development of the Park blade
septostomy procedure, permitting the septostomy concept to
be applied to the older patient with complex lesions.6
The most recent and dramatic advances in interventional
cardiology began in 1978 when Gruentzig and Hopff7 dem-
onstrated that fixed-diameter cylindrical balloons could be
positioned within a stenosis in a vessel and when inflated at
high pressure the obstruction was relieved. In 1982, Kan et
al.,8 using much larger diameter balloons, applied this tech-
nique to pulmonary valvular stenosis in congenital heart
patients. The results were excellent and were accepted enthu-
siastically by pediatric cardiologists, with rapid extension of
the technique to the other cardiac valves and to vascular
obstructions. Balloon valvuloplasty and balloon angioplasty
now are applied effectively to all four valves and all major
blood vessels and in children with cardiovascular disease. In
the relatively short time since its inception, balloon valvu-
loplasty has led to a tremendous increase in technology,
including the development and use of balloon-expandable
stents in conjunction with the dilation of vessels. During
this same time span, there were dramatic developments in
transcatheter devices and techniques for closing abnormal or
persistent intracardiac and vascular communications. Ini-
tially these devices were only for the occlusion of aortopul-
monary collateral vessels, but soon evolved into the closure
of the patent ductus arteriosis and intracardiac septal
defects.
As patients with operated congenital heart disease have
reached adulthood, it has become clear that many have resid-
ual cardiovascular problems, which are particularly difficult
to approach surgically. Therapeutic cardiac catheterization
procedures in many instances now offer alternatives to
surgery for these patients. This chapter discusses therapeutic
interventional catheterization techniques, which should be
considered when evaluating the adult with congenital heart
disease. A brief technical description of each procedure is
included.
Each congenital lesion is somewhat different from the
same lesion in another patient. Cardiac catheterization of
these patients requires a three-dimensional understanding
and visualization of the anatomy, which in turn, requires
biplane fluoroscopic and angiographic visualization. Each
procedure requires special technical skills and training in
order to perform the individual catheter manipulations and
12
to use the specialized catheters and devices. Each procedure
also requires a large inventory of specialized and expensive
expendable equipment. In addition to the training in the use
of the equipment, the cardiologist performing these proce-
dures must have training and experience in when to use the
various techniques or devices and must know the contrain-
dications for each device. Obviously, not every center should
plan to perform every type of therapeutic catheterization
procedure on congenital heart patients. However, all cardi-
ologists who care for these patients must be aware that these
procedures are available in order to advise their patients most
appropriately of the therapeutic options.
Valvular Stenoses
General Considerations
In the 25 years since Kan et al.8 first introduced the concept
of balloon valvuloplasty for the pulmonary valve, techniques
have developed rapidly for the aortic, mitral, and tricuspid
valves. Early in the experience with these techniques, the
voluntary Valvuloplasty and Angioplasty of Congenital
Anomalies (VACA) registry was established. This registry
included 28 centers where these procedures were performed.
This registry was intended to record primarily the basic
results and the complications of dilation procedures.9 The
registry rapidly accumulated information on a large number
of patients with a large variety of lesions undergoing dilation
procedures by pediatric cardiologists. Now there are many
additional reports documenting the results of these proce-
dures in both pediatric and adult patients with congenital
and acquired heart disease. There is a place for balloon dila-
tion of stenosis of each of the four cardiac valves. These pro-
cedures have special applications in selected adult patients,
especially women during later stages of pregnancy and in the
elderly.
Before a valvuloplasty procedure is performed a complete
diagnostic cardiac catheterization is performed to document
the exact anatomy and hemodynamics of the lesion and
exclude additional congenital or acquired heart disease.
Angiography is performed to delineate the anatomy of the
valve exactly and measure the valve annulus very precisely.
Additional angiography may be necessary to evaluate valvu-
lar insufficiency prior to balloon valvuloplasty, particularly
for the left-sided valves. A catheter with calibrated centime-
ter marks embedded in it, a calibration grid, a large sphere
of known size, or a calibrated centimeter reference system
built into the x-ray system should be used as the reference
measurement. Using the diameter of a catheter as the refer-
ence for large structures leads to huge calibration errors. The
reference object must be recorded in the exact plane of the
valve, which is being dilated in order to achieve accurate
measurements of the valve.
Dilation of Pulmonary Stenosis
With the current safety of this procedure in experienced
hands, the indications for transcatheter intervention for
pulmonary valvular stenosis are less stringent than the
indications for the comparable surgical valvuloplasty. The
 c ong e n i ta l h e a rt di se a se i n t h e a du lt
indications for treatment of pulmonary stenosis include sig-
nificant right ventricular outflow tract obstruction, any evi-
dence of right ventricular hypertrophy, and any evidence of
right ventricular fibrosis or dysfunction.10 The severity of
pulmonary valvular stenosis correlates quite well with the
peak instantaneous gradient by echo, but is determined
definitively at catheterization by the peak systolic gradient
across the valve in the presence of normal cardiac output. A
gradient of less than 10 mm Hg is considered trivial, 10 mm Hg
to less than 30 mm Hg is considered mild, 30 to 60 mm Hg is
considered a moderate obstruction, and greater than 60 mm Hg
is considered severe stenosis. Natural history studies have
documented that moderate and severe pulmonary valve ste-
nosis tend to develop more obstruction with time, whereas
mild pulmonary valve stenosis usually does not progress.11,12
At the time of catheterization, a favorable valve with fused
commissures, a peak systolic gradient of 30 mm Hg or more
across the pulmonary valve, and association with clinical
evidence of right ventricular hypertrophy or dysfunction
should undergo catheter intervention.
There are a variety of balloons in use for pulmonary val-
vuloplasty. These are cylindrical, predominantly polyethyl-
ene balloons that are noncompliant and have parallel walls
at the fixed, predetermined diameter at the maximum infla-
tion pressure. The balloons are available in a wide range of
diameters from as small as 2 mm to as large as 26 mm. When
inflated to their maximum recommended pressure of
between 2.5 and 12 atmospheres, they reach their advertised
fixed diameter and become very rigid.13 The balloon is pre-
pared by purging it of air with repeated flushing and low-
pressure inflations with a solution of contrast, which is
diluted with saline in a 1 : 5 dilution. The same contrast solu-
tion is used to inflate the balloon during the balloon
valvuloplasty.
To perform the valvuloplasty, the pulmonary valve, valve
annulus, right ventricular outflow tract, and main and branch
pulmonary arteries are imaged with a right ventricular
angiocardiogram in the posteroanterior (or cranially angu-
lated posteroanterior) and lateral views.13 Measurements of
the valve annulus diameter are obtained using an accurately
calibrated reference. Preferentially, a double-balloon dilation
procedure is used for the pulmonary valve. Not uncommonly,
the valve annulus is too large for a single-balloon technique
(greater than 18 mm in diameter), or the use of a single very
large balloon would require the introduction of a very large
and traumatic balloon surface profile into the vein. Under
these circumstances, the double-balloon technique is used.14
The balloon diameters of the two balloons are chosen so that
the sum of the diameters of the two inflated balloons is 1.5
to 1.6 times the diameter of the pulmonary valve annulus.14
Of equal importance to the size of the annulus being too
large for a single balloon, the double balloons allow the
introduction of two much smaller profile balloons, and when
the two balloons are inflated simultaneously within the
annulus, they provide two persistent lumina adjacent to the
inflated balloons within the annulus. For these reasons,
the double-balloon technique is preferentially employed,
even when a single larger balloon may be available.10,13,14 The
length of the balloons is chosen according to the patient’s
size. In general, much longer balloons (6 to 8 cm) are used in
the adult congenital patient.
313
An end-hole diagnostic catheter is advanced through the
right heart and into the distal left pulmonary artery. It is
important that this catheter passes through the center of the
tricuspid valve and not between or through the chordal
attachments. A stiff exchange guidewire is passed through
this catheter and into a large distal left pulmonary artery.
With the wire carefully fixed in place, the catheter is with-
drawn and replaced with the previously prepared balloon
catheter. The balloon catheter is advanced over the wire until
the balloon is centered across the annulus. This procedure is
repeated with a second catheter from a second femoral intro-
ductory site for the second balloon.
Exact centering of the balloons on the valve is important
so that the balloons are not squeezed forward or backward
out of the valve during inflation. The balloons are inflated
to their designated maximum pressures using inflation
devices that include a pressure manometer. The balloons are
observed first for the development of a “waist” or circumfer-
ential indentation in the balloons, followed by disappearance
of the waists with further inflation. Once the waist disap-
pears or the maximum pressure of the balloon is achieved,
the balloons rapidly are deflated, with the entire inflation/
deflation cycle taking place over less than 10 to 15 seconds.
This process is repeated several times with slight to-and-fro
repositioning of the balloons to ensure their centering across
the valve.13 In the presence of a very large annulus, a balloon
dilation using three balloons may be more satisfactory than
two very large balloons. Occasionally, only one venous access
is available, or an operator chooses to use a single balloon for
a pulmonary valve dilation. When a single balloon is used,
the diameter of the single balloon should be 1.3 to 1.4 times
the diameter of the valve annulus.10,13
As the first valve to be successfully dilated and with the
relatively easy approach to this valve, data on pulmonary
valve dilation accumulated rapidly. In 1990 the voluntary
VACA registry reported on the results of 784 pulmonary
valvuloplasties, including 33 neonates, 716 children, and 35
adults.15 For the whole group of patients, the gradient across
the pulmonary valve decreased from 71 ± 33 mm Hg to 28 ±
21 mm Hg, with an incidence of complications of only 1.3%.
In the VACA registry, there was no difference in success of
the procedure with age, but only nine adults between the
ages of 21 and 79 years were included in the analysis. In 196
of the VACA patients, the residual gradient was subdivided
into infundibular (18 ± 24 mm Hg) and transvalvular (16 ±
15 mm Hg).15 Unsuccessful procedures were associated with
dysplastic valves and, remarkably, with the inability to cross
the valve by less experienced operators. Pulmonary balloon
valvuloplasty now is the procedure of choice for children and
adults with pulmonary valvular stenosis.
The experience at Texas Children’s Hospital has been
very positive and similar to that in the VACA report. Pulmo-
nary valvuloplasty was performed in 102 patients including
three patients who were 51, 71, and 76 years of age.13,16 The
mean gradient was reduced by 69% for the whole group, and
the valve angiographically opened significantly more than
prior to valvuloplasty. There often was an associated dynamic
or reactive infundibular narrowing, which often actually
increases immediately following the valvuloplasty. The
residual infundibular gradient tends to decrease with
time.13
314 chapter
There is less information available for adult patients with
pulmonary valvular stenosis because it is relatively rare for
a patient with this lesion to reach adulthood without prior
diagnosis and treatment. Chen and colleagues17 reported
their experience in 53 adolescent and adult patients 13 to 55
years of age. With pulmonary balloon valvuloplasty, the sys-
tolic pressure gradient across the pulmonary outflow tract
decreased from 91 ± 46 mm Hg to 38 ± 32 mm Hg in their
patients. There was a further decrease in gradient at follow-
up catheterization in nine patients who were restudied.
Teupe et al.18 reported a similar experience in 24 adult
patients who were 19 to 65 years of age, 14 of whom had late
follow-up of 5 to 9 years. In those 14 patients, the mean peak
systolic gradient prior to valvuloplasty was 82 ± 29 mm Hg.
Immediately after intervention, the gradient fell to 37 ±
14 mm Hg, and it was 31 ± 7 mm Hg at a mean follow-up of
6.5 years. Three patients in this study had a peak systolic
gradient of more than 100 mm Hg prior to valvuloplasty. All
three had high residual gradients immediately after the pro-
cedure, which were shown to be dynamic in nature. In these
three patients, the subvalvular hypertrophy resolved by 3
months following the procedure, and they had a permanently
lower gradient at late follow-up. Both authors felt that balloon
valvuloplasty for pulmonary valvular stenosis in the adult is
highly effective and associated with an excellent long-term
outcome.17–19 Now a much better relief of the gradient would
be expected.
Dilation of Aortic Stenosis
Aortic valve dilation was first reported by Lababidi20 in 1984.
This technique was slower to gain acceptance than pulmo-
nary valvuloplasty because of concerns of producing poten-
tial aortic regurgitation. The early and subsequent follow-up
experience has been favorable, without an inordinately high
incidence of this complication. The alternative of surgical
valvotomy is not without this complication and often results
in valve replacement, which is best delayed as long as possi-
ble in children and adolescents because of size issues and
difficulties with anticoagulation. Children, adolescents, and
young adults with congenital aortic valve stenosis now rou-
tinely undergo balloon valvuloplasty. Indications for balloon
valvuloplasty of the aortic valve are similar to those for sur-
gical intervention for aortic stenosis. Although no single set
of diagnostic criteria is agreed upon when judging the sever-
ity of aortic stenosis, most pediatric cardiologists would
agree that in the presence of normal cardiac output, a systolic
gradient of ≥50 mm Hg at rest, or a peak gradient of 40 to
50 mm Hg with symptoms and/or signs of ischemia indicate
the need for some form of intervention.21
A major contraindication to performing aortic balloon
valvuloplasty is the presence of more than 2+ aortic regurgi-
tation, as 25% to 30% of patients develop some increase in
degree of regurgitation with this procedure.13
The balloon catheters are similar to those used for the
pulmonary valve, with the exception that longer, 6- to 8-cm
balloons are utilized to help stabilize them across the aortic
valve. The longer balloons are less likely to be ejected from
the valve with inflation during systole. In addition to the
longer balloons, the use of Super StiffTM wires (Boston
Scientific, Natick, MA) and rapid ventricular pacing during
12
inflation helps to stabilize the balloons in the aortic orifice.
Although a single-balloon technique was originally
described,21 many centers have switched to a double-balloon
technique for the same advantages seen in pulmonary valve
dilation.13,14,21 When the double-balloon technique is used,
the combined diameter of the two balloons is a maximum
of 1.1 to 1.2 times the measured diameter of the aortic valve
annulus.13,14,21 If only one balloon catheter is used, the diam-
eter of the single balloon should be approximately the same
as the diameter of the aortic annulus.21
The procedure requires a full cardiac catheterization
with complete hemodynamic measurements including
simultaneous measurements of left ventricular and ascend-
ing aorta pressures along with an assessment of cardiac
output. A transseptal approach allows a transseptal sheath
to be positioned in the left ventricle, and by using a floating
balloon catheter one French size smaller advanced through
the transseptal sheath and into the ascending aorta, simul-
taneous left ventricular and ascending aorta pressure
measurements are obtained before, during, and after aortic
valve dilation without a separate arterial catheterization or
exchange of any balloons/catheters. Angiograms are obtained
in the left ventricle and ascending aorta, and using a large-
diameter calibrated reference grid or calibrated marker cath-
eter, careful measurements of the diameter of the aortic
valve annulus are obtained. The presence and amount of
aortic regurgitation must be evaluated initially to assess
appropriateness of valvuloplasty.
Once the catheters are introduced into the left heart,
heparin, 100 U/kg, is administered intravenously. The appro-
priate-size balloons are chosen and prepared using a dilute
solution of contrast and saline (1 : 5). Two end-hole catheters
are introduced into separate femoral arteries, and advanced
retrograde across the aortic valve into the left ventricular
apex. A 180-degree curve is preformed at the transition area
between the stiff and floppy portions of the distal ends of
two Super Stiff exchange wires. One by one, the wires are
positioned through the end-hole catheters into the left ven-
tricular apex with the floppy tip curled toward the outflow
tract. With both wires fixed securely in position, the end-hole
catheters are withdrawn. The two balloon catheters are
advanced retrograde into position across the aortic valve
annulus. The balloons are centered side by side across the
valve, the patient is paced at 200 beats/min, and the balloons
are inflated until the waist of circumferential narrowing
disappears. It is important to keep the balloons stable within
the valve annulus by the use of stiff wires, rapid [200 to 240
beats per second (bps)] ventricular pacing just before and
during the balloon inflations, and maintenance of proper
positioning of the wires in order to prevent “shear” trauma
against the leaflets from the balloons moving in and out of
the valve. The total inflation/deflation cycle should be com-
pleted within 10 to 15 seconds. Balloon inflations are repeated
as many as four to eight times while repositioning the balloon
catheters within the valve as necessary. After completion of
the balloon inflations, the balloons are withdrawn to the
descending aorta, the measurement of the valve gradient is
performed and angiography in the aortic root is repeated. The
balloons and the sheaths are withdrawn, and hemostasis
achieved by careful pressure over the femoral puncture
sites.
 c ong e n i ta l h e a rt di se a se i n t h e a du lt
It is preferable to delay valve replacement as long as
possible—optimally well into adulthood and past the child-
bearing years for women. Realizing that both surgical val-
votomy and balloon dilation are palliative, both children and
younger adults with aortic stenosis that is severe enough to
warrant intervention are offered the alternative of balloon
valvuloplasty. Although long-term outcome studies of aortic
balloon valvuloplasty are just now appearing, it does appear
that this procedure is comparable to surgical valvotomy for
the short- and midterm relief of aortic stenosis. This is sup-
ported by reports by Justo and colleagues22 and by the VACA
registry.23 Justo et al. compared 110 patients with balloon
valvuloplasty to 103 patients following surgical valvotomy
and demonstrated that the left ventricle to aorta pressure
gradient is reduced equally well in both, with the procedures
having a similar likelihood of having recurrence of the aortic
stenosis with time. Additionally, their study verified that the
risks of creating aortic valve regurgitation by either surgical
valvotomy or balloon valvuloplasty were equal and equally
unpredictable.
The report of the VACA registry, which examined results
in 606 patients from 23 participating institutions, also dem-
onstrated a comparable relief of obstruction and a similar
incidence of aortic insufficiency.23 In this report, the left
ventricle to aorta systolic gradient was reduced by a mean of
60% ± 23%, with 7.3% (n = 46) developing either severe aortic
insufficiency, or an increase in valve insufficiency of equal
to or greater than two grades. Independent predictors of
development of more severe aortic regurgitation included an
increased balloon to annulus ratio, larger diameter valves,
and the presence of preexisting aortic regurgitation (mild or
more), all presumed to signify valves with morphologic
abnormalities that can be exacerbated by valvuloplasty.23
Procedure-related mortality for this large cohort of patients
was 1.9%. The procedure could not be performed or com-
pleted in 4.7%, with a suboptimal result in 17%. Both sub-
optimal outcome and mortality were highly correlated with
young age (<3 months). Midterm follow-up studies continue
to suggest that aortic balloon valvuloplasty is an effective
and relatively safe palliation for children and adolescents
with valvular aortic stenosis.24,25
Balloon valvuloplasty of the aortic valve has outcomes
for young adults with bicuspid aortic valve that are similar
to those in children,26 and it is utilized in young adults with
significant stenosis. Balloon valvuloplasty is useful particu-
larly in those adults in whom anticoagulation presents an
increased risk due to lifestyle or employment demands and
in women who are interested in becoming pregnant (because
of the known teratogenic effects of warfarin anticoagula-
tion). Balloon valvuloplasty of the calcific aortic valve in the
elderly is unlikely to result in any beneficial effect,27,28 and,
as a consequence, valve replacement is the procedure of
choice in the presence of a calcified valve. Lieberman et al.27
evaluated the results in 165 symptomatic adult patients who
underwent balloon aortic valvuloplasty and found that event-
free and actuarial survival after this procedure resembles the
natural history of untreated symptomatic aortic stenosis,
and is even more dismal for patients who are not candidates
for aortic valve replacement. Although it has been shown
that balloon valvuloplasty will improve symptoms in very
old patients, this effect provides only a short period of symp-
315
tomatic relief at best, and better overall survival is obtained
with direct valve replacement.27,28
Mitral Stenosis
Young adults may have either congenital or rheumatic mitral
stenosis. Congenital mitral stenosis is a rare form of congeni-
tal heart disease, which is actually a spectrum of abnormali-
ties. The obstruction may occur in the supravalve area, the
annulus, the leaflets, the chordae tendineae, the papillary
muscle level, or any combination of these. The most typical
form of congenital mitral stenosis consists of thickened leaf-
lets and shortened chordae tendineae with decreased inter-
chordal spaces.29,30 Other typical forms include supravalve
mitral membrane or a parachute mitral valve.29,30 The diag-
nosis of mitral stenosis may be delayed or masked in these
patients due to associated lesions, most commonly other
obstructions to left heart outflow.31,32
Intervention is indicated for severe mitral stenosis, par-
ticularly when it causes pulmonary hypertension. Symptoms
of severe stenosis include shortness of breath, orthopnea, and
marked limitation in exercise tolerance. The presence of
significant mitral stenosis is confirmed by echocardiographic
evidence of a significant mitral gradient and a prolonged
pressure half-time of ≥220 ms. The severity of the mitral
stenosis is confirmed definitively at catheterization by find-
ings of a high left atrial pressure, a significant pressure gradi-
ent across the mitral valve with a calculated mitral valve
area ≤0.5 cm2/m2 and secondary pulmonary hypertension.
Surgical mitral valvuloplasty in the congenital lesions is
associated with significant morbidity and mortality. Patients
with congenital mitral stenosis or even acquired rheumatic
mitral stenosis in young adults frequently have a mitral
annulus that is small, and insertion of a prosthetic mitral
valve prohibits any further growth of the annulus. In an
effort to provide symptomatic relief and allow growth of the
mitral annulus along with other left heart structures, balloon
valvuloplasty is attempted for severe congenital as well as
rheumatic mitral stenosis in children and young adults.33–36
Appropriate hemodynamic measurements including the
simultaneous measurement of left atrial and left ventricular
pressures are obtained and angiography is performed in the
left atrium or the left ventricle in a right anterior oblique/
caudal view and a steep left anterior oblique/cranial view in
order to align the valve “on edge” and obtain accurate mea-
surements of the mitral valve annulus. The diameter of the
annulus is measured angiographically by comparing to a
catheter with special calibration marks (calibrated in centi-
meters) or to another large reference device. The valve
annulus diameter also is measured by TTE.
The InoueTM balloon and technique, which is in wide use
for rheumatic mitral stenosis, produces comparable results
with fewer complications and less fluoroscopy time than
other types of balloon valvuloplasty in the larger adolescent
and in adult patients with mitral stenosis of rheumatic
origin.37 This technique should be considered for larger
patients with congenital mitral stenosis in centers where
this balloon is available and there is a familiarity with the
technique.
The Inoue balloon is a unique balloon designed specifi-
cally for dilation of the stenotic mitral valve. The final
316 chapter
inflated balloon is shaped like a fat dumbbell with the central
fat waist expanding to a specific diameter with each specific
amount of fluid, which is instilled into the balloon. The
Inoue balloon catheter is positioned across the mitral valve
with the deflated balloon completely within the left ven-
tricular cavity. The balloon then is expanded sequentially
with the distal end expanded first well into the left ventricu-
lar cavity. Then the balloon with the distal portion inflated
is withdrawn into the stenotic orifice of the mitral valve with
the inflated portion against the left ventricular side of the
valve. Next, the proximal end of the balloon, which now is
on the left atrial side of the valve, is inflated. Finally, the
waist of the dumbbell, which now is fixed in the valve orifice
by the two expanded ends of the balloon above and below the
valve, is expanded exactly in the orifice.38
Although the Inoue balloon is available in several sizes
and each balloon can dilate to several different sizes, all of
the balloons require a 14-French (F) opening in the vein at
the introductory site and a similar-sized puncture through
the atrial septum. In addition to the large profile of the
deflated Inoue balloon/balloon catheter, there are no bal-
loons for patients with a valve annulus of less than 20 mm
in diameter, and with multiple levels of left ventricular
inflow obstruction as seen in many congenital mitral valves,
the specific shape of the Inoue balloon would be
unacceptable.
The double-transseptal, double-balloon technique is pre-
ferred in smaller patients or in patients whose anatomy is
unsatisfactory for the Inoue balloon.36 The double-balloon
technique is applicable to patients of all sizes. The two bal-
loons are selected and prepared prior to introduction as previ-
ously described using dilute contrast solution. The combined
diameter of the two balloons should be approximately equal
to the diameter of the annulus.36 Relatively long balloons are
preferred (5 to 6 cm for larger patients). Two separate trans-
septal punctures are performed for this procedure, preferably
from opposite legs. If a 12 or 14 French MullinsTM transseptal
set is employed, no further dilation of the atrial septum
should be necessary in order to pass the dilation balloon
catheters into the left atrium. The patient is given heparin,
100 U/kg, as soon as the transseptal procedures are
completed.
To avoid passing through small chordal spaces in the left
ventricle, balloon-tipped or “pigtail” end-hole catheters are
passed through the transseptal sheaths and utilized to cross
the mitral valve into the left ventricle; 180-degree curves are
formed on the transition portion of two appropriate-sized
Super Stiff wires so that the formed curves will fit within
the apex of the left ventricle, while the tips of the wires curve
back on themselves within the left ventricle and toward the
left ventricular outflow tract. Once the wires are positioned
securely in the left ventricle, the end-hole catheters are
removed through the long sheaths and over the wires. Each
of the balloon catheters is then advanced over the wire
through the transseptal sheath to the left atrium. The bal-
loons are subsequently manipulated into position across the
valve, centered side by side precisely across the mitral
annulus, and inflated until the waists on the balloons disap-
pear or until the maximal advertised pressures of the
balloons are reached—whichever occurs first. The inflation/
deflation cycle is performed as rapidly as possible while care-
12
fully controlling the positions of the balloons, particularly
so that they do not move forward into (through!) the left
ventricular apex or backward toward (and into) the atrial
septum. After repositioning the balloons forward or back-
ward over the wires in order to re-center them across the
valve, the inflation/deflation cycles are repeated until the
circumferential waists no longer appear with the initial
inflation of the balloons. In the event of a significant residual
gradient and in the presence of no waist on the balloon and
no significant mitral regurgitation, the procedure is repeated
using larger diameter balloons. At the end of the procedure,
hemodynamic measurements and angiography are repeated
before and after the balloons are removed. 36
Other methods are available for the delivery of double-
balloon catheters to the mitral valve, including a combina-
tion of transseptal and retrograde, a single atrial puncture for
a double-balloon dilation, and a totally retrograde tech-
nique.39–41 None of these techniques appears to have any
advantage over either the Inoue or the double-transseptal,
double-balloon technique, and thus they are not discussed
here.
The long-term benefit of mitral valvuloplasty for severe
congenital mitral stenosis is unknown. It is likely that all of
these patients eventually will require a mitral valve replace-
ment. By delaying operative intervention, this procedure will
delay the need for chronic anticoagulation therapy and may
allow growth of the annulus, permitting the insertion of a
larger prosthetic valve when the inevitable valve replacement
is necessary. In adults with rheumatic mitral stenosis,
balloon valvuloplasty has been proven to be beneficial with
longer follow-up.42 Although balloon mitral valvuloplasty
has had limited use in congenital mitral stenosis, this should
be the initial interventional procedure for most adolescents
and young adults with severe congenital mitral stenosis.
Tricuspid Stenosis
Isolated tricuspid valve stenosis is very rare in either child-
hood or in adults. The etiology can be congenital, rheumatic,
stenosis of a bioprosthetic valve, or acquired with systemic
illnesses such as carcinoid. When tricuspid stenosis is present
in children, it is often associated with a hypoplastic tricuspid
valve annulus and right ventricle, so that this type is rarely
amenable to surgical or balloon valvuloplasty. The early and
limited experience with tricuspid valvuloplasty in children
and young adults for either congenital or acquired tricuspid
stenosis has demonstrated that it is possible to achieve some
dilation of the valve in these patients.
Symptoms of severe tricuspid stenosis include tiring and
peripheral as well as central edema. These symptoms corre-
late with a gradient demonstrated by echocardiography or
catheterization, although the right atrium is so extremely
compliant that the gradient across the tricuspid valve usually
is very small. The lesion is usually well demonstrated by
right atrial or right ventricular angiography when obtained
in a caudal right anterior oblique view.
The procedure for tricuspid stenosis is similar to that
described for mitral stenosis, although it is slightly safer and
easier to perform. Due to the large size of the tricuspid
annulus, a double-balloon technique is necessary. The
sum of the diameters of the two balloons should match the
 c ong e n i ta l h e a rt di se a se i n t h e a du lt
diameter of the valve annulus, and longer, 5.5- or 8-cm
balloons are used. The Super Stiff wires with a long floppy
tip can be curled in the apex of the right ventricular, or they
can be stabilized in the left pulmonary artery. If no waist
appears in the balloons with the inflation/deflation cycle,
larger balloons are utilized. The Inoue balloon also has been
used for dilation of tricuspid valve stenosis.43
Case reports of successful tricuspid valvuloplasty are
available in adult patients with rheumatic tricuspid stenosis,
often accompanying mitral stenosis.44 This valve has also
been successfully dilated during pregnancy to allow comple-
tion to term.45 The procedure should be attempted for any
patient with tricuspid stenosis in whom surgery is being
considered.
Obstruction of the Great Vessels
General Considerations for Angioplasty
and Stent Placement
After the original description of balloon angioplasty for coro-
nary arteries,7 the procedure was soon extended to all other
blood vessels by both adult and pediatric cardiologists.46,47
The techniques for relieving congenital or surgically acquired
vascular lesions by balloon angioplasty now is routine and
is employed with variable success for stenoses anywhere
within the great vessels.13,48–50 The technique is similar for
systemic arterial, pulmonary arterial, and systemic venous
obstructions. The most common congenital lesions to be
dilated are stenoses of branch pulmonary arteries, systemic
veins, systemic venous “channels,” and coarctation of the
aorta. The vessel to be dilated is identified and measured
angiographically using a calibrated measuring system with
large distance reference marks, which are filmed in the same
planes as the vessel. Both discrete stenoses and longer
segment lesions can be dilated, and more than one site can
be dilated in the same patient during one catheterization.
The diameter of the balloon selected for angioplasty alone
should be three to four times the diameter of the stenotic
diameter, but no more than 1.5 times the diameter of the
normal pulmonary artery or systemic vein on either side of
the stenosis.13,47 Systemic arterial lesions are dilated with
balloons the exact diameter of the adjacent normal vessel.13,47
Overdilation of the adjacent normal vessel can result in tears
or rupture of the normal vessel. If there are multiple stenoses
in separate vessels, the most severe obstruction is dilated
first. In general, it is better to perform angioplasty on the
more distal lesions before the more proximal ones in the
same vessel, so that freshly dilated areas are not reentered
or crossed repeatedly.
The success of balloon angioplasty of pulmonary branch
stenoses varies from 20% to 70%, depending on the criteria
used for success.51,52 Success has been defined as a greater
than 50% increase in diameter of the lumen, or as little as a
50% drop in the pressure gradient across the stenosed area.
This degrees of success itself leaves much to be desired in
spite of an incidence of serious complications of greater than
5%.53 Although very long-term follow-up still is not avail-
able, persistent stenosis or restenosis is reported in as many
as 90% of the vessels dilated successfully originally.
317
To perform dilation of a vascular stenosis, the stenotic
area is crossed with an end-hole catheter. An exchange length
stiff or Super Stiff wire is positioned across and as far distal
to the site of stenosis as possible, the diagnostic catheter is
removed over the wire, and the appropriate dilation balloon
is advanced over the wire to the area of stenosis. After posi-
tioning the balloon precisely in the stenosis, the balloon is
inflated to its maximum advertised pressure for several
seconds or until the circumferential deformity or waist in
the balloon disappears on the fluoroscopic screen. The
balloon is repositioned across the area of stenosis, and the
dilation is repeated to achieve maximum effect. After com-
pletion of the dilation procedure, the pressure measurements
and angiography are repeated to assess improvement in vessel
diameter and identify any disruption in the vessel wall.
Balloon angioplasty enlarges stenotic vessels acutely by
stretching the intima/media and more permanently by
causing a tear in the vessel intima while stretching or tearing
surrounding scar tissue. This is reasonably safe in stenotic
areas, which are due to previous surgical manipulations
where the vessel is supported and surrounded by dense scar
tissue, which presumably will prevent more extensive tearing
or rupture. Care must be taken to prevent overdilation of
congenital vascular stenosis in native vessels, which have no
surrounding scar tissue. Dilation of these lesions has a
greater probability of extending the tear in the vessel wall
through the media, with the potential for vessel rupture or
aneurysm formation. Extreme care is necessary when advanc-
ing wires, catheters, or balloons across freshly dilated seg-
ments of vessels, as this may create or extend tears/aneurysms.
Other concerns related to specific lesions are discussed with
each defect.
Balloon angioplasty has variable success, depending par-
ticularly on the criteria for success utilized in the report.
Balloon dilation alone usually expands the stenotic area
acutely and usually reduces the obstructive gradient at least
a little, producing a satisfactory result, but at the same time
dilation alone leaves the vessel with some residual obstruc-
tion even though the stenosis in the vessel was dilated
acutely to three or four times the size of the original narrow-
ing during the balloon expansion. It is not uncommon for
the postdilation angiogram to be indistinguishable from the
preintervention study because of the elastic recoil of the
vessel wall.52 In adult congenital heart patients, balloon dila-
tion alone of vascular stenosis is seldom indicated or
attempted without the concomitant implant of intravascular
stents.
Intravascular Stents
The implant of intravascular stents into rabbit aortas and dog
coronary arteries by Palmaz et al.54 in the mid-1980s was
revolutionary for the treatment of vascular stenosis particu-
larly in the face of the dismal long-term results of the dila-
tion alone of vascular structures. Palmaz et al. designed a
stainless steel mesh stent that could be delivered into the
vascular system over an angioplasty balloon and expanded
by that balloon to hold the vessel open permanently.54,55 Fol-
lowing these reports, Mullins et al.52 in 1988 performed an
animal study in which the feasibility of stent implantation
318 chapter
in the pulmonary arteries and systemic veins was docu-
mented. As a result of that animal work, a collaborative
investigation of the uses of larger intravascular stents in
stenotic pulmonary arteries and systemic veins in humans
was initiated.56 Others reported laboratory successes with
encouraging results.57,58 The excellent results in these series,
along with the persistent long-term results,59 led to the
acceptance of stents as the standard, approved therapy for
patients with both native congenital or postoperative vascu-
lar stenoses.
The PalmazTM balloon expandable stent (Johnson &
Johnson, Warren, NJ) was the first and initially the only stent
in the original investigation for treating the vascular steno-
sis, which occurred in children with congenital heart disease.
This stent is manufactured from a stainless steel tube with
staggered longitudinal slots cut along its length, which,
when expanded with a balloon, form diamond-shaped spaces
circumferentially around the expanded tube. The diamonds
of these tubes of expanded metal proved to be very resistant
to collapse and, in turn, to the elastic recoil of the dilated
vessel. The intravascular stents have the drawback of each
particular stent having a finite maximum diameter, which
if not large enough for the vessel at the time of implant, or
subsequently with growth, will in itself create an obstruc-
tion that cannot be dilated further. The Palmaz stents were
the precursor to all of the intravascular stents that currently
are available for use in congenital heart patients.
The Palmaz iliac stents, which were the most commonly
used, were 18 or 30 mm long and had a nonexpanded external
diameter of 3.4 mm. These stents can be expanded with an
angioplasty balloon to a maximum diameter of 18 mm. With
full expansion, the stents shorten by 45% to 50%. Smaller
“renal” stents with a 2.4-mm nonexpanded diameter and
lengths of 10 and 20 mm but with a maximum expanded
diameter of only 10 to 11 mm could be used in the smaller
peripheral vessels. The renal stents also shortened by 40% to
45% at maximum expansion.
The diameter of the stent at implant is determined by the
diameter of the angioplasty balloon utilized to deploy the
stent. The larger-diameter stents can be implanted initially
over a smaller angioplasty balloon and then be expanded
further with a larger balloon up to the maximum diameter
of the stent either during the same catheterization or at a
much later time.60,61
During the two decades of the use of stents in congenital
heart lesions, several additional stents have become available
for use in the larger diameter congenital lesions; however,
the techniques for delivery have remained essentially
unchanged. The P-8 stents (Johnson & Johnson, Warren, NJ)
have been supplemented by the even larger P-10 Series
stents (Johnson & Johnson-Cordis Corp., Miami Lakes, FL),
which have a maximum expanded diameter of 26 mm for use
in the larger vessels. The original P-8 stents have been
replaced by the Genesis XDTM stents (Johnson & Johnson-
Cordis Corp.). The Genesis XD stents have small flexible
connections between circumferential rows of diamonds and
smoother closed cells at the ends, which gives the stents
some flexibility and makes them less prone to puncture of
adjacent structures. The Mega XDTM and Maxi XDTM series
of larger stents (ev3, Plymouth, MN) have an “open-cell” wall
configuration as well as smooth ends. These features make
12
them flexible and they do not shrink in length when expanded
sequentially. In addition, the open cells allow passage through
the side cells of the stent with the capability of dilation of
the side cells up to 12 mm.
Other types of stents are being used in adult vascular
lesions including self-expanding wire mesh and nitinol
stents,62 which do not require a balloon angioplasty catheter
for implant. These stents have some theoretical advantages
including smaller sheath size and even greater flexibility. No
experimental and very little clinical information is currently
available on their use in congenital lesions. In congenital
heart children, there have been very severe long-term adverse
sequelae including total obliteration of the vessel by the self-
expanding stents. This may not be a problem in the full-
grown adult congenital heart patient.
In addition to the newer larger stents, there are several
stents with a smaller maximum expanded diameter of 10 to
11 mm, which are usable only in the more peripheral vessels.
These stents are available very firmly premounted on deliv-
ery balloons, which in turn makes them easier to deliver.
The most readily available of these are the large and medium
GenesisTM stents (Johnson & Johnson-Cordis Corp.) and the
Express StentsTM (Boston Scientific).
When the implant of a stent is considered, the hemody-
namic gradients are determined and very precise angio-
graphic measurements are performed in the area of stenosis.
The diameter and the length of the stenotic area along with
the diameters and length of the adjacent normal vessel both
proximal and distal to the site of stenosis in the area where
the stent is to be placed are measured precisely using a large-
dimension calibration-reference system. Using these mea-
surements, the angioplasty balloon for the stent delivery is
chosen so that the expanded stent diameter will be the same
diameter as the contiguous normal vessel. The stent should
have the capability of dilating to the eventual maximum
diameter of the vessel after any growth and long enough to
cover the entire lesion. The balloon length should be the
same or slightly shorter than the unexpanded length of the
stent. When the balloon is too long, the ends of the balloon
inflate first, creating a dumbbell configuration. This often
leads to an uneven expansion of the stent, displacement of
the stent during inflation, or perforation of the balloon by
the stent.
Two or more catheters are utilized simultaneously for a
stent implant procedure. One catheter is required for the
delivery of each stent while an additional catheter is utilized
for precise angiography during the positioning of the balloon/
stent(s). The delivery of the large stents is accomplished
through a Mullins transseptal or other long sheath with a
diameter, which is at least two French sizes larger than
required for the angioplasty balloon in order to accommodate
the combined angioplasty balloon and mounted stent. This
requires a minimum of a 9F to 13F diameter sheath for the
implant of stents in the larger vessels.
An end-hole diagnostic catheter is advanced as far as pos-
sible beyond the site of stenosis, and a Super Stiff wire is
advanced through the catheter and anchored as far distally
beyond the stenosis as possible. The anchoring of the wire
prevents the dislodgment of the sheath as well as the stent
during its subsequent delivery and also helps to maintain a
firm fixation of the stent/balloon within the lesion during
 c ong e n i ta l h e a rt di se a se i n t h e a du lt
balloon inflation. The diagnostic catheter is removed over
the wire leaving the Super Stiff wire in place. The long
sheath/dilator set is advanced over the wire until the tip of
the sheath is well distal to the stenosis. Occasionally, the
stenosis requires predilation with a smaller balloon in order
to permit the large-diameter sheath to pass through a very
tight lesion.
The larger stents are mounted on the balloons by force-
fully “crimping” the stent over the balloon by circumferen-
tially and repeatedly compressing the stent between thumb
and forefinger throughout its length. After the long sheath is
in place and the stent is mounted on the balloon, the dilator
is removed from the sheath over the wire and the stent on
the angioplasty balloon is introduced over the wire into the
sheath. The stent/balloon is advanced over the wire through
the sheath to the desired location. The sheath is withdrawn
just off the balloon/stent and a repeat selective angiography
is performed to confirm proper stent position across the site
of stenosis.
The balloon is expanded slowly to its maximum recom-
mended pressure, which expands the stent in the stenotic
area. Once the stent is fixed in the lesion, the balloon is
deflated, adjusted forward or backward slightly, and the infla-
tion of the balloon is repeated several times within the
implanted stent in order to ensure full expansion of the stent.
The angioplasty balloon catheter is withdrawn into and then
out of the sheath, and angiography of the lesion is repeated.
If necessary, the stent can be dilated further with a larger or
a higher-pressure angioplasty balloon. For long-segment ste-
noses that are longer than the available stents or in a curved
vessel, overlapping stents are placed sequentially using the
same wire and sheath.
Pulmonary Artery Stenosis
Branch pulmonary artery stenosis may be an isolated lesion
but more commonly occurs in conjunction with other con-
genital heart lesions such as part of defects as in tetralogy
of Fallot or pulmonary atresia. Branch stenoses are also a
significant part of the heart disease accompanying rubella
syndrome, Williams syndrome, and Alagille syndrome.
Additionally, branch stenoses occurs frequently following
any surgical procedure on or about the pulmonary arteries,
including shunt procedures, previous pulmonary artery
banding, the arterial switch procedure, and right ventricle to
pulmonary artery conduit repairs for severe forms of right
ventricular outflow hypoplasia/atresia. Whether congenital
or following operative intervention, pulmonary artery branch
stenosis is a difficult problem for the cardiovascular surgeon.
The site of stenosis is frequently deep within the lung paren-
chyma, distal to the hilus or embedded in scar tissue.52 These
stenoses occasionally can be improved a small amount and
usually transiently by balloon angioplasty alone, but can be
totally and permanently relieved by the implant of appropri-
ate intravascular stents. The only patients unlikely to achieve
a correction of their lesion by the implant of pulmonary
artery stents are those with generalized hypoplasia or mul-
tiple stenoses throughout the entire pulmonary vascular
bed, and even these patients often achieve very significant
sustained benefit. Indications for stent intervention include
obvious angiographic stenosis with or without a gradient,
319
significant right ventricular hypertension, right ventricular
failure, unbalanced pulmonary blood flow by perfusion scan,
and excessive pulmonary regurgitation.52,56 In addition, any
visible discrete pulmonary artery obstruction in a patient
with a cavopulmonary anastomosis or other modifications
of the Fontan procedure warrants intervention even without
a measured gradient.
Balloon angioplasty alone for congenital vascular lesions
is indicated only for those patients in whom delivery
and implant of a stent is not possible. The experience at
Texas Children’s Hospital and other institutions confirms
such a high rate of success and low risk of stent implant
in patients with native or postsurgical pulmonary branch
stenosis that angioplasty in these patients prior to stent
implant is no longer attempted.56,59 Stent implant should be
considered in any patient with important pulmonary branch
stenoses who is large enough to accommodate the delivery
of the potentially adult-sized stents. The procedure for stent
delivery is described above. Adolescent or adult patients are
the most ideal for stent implant, as they can tolerate place-
ment of the large sheaths required, and their stents can be
fully expanded to 15 to 18 mm at the time of initial
implantation.56,59
The occurrence of significant restenosis after stent
implant is extremely low, and residual or restenoses because
of vessel growth can be re-dilated or re-stented.63 For some
patients with multiple lesions, the initial therapy is a com-
bination of balloon angioplasty and stent implantation. For
example, angioplasty alone may be performed at branch
points in vessels that are more distal, particularly if the ste-
nosis is exactly at a distal bifurcation or trifurcation or if
stenting of one or even two vessels would lead to occlusion
of a significant branch artery. In the same patient, one or
even a series of stents could be implanted in stenoses of more
proximal and larger vessels. When two important nearby
branches are stenotic and when the placement of a single
stent likely will block access to a significant neighboring
branch, two stents are implanted and bifurcating or “open-
cell” stents are used.62 To implant bifurcating stents, two
wires and two long sheaths are placed, one across each vessel,
and the two stents are implanted simultaneously.62 Similar
considerations must be made when placing a stent in the
orifice of the proximal right or left pulmonary artery or when
a single stent would partially occlude or “jail” the contralat-
eral pulmonary artery and at the very least make it difficult
or impossible to ever reenter the vessel.
Stents are used sparingly in proximal conduits adjacent
to the muscular insertion of the conduit because the repeti-
tive compression from the beating heart can lead to stent
fracture.64 If right ventricular dilation and failure are already
present, care must be taken that the implant of a stent will
not impinge on the pulmonary or homograph valve and cause
increased pulmonary regurgitation. On the other hand,
“crossing stents” placed in proximal branch stenoses at a
distal obstruction in a conduit or homograph relieves the
distal obstruction and can delay further surgery. Whenever
large sheaths and stiff wires are placed across a tubular
conduit of prosthetic material, an intimal peel can be lifted
and become obstructive.56 Pressure measurements and angi-
ographic assessment are repeated at the end of the procedure
to document the final results.
320 chapter
Coarctation of the Aorta
Coarctation of the aorta is a relatively common form
of congenital heart disease that frequently is seen in the
adult population. There is a long surgical experience, and
the late results of surgical repair of coarctation are not
always completely satisfactory, particularly when the patient
initially was operated on early in infancy. A significant
number of these patients have persistent or recurrent
obstruction at the aortic isthmus due to isthmus hypoplasia,
or at the site of previous coarctation repair.65–67 When the
obstruction at the site of previous coarctation repair is a
persistence of the original membrane or it is the suture line
itself, both are successfully treated either by balloon angio-
plasty or with stent implant. Dilation of recurrent coarcta-
tion of the aorta was one of the first lesions approached with
balloon angioplasty.68 This lesion was thought to be ideal
for this procedure, with the speculation that the extensive
surrounding scar tissue would provide extravascular support
and some safety against bleeding and extension of wall
tears.56 In 1990 the VACA registry originally reported
on the multicenter experience with dilation in 200 patients
with residual or recurrent coarctation of the aorta.50 In these
patients, the peak systolic pressure difference across the
aortic obstruction was decreased from 41.9 ± 19 to 13.3 ±
12.1 mm Hg and the diameter or the re-coarctation site was
increased from 5.2 ± 2.9 to 8.9 ± 3.4 mm. A residual resting
gradient of <20 mm Hg originally was considered a good or
even excellent result, and this was accomplished in 78.4%
of patients dilated. Five patients (2.5%) died of complications
related to the procedure, which included aortic rupture (n =
1), sudden death at 6 and 14 hours after the procedure with
probable exaggerated vagal reactions (n = 2), cerebral vascular
accident due to carotid occlusion (n = 1), and persistent con-
gestive heart failure unimproved by angioplasty (n = 1). The
angioplasty success rate for recurrent coarctation of the
aorta and relatively low mortality compare well with surgi-
cal results for reoperation of recurrent coarctation of the
aorta.50
Balloon angioplasty for native coarctation of the aorta is
more controversial because of a higher potential for intimal
tears, aneurysm formation, and the potential difficulties in
repairing the coarctation after one of these complications
plus a successful dilation. Histologic specimens of excised
human coarctation segments from surgical repairs of native
coarctation demonstrate cystic medial necrosis of varying
degrees in virtually all of the specimens, with severe changes
in 67%.69 There is extension of the necrosis into the aorta
proximal or distal to the coarctation in 80%. This has been
proposed as a part of the mechanism of late aneurysm forma-
tion after balloon dilation. In 1981, Lock et al.70 performed
balloon angioplasty in seven explanted coarctation segments
using a balloon approximately twice the size of the stenotic
diameter, and was able to increase the vessel diameter by
85%. However, four of the specimens had tears extending
into the media, and three had complete tears completely
through the media. In vivo studies on an animal model with
surgically created coarctation found less extensive tears of
the media following angioplasty and some healing with
time.71
12
Balloon angioplasty was subsequently performed in chil-
dren and young adults with native coarctation with variable
results, including a continued incidence of aneurysm forma-
tion.49,72 The original VACA registry report included the mul-
ticenter combined early experience with native coarctation
in 140 patients with significant complications in 17% includ-
ing two early and six late aneurysms. In those patients, the
aorta adjacent to the coarctation frequently was dilated to a
diameter significantly larger than the aorta in order to
achieve a relief of the gradient. To avoid the creation of tears
and the development of aneurysms later on, more conserva-
tive dilations are performed, however, with resultant higher
residual gradients. To achieve an even better relief of the
gradient without any overdilation of the adjacent vessel,
most centers are implanting stents in larger patients during
the initial dilation of any type of coarctation. This is
discussed subsequently. Further long-term follow-up is
necessary to know if this procedure can match the low
complication rate of initial operative intervention.
The technique for balloon angioplasty is the same for
both native and recurrent coarctation. A complete cardiac
catheterization is performed. This includes measurements of
gradients and precise, calibrated angiography of the aortic
arch, the coarctation, and the aorta adjacent to the coarcta-
tion. When large collateral vessels are present, little empha-
sis is placed on gradient across the coarctation and more on
the angiographic appearance of the coarctation itself. To
obtain the aortic pressures and precise measurements, a
catheter is positioned in the transverse or proximal descend-
ing aorta. This preferentially is introduced from a prograde
approach where the left heart is entered via a transseptal
technique and a catheter is advanced from the left atrium,
left ventricle, and into the ascending aorta. This catheter
remains just proximal to the coarctation before, during, and
after the dilation and avoids crossing the coarctation site
even once during or after angioplasty. A calibrated catheter
or grid is filmed at the time of angiography to obtain very
accurate vessel measurements.
The discrete, shelf-like coarctation represents the ideal
lesion for successful dilation. Patients with a long tubular
coarctation probably are not candidates for balloon dilation
alone.73 The narrowest diameter of the adjacent aorta is the
limiting diameter, which determines the diameter of the
balloon used for dilation and usually is the segment of
the aorta just proximal to the coarctation. The angioplasty
balloon is selected to be no more than 1 to 2 mm greater than
the diameter of this area in the larger patient. The patient is
anticoagulated using 100 mg/kg intravenous heparin for the
procedure. A Super Stiff wire with a long floppy tip is posi-
tioned retrograde across the coarctation, across the aortic
arch, and preferentially as far into the right subclavian
artery as possible. The angioplasty balloon is introduced
through a sheath, advanced retrograde, and centered over the
tightest area of the coarctation. The balloon is inflated until
it reaches its maximum recommended pressure or until
the waist (circumferential narrowing in the balloon)
disappears—whichever occurs first. Following slight repo-
sitioning of the balloon, the inflations are repeated up to
the maximum pressure of the balloon until the waist
disappears.
 c ong e n i ta l h e a rt di se a se i n t h e a du lt
The balloon is withdrawn gently out of the angioplasty
site so as not to increase trauma to the freshly dilated area.
An end-hole diagnostic catheter is reintroduced over the
Super Stiff wire, and the wire is withdrawn through the
catheter so that the wire itself does not abrade the angio-
plasty site. The gradient is measured with pressures obtained
simultaneously through the prograde catheter in the ascend-
ing aorta and the retrograde catheter in the descending aorta
or by a direct pressure withdrawal of the retrograde catheter
across the coarctation site. Angiography is repeated to visual-
ize the result and to ensure that no tear or dissection has
been created. The patient is maintained well hydrated over-
night with supplemental intravenous fluids to minimize any
effects of hypovolemia or volume shifts. Persistent back or
chest discomfort of any type is not normal and should be
investigated immediately. Both immediate and long-term
patient follow-up are mandatory, and should include mag-
netic resonance imaging or repeat catheterization with angi-
ography within 1 to 2 years after the angioplasty.
Morrow et al.74 initially demonstrated that stents that
were implanted in the normal aorta of juvenile animals then
could be reexpanded after vessel growth. Histopathologic
specimens from the aortas did not suggest significant intimal
or medial injury from either the initial implant or subse-
quent reexpansion of the stents. There was some limited use
of the P-8 stents in adolescent and adult humans all with
good short-term success.75,76 However, because of the con-
cerns with the placement of fixed-diameter stents with a
maximum expanded diameter of 18 mm, which is smaller
than the adult aorta, there was limited enthusiasm for stent
implant as a definitive therapy for coarctation of the aorta.
It was obvious that the implant of the smaller diameter
stents, which could not be dilated to an adult diameter,
would create an eventual lesion worse than the original.
Larger diameter P-10TM stents (Johnson & Johnson-
Cordis Corp.), which are identical to, but larger and sturdier
than, the P-8 iliac stents and the Maxi LDTM (ev3,
Plymouth, MN), now are available commercially in the
United States. These stents expand to 26 and 25 mm diam-
eters, respectively. The relief of obstruction with these
stents has been excellent; however, several cases of aneu-
rysms still have been reported following the implant of the
P-10 stents. These aneurysms may be related to the marked
increase in diameter of the vessel from a very tight stenosis
or due to the circumferential ring of sharp tips that occurs
when the P-10 stents are expanded to their full diameter on
a single large balloon. When large-diameter stents are
implanted in a very tight lesion, the lesion should be dilated/
stented only partially with the stent at the initial catheter-
ization, or when the lesion is to be dilated to an initial large
diameter, the stent should be expanded sequentially on a
BIBTM balloon (NuMED Inc., Hopkinton, NY). The sequen-
tial staged expansion on the BIB balloon prevents the sharp
flaring of the ends of the stent. The large stents mounted on
a BIB balloon require sheaths between 10F and 14F for intro-
duction. A larger experience with more information about
the cause of the aneurysms and longer follow-up still is nec-
essary to document whether the primary implant of a stent
represents the preferable alternative treatment for coarcta-
tion of the aorta.
3 21
Systemic Veins
Obstruction of systemic veins in patients with congenital
heart disease usually is iatrogenic. It can be due to previous
surgical intervention on or adjacent to the vein, indwelling
intravenous lines, or cardiac catheterization, but also can
occur secondary to inflammatory illnesses or tumors. Sys-
temic venous obstruction usually is diagnosed angiographi-
cally and often incidentally when a catheter will not pass
through an expected venous channel. Because of the combi-
nation of the normally low venous pressures, the massive
compliance of the systemic venous system, and the extensive
collateral channels, severe degrees of systemic venous
obstruction usually result in very little or even no gradient
across the lesion, with no increased velocities detected by
echocardiography. Treatment is based on the angiographic
appearance of stenosis.
The most common venous obstructions encountered
in the congenital heart patients are the peripheral venous
obstruction secondary to prior indwelling lines or prior
cardiac catheterization. This frequently goes undetected
until the patient is to undergo a repeat catheterization, par-
ticularly where a catheter intervention requires the same
particular venous route! Another more recent and very com-
plicated arrival to the arena of venous stenoses are the ste-
noses in the channels/anastomoses of the various types of
single-ventricle Fontan repairs. These can be very subtle but
at the same time cause severe symptoms including protein-
losing enteropathy. Obstruction of one limb of the baffle,
which occurs following either the Mustard or Senning
“venous switch” operation for transposition of the great
vessels, is another venous obstruction found in adult con-
genital patients. With severe obstruction of the upper limb
of the baffle, symptoms include upper trunk, head, and neck
swelling and venous distention, headache, and even com-
municating hydrocephalus. Some of these patients, however,
have no signs or symptoms, but because of the high incidence
of sick sinus syndrome in these patients, many need this
venous channel opened for the implant of a transvenous
pacemaker. The inferior limb vena caval of the baffle also
can be obstructed, although this is much less common.
Obstruction to inferior vena cava (IVC) flow can cause
abdominal ascites or peripheral edema but also may go
unrecognized. In most centers, the venous switch repairs of
transposition have been replaced by the arterial switch pro-
cedure, and most patients who survived one of the venous
switch operations are now adults. Any of these symptoms or
signs in a patient who has had a venous switch repair should
be investigated with a detailed cardiac catheterization with
venous angiography. The surgical approach to these problems
requires complete revision of the baffle, with frequently less
than satisfactory results due to the dense adhesions and
scarring.
Although the systemic veins and venous channels usually
tolerate significant overdilation with a balloon, the recoil/
rebound is equally as aggressive and the results of balloon
dilation alone generally are unsatisfactory. Reports of balloon
angioplasty for superior vena cava (SVC) obstruction follow-
ing the venous switch operation indicated some improve-
ment in vessel diameter following this procedure, but the
322 chapter
improvement frequently was only temporary.77–79 The use of
intravascular stents in systemic venous and systemic venous
baffle obstructions now is the accepted standard primary
treatment where a permanent result is desired.59,80 Indica-
tions for stent implant have been expanded to include patients
of all ages with SVC syndrome of any etiology with very
successful results.81
For implant of stents in systemic veins, the diameter and
length of the stenosed segment as well as of the normal vein
adjacent to the obstruction are measured angiographically.
The obstruction is crossed with an end-hole catheter. In the
cases of complete occlusion, the area is crossed initially by
advancing the end of a GlideTM wire, a radiofrequency wire,
or a transseptal needle out of a long dilator to penetrate the
obstruction.79 To direct the wire or transseptal needle accu-
rately, biplane fluoroscopy/angiography must be utilized both
above and below the obstruction. When puncturing, it also
is helpful to position a catheter at the opposite end of the
obstruction in the nearest accessible part of the vessel so as
to provide a target for the wire or needle from the puncturing
end. Once a wire has been passed across the obstructed area,
predilation with a small angioplasty balloon is performed
before the large-diameter, long sheath for stent implant can
be introduced across the obstruction.80 The patient is given
heparin once the obstruction is crossed. The diameter of the
angioplasty balloon selected for the stent implant should
approximate the diameter of the adjacent vessel proximal or
distal to the obstruction, whichever is the smaller diame-
ter.80 The stent is mounted on the angioplasty balloon and
delivered as described previously. Following the implant of
stents in systemic veins, the patient remains on aspirin for
at least 6 months. Although extreme long-term hemody-
namic follow-up for stents placed in systemic veins is not yet
available, lack of recurrent symptoms as well as continued
patency of these vessels by echocardiography and early
recatheterization for as long as 8 years suggests good long-
term results as long as good flow was established through
the stent.80
Pulmonary Veins
Congenital pulmonary vein stenosis is very rare, and it com-
monly occurs with other congenital heart lesions with or
without associated surgical intervention.82,83 Pulmonary
vein stenosis is becoming increasingly more prevalent with
ablation procedures around the orifice of the pulmonary
veins. This lesion is the most discouraging of all of the
stenotic lesions for both the cardiovascular surgeon and for
the interventional cardiologist. Balloon dilation has been
attempted in many cases with very transient acute success,
only to find recurrence of the stenosis within weeks or
months.56,83 Stent implant has been similarly unsuccessful
in the limited number of pediatric patients in whom it has
been tried.84 This is due not only to the technical difficulties
of the procedure but predominantly to the progression of
underlying sclerotic disease of the affected veins. In the
failure of all attempted treatments of these lesions the reste-
nosis occurs further within the parenchyma of the lung.
Obstruction of the common pulmonary venous channel after
venous switch transposition or total anomalous pulmonary
12
vein repair has been successfully treated with the implant
of stents and should be considered as the treatment of choice
when this problem occurs in adult patients following either
of the venous switch operations.85
Occlusion of Intracardiac Defects
Atrial Septal Defect: Background and
General Considerations
An atrial septal defect (ASD) usually does not cause problems
in childhood, but when persisting into adulthood may have
serious implications. These include the development of con-
gestive heart failure, arrhythmias, paradoxical embolism, or,
very rarely, pulmonary vascular disease. The diagnosis of
ASD can be missed in childhood because of the low-intensity
murmur and lack of symptoms, only to have the patient
present in adulthood with a murmur or arrhythmia, or inci-
dentally as the result of an abnormal study obtained for some
other reason. Some adult patients with known atrial septal
defects have declined surgical repair because of fear and the
lack of symptoms during early life.
Probably due to its frequency, its known eventual late
complications, and, at the same time, relative ease of cathe-
ter approach, the atrial septal defect was the first intracardiac
septal defect to be considered for a transcatheter occlusion
device. King et al.86 in 1976 reported on an effective double-
umbrella device that was used successfully in a few patients.
Because of its very large delivery system and its very rigid
frame, its use was limited to patients of adult size and it
never gained wide acceptance. However, the few patients
who were treated with this device still are doing well and
provide a perspective about the long-term follow-up of the
ASD occluded with a catheter delivered device.
The next major development in catheter closure of atrial
septal defects was reported in 1977 by Rashkind and Cuaso,87
who developed a hooked, six-legged, self-centering, single-
umbrella device [United States Catheter, Inc. (USCI) BARD,
Glens Falls, NY), which could be delivered through a slightly
smaller catheter system. For a very short time this hooked
device was implanted in humans under an investigational
protocol, but its use was discontinued because the tiny hooks
often would become attached prematurely to structures
within the left atrium before the septum could be engaged,
which, in turn, led to erroneous placement. Although aban-
doned even for clinical trials, the Rashkind ASD device
stimulated an almost frantic development of additional
devices for ASD closure.
Lock et al.88 used the experience from the already devel-
oped patent ductus arteriosus (PDA) devices to create the
next generation of ASD occlusion devices. First they used a
larger version of the Rashkind PDA double-umbrella (USCI
BARD), which, however, did not clamp onto the septum suf-
ficiently. They next added hinges or joints to each arm of
both umbrellas and used woven Dacron as the umbrella
fabric instead of the earlier polyurethane foam. This ASD
device had the appearance of a clamshell when viewed on
edge and was marketed as the Clamshell DeviceTM (USCI
BARD).89 The long sheath delivery system and technique
that had been developed for the Rashkind PDA devices were
 c ong e n i ta l h e a rt di se a se i n t h e a du lt
used for the Clamshell device and still is employed with
some of the current ASD occlusion devices.90 The Clamshell
ITM ASD occlusion device underwent a Food and Drug Admin-
istration (FDA) Investigational Device Exemption (IDE) pro-
tocol clinical trial in five centers and was implanted in 545
patients, with 97% successful implants. At follow-up, only
64% of implanted patients had complete closure of the ASD,
but of the remainder, 34% had only a very small residual
shunt.91
Fractures of the legs of the device were identified inciden-
tally on follow-up x-rays, although the fractures did not result
in clinical consequences on long-term follow-up. However,
four of the asymptomatic patients with a protrusion of a
fractured leg against an adjacent wall developed a mass in
the area. This mass led to surgery of the four patients, and
although the mass turned out to be a benign, fibrous, “callous-
like” lesion, this finding plus the unknowns of the fractures
led to the withdrawal of the device.
Even though it was removed from clinical trials, the
success of the Clamshell device demonstrated unequivocally
that most secundum atrial septal defects could be closed
nonsurgically, both safely and effectively. This stimulated a
further proliferation of new ideas and designs for devices for
ASD closure, some of which have come and gone but several
of which still are employed in Europe and one of which has
FDA approval for routine use.
CardioSEAL and STARFlex Devices
The CardioSEALTM device (NMT Medical Inc., Boston, MA)
is a further modification of the withdrawn Clamshell device.
The CardioSEAL is produced by a different manufacturer and
has a new design with an additional hinge on each arm, and
the arms are manufactured with new MP35n metal alloy,
which is more flexible and corrosion resistant. The
STARFlexTM device (NMT Medical Inc.) is a further modifi-
cation of the CardioSEAL device and has four very fine,
nitinol spring wires extending from the tip of each leg on one
umbrella of the device to the tip of the nearest apposing leg
on the opposite umbrella of the device. These fine spring
wires do not affect folding or delivery but do tend to center
the device once it is implanted.
Although the devices themselves were totally new, they
initially were delivered using the same technique established
with the Clamshell device. In the in vitro studies, in animal
trials, and now in extensive clinical use in the patent foramen
ovale (PFO), the new material and designs have eliminated
the clinical problem of strut fractures. The CardioSEAL
and STARFlex devices themselves consist of two opposing
umbrellas made of woven Dacron. Similar to the Clamshell
device, the two umbrellas are attached to each other at their
centers. Each umbrella has four metal arms of MP35n alloy,
but each arm now has two joints along its length in addition
to the central hinge point. The two umbrellas are attached
in their open positions with the concavity of the two umbrel-
las facing each other. The two umbrellas fold away from each
other for delivery. Both the CardioSEAL and the STARFlex
devices are available in 17-, 23-, 28-, 33-, and 40-mm diame-
ters. The 17- and 23-mm devices can be delivered through a
10 F long MullinsTM sheath (Cook Inc., Bloomington, IN),
whereas the 28-, 33-, and 40-mm devices require an 11 F long
323
Mullins sheath for delivery. A HausdorffTM modification
(Cook Inc.) of the Mullins sheath with a special compound
lateral and a rightward curve at the tip now is used for deliv-
ery to true atrial septal defects.92
The CardioSEAL and STARFlex devices are supplied in
the open position and must be loaded into the delivery
sheath. The tips of the distal arms are attached to a pair of
sutures that, in turn, pass through a loading device. Like the
Clamshell device, the size of the CardioSEAL/STARFlex
device that is chosen is at least two times the diameter
of the ASD but cannot exceed the diameter of the septum
itself. The device is attached to the delivery wire/catheter
at the center of the proximal umbrella. The CardioSEAL
device is folded for delivery by drawing it into the loading
device using the sutures attached to the tips of the distal
arms. Originally the CardioSEAL was loaded for delivery
by withdrawing the folded device from the loading device
into a metal delivery pod at the end of the delivery catheter.
The more recent CardioSEAL and the STARFlex devices
are “front-loaded” directly from the loader into the preposi-
tioned long delivery sheath with no delivery pod on the
catheter.
In the United States only the CardioSEAL device is avail-
able and then only for humanitarian use in the PFO follow-
ing a stroke, in surgical fenestrations, in muscular ventricular
septal defects, and in a prospective IDE clinical trial for PFO
closure. In Europe, both the CardioSEAL and the STARFlex
devices are commercially available for use in both the ASD
and the PFO.93,94
For the delivery of either the CardioSEAL or the
STARFlex device, a long Mullins sheath is positioned in the
left atrium with the tip between the left pulmonary veins
and the left atrial appendage. The delivery catheter with the
attached device is then introduced from the loader into
the long sheath and advanced until the folded device is in
the area of the right atrium. The sheath and the delivery
catheter are fixed in position while the proximal delivery rod
is advanced. This advances the wire with the attached device
within the sheath. This and subsequent maneuvers are
observed very closely on both fluoroscopy and transesopha-
geal echocardiography (TEE) or intracardiac echocardiogra-
phy (ICE). The sheath now acts as a curved delivery catheter.
As the device is slowly advanced beyond the end of the
sheath, the distal umbrella springs open in the left atrium.
When all of the distal legs are confirmed both by fluoroscopy
and by TEE or ICE to be open and not entangled in the left
atrium, the entire system is withdrawn as a single unit
toward the right atrium. Because of the usual and significant
malalignment of the long axis of the standard delivery sheath
to the perpendicular axis of the septum, the surface of the
distal umbrella usually does not align even close to parallel
to the septal surface. The more cephalad arms touch the
septum well before the caudal arms are even near the septum
by echocardiography. During an ASD closure, no attempt is
made to have the more caudal arms approximate the septum,
as any further withdrawal proximally on the device will
cause one or more of the more cephalad arms to pull through
the septum.
Once the initial legs of the left atrial umbrella of the
device touches against the septum, the delivery wire and
delivery catheter are fixed in place while the sheath alone is
324 chapter
withdrawn. Because of the length of the collapsed device,
this allows the proximal legs to spring open on the right
atrial side of the defect. Once both umbrellas are opened and
the sheath has been withdrawn, the device usually aligns
itself better on the septum and in a relatively secure position.
However, while the device is still attached to the delivery
wire, all of the legs usually do not come in contact with the
septum. When assured by TEE/ICE and fluoroscopy that all
of the legs are on the appropriate side of the septum, the
release mechanism is activated. This allows the delivery
wire/catheter to spring away from the device as the device
moves away from the cable and aligns with the septum as it
is released. The proper position of the device on the septum
and the degree of closure are confirmed by TEE/ICE. A right
atrial angiocardiogram is obtained with the x-ray tubes in a
four-chamber view. This images the right atrial surface of
the device as well as the left atrial side of the device during
the recirculation phase of the contrast through the left heart.
Manipulation of a catheter into the pulmonary artery for
angiography after the implant is unnecessary and potentially
dangerous because of the possibility of dislodging the newly
implanted device.
Atrial Septal Defect Occluding System and Angel
Wings Devices
In addition to the Clamshell and CardioSEAL devices, two
additional atrial septal occlusion devices were developed and
introduced into clinical use but now have disappeared from
all use. These were the Atrial Septal Defect Occluding
System (ASDOS)TM (Osypka Co., Germany) and the Angel
WingsTM ASD occlusion device (Microvena Corp., White Bear
Lake, MN). The ASDOS device underwent investigational
clinical trials in Europe and for a short time was commer-
cially available in Europe,95 whereas the Angel Wings device
underwent a successful FDA clinical pilot trial in the U.S.
and also was commercially available in Europe for a short
time.96 However, both devices were found to erode through
adjacent structures and were withdrawn from any use.97
There have been preliminary rumors that the Angel Wings
device had been modified markedly into an easier to use and
safer Guardian Angel septal occluder, but no medical reports
have been forthcoming.93
Sideris Button Occlusion Device
One of the earliest ASD occlusion devices, which did undergo
at least one FDA clinical pilot study in the U.S. and currently
is in its fifth generation of modification, is the Sideris But-
tonTM device (Pediatric Cardiology Custom Medical Devices,
Athens, Greece). This device has been available outside of
the U.S. It has had extensive use in numerous centers around
the world and has persisted longer than many of the other
ASD devices.98 The many modifications that it has under-
gone were to correct serious deficiencies in earlier designs
that prohibited its general use in the U.S.
The Button occluder began as a single square umbrella
that was cut from a sheet of polyurethane foam and attached
to a frame consisting of two crossed pieces of spring guide-
wire. It was held against the septum by a “counter-occluder,”
which buttoned to the occluder. The counter-occluder ini-
12
tially consisted of a single strand of spring guidewire. After
the occluder umbrella was positioned on the opposite side of
the septal defect, the center of the counter-occluder was but-
toned against the center of the occluder umbrella by a very
unique, latex, buttoning mechanism—thus its name. The
umbrella and the counter-occluder were delivered separately
and sequentially through a single long sheath and over a long
loop of a control suture. Once buttoned together, the delivery
catheter was released from the occluder by withdrawing one
end of the long control suture from the device mechanism.
The delivery sheath was then withdrawn.
The early generations of this device were very flexible
and the polyurethane foam was very compressible, so that
the device could be folded into a small diameter and deliv-
ered through a much smaller sheath than any of the other
ASD occlusion devices. The newer generation devices still
are square umbrellas of polyurethane foam, but with a
thicker counter-occluder, which is not as compressible. They
now reportedly require 10 F to 12 F sheaths for delivery.99
Defect sizing, the ratio of device to defect size, and the deliv-
ery through a long sheath are similar to the other devices.
The button device is available in very small sizes suitable for
the small defects, and also in sizes up to 60 mm in diameter
for very large ASDs. Because of the attachment with a suture
during delivery and its flexibility after seating on the septum,
it is easily retrievable until it is released purposefully from
the control suture and generally retrievable by a catheter
technique even after release.
The earlier generations of Button devices had a high inci-
dence of residual and recurrent leaks. There were also reports
of embolization from poor fixation or unbuttoning. Because
of these problems, the device underwent several significant
changes and it now is in its fifth generation since the initial
FDA pilot study.99 Although the Button device has been used
in many centers throughout the world, there have not been
large enough numbers with the same generation of device in
any individual center for data analysis. The current-genera-
tion Button device has not undergone an FDA IDE clinical
trial but is available for commercial use in many countries
outside of the U.S.
Helix Device
A more recent addition to the devices for transcatheter
occlusion of atrial septal defects is the Helix device (W.L.
Gore & Associates, Flagstaff, AZ). This device is very differ-
ent from all previous devices. It is manufactured from a
curtain of polytetrafluoroethylene (PTFE) fabric stretched
over a long nitinol wire. The nitinol wire curls into a double
circle or helix in its relaxed state. It is loaded and delivered
as a straightened wire, which, as it is extruded, curls into
separate disks on each side of the septum. The Helix device
is available in multiple diameters (sizes) of the disks in 5-
mm increments up to 35 mm in diameter. Like the other
devices that rely on the double disks for fixation, it is recom-
mended that a Helix device be twice the diameter of the
defect for an ASD occlusion. The Helix device is round, quite
flexible, and after being fully implanted is totally retrievable
until a final safety thread is purposefully withdrawn. The
Helix device is available commercially in Europe and it has
completed a successful IDE clinical trial in the U.S. and is
 c ong e n i ta l h e a rt di se a se i n t h e a du lt
awaiting an FDA decision for use for ASD occlusions in the
U.S.
Amplatzer Atrial Septal Defect Occlusion Device
The AmplatzerTM atrial septal occluder (AGA Medical Corp.,
Golden Valley, MN) is the one device that has successfully
completed European and FDA IDE clinical trials and
now is available commercially throughout the world and
since 2002 even in the United States. The Amplatzer ASD
occluder is by far the most effective, easiest to deploy, and
safest occlusion device to be developed.100 In the 3 years
since its release in the U.S., the Amplatzer ASD occluder
has become the standard accepted treatment for the majority
of secundum atrial septal defects. The one potential short-
coming of this device is a very small but finite incidence
of its erosion through the aorta or atrial wall. The incidence
is probably less than 0.1%, but of the 29 reported cases there
have been three permanent neurologic sequelae and five
deaths as a result of the erosions.101 The erosions have
occurred from a few hours to 3 years after implant, and so
far there are no distinguishing features of the patients
involved.
The concept of this device, again, is different from all of
the previously described devices. The Amplatzer ASD device
has two disks that rest on the opposite sides of the atrial
defect; however, it is fixed in place in the defect by a broad
central hub that fits exactly and tightly within the defect to
accomplish the occlusion. The central hub, which completely
fills the defect, is the main mechanism of fixation and occlu-
sion. The entire device is composed of a weave of fine nitinol
metal wires, which retain their shape as a consequence of
the memory of the nitinol metal. In its relaxed state, the wire
mesh forms the pair of circular end disks, which are an
extension of the broad circular central hub of the same mate-
rial. The device is held in place by the central hub expanding
into the circumferential rim of the atrial defect and tightly
filling the atrial defect while the two disks stabilize the
device against each side of the septum. The left atrial disk
is 14 mm larger and the right atrial disk is 12 mm larger in
diameter than the central hub. There are thin polyester disks
within each of the two nitinol disks and one within the
central hub to promote occlusion. The diameter of the hub
represents the size of the device. The size of the device (hub)
should correspond very closely to the balloon-occluded diam-
eter of the atrial defect. These devices are available in sizes
between 4 and 38 mm for occlusion of atrial defects up to
38 mm in diameter.102
In spite of its considerably different design, the Am-
platzer device is delivered to the left atrium through a long
sheath in a similar fashion to the original ASD devices. The
delivery of the device is guided with a combination of fluo-
roscopy and by TEE or ICE. The smaller devices pass through
a 7 F sheath, whereas the larger devices require up to a 12 F
sheath. The long sheath is positioned across the atrial septum
with the tip of the sheath free within the body of the left
atrium. For delivery, the device is attached to a delivery cable
by a very fine screw mechanism. It is then stretched into a
long, thin braid of the nitinol wires by withdrawing it into
a loader, which is the same French size as the delivery sheath.
The elongated device is introduced into the proximal end of
325
the long sheath by pushing it out of the loader and then
advanced to the ASD through the long sheath.
General Procedure for Atrial Septal Defect Closure
The final suitability of an ASD for transcatheter closure is
determined by TEE or ICE and confirmed during cardiac
catheterization with a very accurate balloon sizing of the
defect. The standard transthoracic echocardiogram (TTE) is
useful in screening patients to confirm the diagnosis and
location of the defect. It is also useful to rule out a sinus
venosus, a primum or a very large ASD, which would be
totally unsuitable for transcatheter closure, and to exclude
other intracardiac defects. The TTE cannot determine the
precise size or the absolute suitability of the ASD for trans-
catheter closure either accurately or unequivocally. The TEE
and ICE are more accurate for sizing and localizing the ASD,
but in borderline cases even they do not correlate accurately
enough with the definitive size found with the stretched
sizing performed at catheterization to make an absolute
determination of appropriateness for transcatheter closure
without the balloon sizing.
The catheterization procedure is similar for most of the
ASD devices currently in use and in trials in the U.S. If a
patient is considered a possible candidate for ASD occlusion,
strict operating room sterile precautions are observed in
the catheterization laboratory. A 9 F sheath is placed in the
right femoral vein and a small cannula or dilator placed
in the femoral artery for monitoring. When TEE is used, a
7 F sheath is introduced into the left femoral vein, but when
ICE is to be used, an 11 F sheath is placed in the left femoral
vein to accommodate the 10 F ICE catheter. A detailed
right heart catheterization is performed to determine the
magnitude of the shunt in order to confirm the significance
of the ASD. An angiographic catheter often is introduced
and advanced to the mouth of the right upper pulmonary
vein for angiography. A shallow four-chamber view, with
either x-ray tube at approximately 30 to 45 degrees left
anterior oblique (LAO) and 25 to 45 degrees cranial angula-
tion should produce a good on-edge view of the atrial septum,
which can provide additional information about the size
and position of the ASD and help to rule out additional
defects. If the septum is not cut precisely on edge by the
first angiogram, it is repeated using a different angulation
of the x-ray tube or with the sizing balloon inflated across
the defect until the septal defect is clearly demonstrated.
An appropriate calibration grid or other large diameter
reference device for measuring is filmed in the same
plane for accurate measurement of the defect. Heparin,
100 mg/kg, is administered to prevent thrombus formation
on the delivery catheter/wires or within the large delivery
sheath.
The TEE or ICE echo probe is introduced at this time.
Images of the defect, the rims around the defect, and the
adjacent structures are obtained to assist with defect mea-
surement and later visualization during implant. An end-
hole catheter is introduced through the right femoral vein
sheath and advanced through the right heart, through the
ASD, and out into a left upper pulmonary vein. With extreme
care to avoid introduction of air, an exchange length 0.035-
inch stiff guidewire is advanced through this catheter into
326 chapter
the peripheral pulmonary vein and the catheter is withdrawn
over the wire.
Accurate sizing of the atrial defect is performed using
a special, very compliant, cylindrical, AmplatzerTM sizing
balloon (AGA Medical Corp., Golden Valley, MN). A 24- or
34-mm (depending on the estimated size of the defect by
echo) sizing balloon catheter is advanced over the exchange
wire and is positioned straddling the atrial defect. The
balloon is inflated very slowly with a 1 : 5 dilution of contrast
until a slight waist appears on the circumference of the
balloon or until all flow across the defect as visualized by
color Doppler is stopped. Once flow through the defect is
stopped, the narrowest diameter of the balloon is measured
on TEE or ICE and by angiography. The entire circumference
of the balloon is scrutinized by TEE or ICE for adequate rims,
additional atrial defects, adequate additional length of the
septum for the device, and the proximity of the balloon/
defect to adjacent critical structures. If a waist does not
appear or flow is not stopped with the 24-mm sizing balloon,
the balloon is replaced with the 34-mm sizing balloon and
the measurements repeated. The 34-mm balloon often
requires a 10 F introductory sheath and can be inflated to a
40+-mm diameter with 90+ cc of dilute contrast!
An additional right upper pulmonary vein angiogram can
be performed through the second catheter with the sizing
balloon inflated in the septum. This demonstrates the ade-
quacy of the sizing, and of more importance verifies any
additional small ASD or suggests a peculiar shape of the ASD
that could compromise closure.
The sizing balloon catheter is withdrawn over the wire
and replaced with a long sheath/dilator of an appropriate size
for the size of the particular Amplatzer occluder device. The
Amplatzer ASD occluders come with matched sizes of deliv-
ery sheaths (AGA Medical Corp.), which are appropriate in
size for the various sizes of devices. There are several other
long sheaths with specific curves at the distal end of the
sheath that facilitate the delivery of the Amplatzer ASD
occluders. The HausdorffTM modification of the 10 F and 11 F
Mullins sheaths (Cook Inc., Bloomington, IN) and the 8 F SL2
Fast CathsTM (St. Jude Medical, Woodland Hills, CA) both
have a posterior and a rightward curve at the tips, which
greatly facilitate the alignment of the devices parallel to and
against the septum during deployment. These sheaths now
are used preferentially for the delivery of the Amplatzer ASD
occluders.
The long delivery sheath/dilator is advanced over the
wire and well into the left atrium. The dilator and then the
wire are carefully and slowly withdrawn and the sheath
(including the hub of the back-bleed valve/flush port) is
cleared very meticulously of any air and/or clots preferen-
tially by passive drainage. To verify the exact position of the
tip of the sheath in the left atrium and to confirm that it is
not entrapped in the atrial appendage or a pulmonary vein,
there should be a free back flow of fluid or oxygenated blood
through the side port. Once the free flow of fluid/blood is
obtained, a slow hand injection of contrast is performed
through the sheath. The position of the sheath passing
through the septum should also be clearly identified by fluo-
roscopy and TEE or ICE.
Once the sheath is in position, the collapsed device is
introduced from the loader into the long sheath and advanced
12
until visualized in the left atrium within the sheath on fluo-
roscopy. As the device reaches the tip of the sheath, it is
extruded slowly out of the end of the sheath by simultane-
ously advancing the delivery cable into the proximal end of
the sheath while withdrawing the tip of the sheath back
toward the right atrium. When the left atrial disk is fully
extruded and expanded, the sheath together with the remain-
der of the device is withdrawn until the left atrial disk aligns
against and parallel to the septum. The position of the distal
disk is confirmed by TEE/ICE and fluoroscopy. The sheath
alone is withdrawn, allowing the central hub to expand in
the defect followed by the right atrial disk opening on the
right side of the septum. The length of the folded device
allows considerable leeway in the distance for this full extru-
sion and requires that the delivery cable be readvanced
slightly to allow the right atrial device to assume its relaxed
configuration against the septum. Once fully extruded the
entire circumference of the device is scrutinized by TEE or
ICE for the presence of a “sandwich” of tissue circumferen-
tially between the two disks. To check the security of its
fixation, the device is test wiggled by pushing the delivery
cable forward and backward enough to move the device to
and fro slightly. If the Amplatzer device is malpositioned or
pulls through the defect at any stage of the delivery, it can
be withdrawn back into the delivery sheath and repositioned,
reimplanted, or removed and a different-size device inserted.
Once confident of the fixation, the device is unscrewed from
the delivery wire for release by multiple counterclockwise
turns.
Occlusion of the Patent Foramen Ovale
All of the ASD devices have at one time or another been used
to close a PFO. The major indication for such closures is the
presence of a PFO with significant right to left shunting
through it or a documented central nervous system (CNS)
embolic event in the presence of a PFO. The potential for this
use appears staggering; however, the true risk for embolism
through a PFO has not been documented sufficiently to abso-
lutely justify this use. In the United States, the CardioSEAL
PFO device has FDA approval for closure of the PFO only
under a Humanitarian Device Exemption (HDE) in patients
who have a documented CNS embolic event (stroke) and a
recurrent CNS event on warfarin therapy or failure of war-
farin therapy. The STARFlex device and the Amplatzer PFO
device are in separate randomized controlled IDE trials for
patients with PFO and proven embolic strokes.
In addition to the required documented stroke, there are
several other strong indications for closure of a PFO that are
not approved for official use in the U.S.103 Deep-sea divers
have considerably more frequent and more serious problems
with systemic nitrogen bubble emboli that occur with
decompression in the presence of a PFO.104 Patients with a
PFO and compromised right ventricular function or obstruc-
tive pulmonary vascular disease often develop significant
and debilitating cyanosis.105,106 Orthodeoxia-platypnea is
associated with an intermittent but significant and debilitat-
ing right to left shunting through the PFO.107 Many patients
who did have strokes also were noted to have had a history
of severe debilitating migraine headaches. It was found, coin-
 c ong e n i ta l h e a rt di se a se i n t h e a du lt
cidentally at first, that most of these headaches disappeared
with the closure of the PFO. There appears to be a strong
correlation between severe migraine with aura and the pres-
ence of a PFO even without a prior stroke.108 There now is
one randomized blinded trial of PFO closure for documented
migraine with aura under way in the United Kingdom. The
controlled trials of PFO closure for these various indications
may be necessary to determine the true indication for this
procedure.
The PFO is an extremely variable lesion and not just a
small, discrete, potential hole in the septum. Although the
flap of the septum primum may cover the opening com-
pletely, it often also creates a very long tunnel. Most of the
openings of the PFO in patients who have had strokes are
potentially 10 to 20 mm in diameter. The PFO that is associ-
ated with a very redundant aneurysmal septum and is very
mobile appears to have an even higher risk of stroke. The
majority of the PFO lesions often require the very largest
umbrellas or disks to cover the entire opening and to include
the aneurysm. In the presence of a very long and stiff tunnel,
a transseptal puncture through the septum primum occa-
sionally is necessary to implant the devices without signifi-
cant distortion of the device. These represent much more of
a challenge to implant.
The equipment and technique for PFO occlusion are
similar to those used for ASD closure. The CardioSEALTM
device is used under a humanitarian use approval for patients
with documented recurrent CNS events or intolerance of
warfarin anticoagulation therapy as well as in a randomized
controlled investigational trial. There also is a special
AmplatzerTM PFO occluder (AGA Medical Corp.) for the PFO,
which is in a randomized controlled clinical trial. The Am-
platzer PFO occluder is made of the same materials and has
right and left disks similar to the Amplatzer ASD device;
however, the right disk in the PFO device is slightly larger
than the left disk and the central hub is very narrow and
flexible, which makes it more like the CardioSEAL devices.
The Helix device has been used for PFO closure, and there
is a reverse-button modification of the Sideris Button device
for the PFO. In Europe, there are several other double-
umbrella types of devices for PFO closure.
Although not all institutions still perform balloon sizing/
shaping of the PFO, this definitely is recommended in essen-
tially all PFO occlusions. The sizing balloons from either
NuMED Inc. (Hopkinton, NY) or AGA Medical Corp. (Golden
Valley, MN) are positioned in the defect/tunnel and inflated
at zero pressure until the balloon begins to deform and con-
forms to the shape of the defect. This shape and in particular
the long distorted shapes will determine the approach to the
defect. When the long sigmoid distortion is over 15 mm in
length, particularly in an older patient, a transseptal approach
is recommended and the largest available device will be
used.
All of the PFO devices except the Helix device are deliv-
ered across the septum through long sheaths similar to their
ASD predecessors. When a transseptal puncture through
the septum primum is necessary, all are delivered through
a long sheath. The procedure is controlled with fluoroscopy
and either TEE or ICE. The major difference is in the actual
delivery of the device where the opened left-sided disk/
component is pulled more firmly/securely against the
327
septum before opening/releasing the right-sided component.
This makes the delivery procedure significantly easier and
safer.
The ASD/PFO occluding devices discussed in this section
are available clinically or are in clinical trials in the U.S.
Most of the devices are available routinely in the rest of the
world as of 2005. In the same way that the King-Mills device
and the original Rashkind ASD device stimulated the devel-
opment of the current ASD devices, this group of devices has
already stimulated the development of probably more effec-
tive and even safer transcatheter ASD/PFO occlusion devices/
techniques, which may be in investigational trials by the
time of this publication.
Occlusion of Ventricular Septal Defects and
Other Abnormal Intracardiac Communications
Transcatheter closure of muscular ventricular septal defects
(VSDs) was first performed on a compassionate basis using
the Rashkind PDA-occluding device.109 The defects attempted
were leaks in patches following prior surgery, an acquired
VSD due to myocardial infarction, and some unoperated
native congenital apical and midmuscular ventricular
defects. The Rashkind device frequently was too small,
leaving significant residual shunting or causing emboliza-
tion of the device. Once it became available, the Clamshell
ASD device next was used under a separate high-risk proto-
col for closure of certain ventricular septal defects.110 As a
consequence of a modification of this clinical trial, the Car-
dioSEAL device has received an HDE approval for closure
of muscular ventricular septal defects. In addition, AGA
Medical Corp. now has the Amplatzer muscular VSD
occluder, which is available routinely throughout most of the
world except the U.S.,111 but it has completed clinical IDE
trials in the U.S. and is awaiting approval from the FDA for
this use. The defects chosen for occlusion are in the middle
or apical muscular interventricular septum, away from the
semilunar and atrioventricular valves. The CardioSEAL and
the Amplatzer muscular VSD devices are delivered with a
similar technique.
These particular defects are the most difficult for the
surgeons to repair and frequently have unsatisfactory surgi-
cal results with significant complications or residual leaks.
The device closure of muscular septal defects is complicated
and technically challenging for the interventional cardiolo-
gist; however, the device closure appears safer and more
effective than the comparable surgery.
The muscular interventricular defects are very difficult
to cross from the right atrium/right ventricle to the left ven-
tricle with a catheter due to their apical location, the heavy
right ventricular trabeculations in the area, and the high-
velocity flow against that direction. The acute and com-
pound angle created when the septum is approached from the
IVC, through the tricuspid valve, and to the interventricular
septum at the ventricular apex makes the catheter approach
from the femoral vein particularly difficult for the subse-
quent delivery of a fairly rigid device. The jugular venous
approach with a through-and-through or rail wire system
extending through the left heart is used to overcome these
problems.
328 chapter
The procedure for VSD closure involves crossing the
defect with an end-hole catheter from the left ventricle to the
right ventricle. The left ventricle preferentially is entered
prograde through an atrial transseptal approach or, alterna-
tively, from a retrograde arterial approach. The prograde
transseptal approach provides a better angle toward the left
side of the VSD, better control of the through-and-through
wire, and far less operative time and trauma to the systemic
artery. A second smaller retrograde angiographic catheter,
however, routinely is placed retrograde into the left ventricle
to allow repeated left ventricular angiocardiograms during
positioning and delivery of the initial end-hole catheter and
eventually the device. The x-ray tubes are positioned to cut
the ventricular septal defect exactly on edge, usually in a
slight LAO/cranial angulation. A left ventricular angiocar-
diogram is recorded to serve as a roadmap for the procedure.
The x-ray tubes are maintained at the same angles for the
remainder of the procedure. Often the left ventricular side of
the muscular VSD will be broad and single whereas the VSD
will taper into relatively narrow or multiple communica-
tions as it approaches the right ventricular side of the
septum.
Entrance into the left ventricular side (end) of the VSD
also can be quite difficult and often requires a combination
of tip deflector wires, torque-controlled catheters, and float-
ing balloon end-hole catheters. The use of a balloon end-hole
catheter for this catheter passage helps to ensure passage
through the largest opening from the left ventricle to the
right ventricle through the VSD. Torque-controlled guide-
wires facilitate wire and catheter guidance to the vicinity of
and through the defect once the left ventricular entrance of
the defect has been engaged. After the catheter has been
advanced through the ventricular septum into the right ven-
tricle, the wire and catheter are maneuvered into the pulmo-
nary artery.
A separate venous sheath is introduced into the right
jugular vein and an end-hole floating SwanTM balloon cathe-
ter (Edwards Lifesciences, Irvine, CA) is “floated” through
the tricuspid valve and into the main pulmonary artery. A
floating balloon catheter is used to ensure passage through
the center of the tricuspid valve orifice en route to the
pulmonary artery. A GooseneckTM retrieval snare (ev3,
Plymouth, MN) or an EnSnareTM [MDTECH (Medical Device
Technologies), Gainesville, FL] is advanced through the
balloon catheter from the jugular vein or the balloon catheter
first is replaced in the pulmonary artery with the specific
snare catheter. The free end of the wire, which has passed
through the VSD and into the pulmonary artery, is grasped
with the snare catheter.
Once the wire and catheter have been snared, the distal
end of the wire is withdrawn back through the tricuspid
valve and externalized through the sheath in the right jugular
vein. The catheter through which the wire was introduced
through the VSD remains the left ventricle to protect the left
heart chambers, valves, and vessels from the cutting effects
of the bare wire passing through these structures. A through-
and-through rail wire is created with the wire passing from
the femoral vein, through the atrial septum to the left atrium,
through the mitral valve to the left ventricle, through the
VSD to the right ventricle, through the tricuspid valve to the
right atrium, and out through the jugular vein. An alterna-
12
tive approach is to enter the left ventricle with a retrograde
catheter to create this rail from the femoral artery to the left
ventricle, to the right ventricle, to the right atrium, and out
through the jugular vein.
The jugular venous end of the rail wire is then utilized
to advance the delivery sheath, catheter, and occlusion device
through the right ventricle, through the VSD, and into the
left ventricle. Traction to the opposite end of the rail wire
frequently is needed during the passage of the sheath and
dilator combination through the septum, and during the
advancement of the sheath over the dilator into the left
ventricle.
The dilator is slowly and carefully removed from the
sheath over the wire, and the sheath meticulously is cleared
of all air or clot. After removal of the dilator, the position of
the tip of the sheath within the left ventricular cavity is
verified by a left ventricular angiocardiogram and by TEE or
TTE. If the sheath position is not exactly in position and
needs to be advanced to a more secure position, the dilator
is reintroduced over the wire and to the tip of the sheath
before readvancing the sheath. Advancing the sheath alone
will kink the curved portion of the sheath within the right
ventricle. Since any movement of the patient or the slightest
traction on the sheath can displace the sheath back to the
right ventricular side of the septum, the through-and-through
wire is not removed until the device is loaded and ready for
introduction. In addition, it is useful to keep the end-hole
catheter, which was introduced from the left ventricular end,
over the wire and through the defect within the tip of the
jugular sheath. As the dilator is withdrawn the end-hole
catheter is advanced into the distal end of the sheath follow-
ing the tip of the dilator as it is withdrawn. When the device
is ready for delivery and the position of the sheath within
the left ventricular cavity still is satisfactory, the through-
and-through rail wire is withdrawn from the entire system
but the catheter retrograde into the sheath is left in place.
The catheter retrograde within the sheath provides an access
route to replace the rail wire if it is necessary to reposition
the long sheath. As the wire is removed, the sheath is held
firmly in place and if necessary adjusted forward very gently
in order to keep the sheath tip well within the left ventricle.
Changes in the position of the tip of the sheath are verified
by small left ventricular angiocardiograms.
The device is attached to the delivery catheter/cable and
is withdrawn into its respective loader. The loader contain-
ing the device, which is attached to the delivery catheter/
cable within the loader, is introduced into the prepositioned
sheath. The device is advanced carefully out of the loader and
into the sheath and advanced to the center of the right atrium.
If the retrograde catheter had been introduced into the sheath,
the catheter is withdrawn proportionately to the introduc-
tion of the device into the sheath, keeping the tip of the
device and the tip of the catheter approximated. The sheath
must be allowed to advance or move slightly in order to keep
its tip well within the left ventricle. Advancing the device/
delivery catheter tends to straighten the sheath and, in turn,
pulls it back into the VSD or right ventricle. No attempt
should be made to deliver the device unless the tip of the
sheath remains completely through the defect, secure there,
and yet with the very tip free within the left ventricle. If
delivery is attempted with the tip of the sheath still within
 c ong e n i ta l h e a rt di se a se i n t h e a du lt
the defect, the device will be deployed entirely on the right
side of the defect.
When the device has been advanced to the tip of the
sheath well within the left ventricle or against the free wall
of the left ventricle, the device is advanced very slightly
while the sheath is withdrawn the same distance. This is
repeated until the distal legs/disk of the device spring open
completely within the left ventricular cavity. Once the left
side has opened completely, the entire system is slowly with-
drawn into the left ventricular ampulla of the defect. The
distal left ventricular arms/disk usually conform to the
ampulla with a conical folding into the left ventricular side
of the defect. An angiogram is repeated in the left ventricle
to verify proper positioning. In spite of what appears to be
perfect folding into the defect, the device may still be caught
on a rim of the defect and the center or hub of the device still
can be within the left ventricle, which in turn could lead to
embolization of the device. With predominantly angiographic
and occasionally TEE guidance, the device is withdrawn well
into the defect in order to be sure that the center of the device
is at the narrowest portion of the defect and all of the proxi-
mal side of the device will open on the right side of the
VSD.
The sheath is withdrawn completely off the device to
allow the proximal, right-sided arms or disk to spring open.
The right-sided arms/disk usually are entangled in the right
ventricular trabeculae and may not open completely or sym-
metrically; however, the device does fix very securely on the
right ventricular side. After angiographic confirmation of the
correct positioning in the defect, the device is released and
the delivery catheter and sheath are removed. Because of the
complexity of this procedure, transcatheter closure of the
muscular VSD will certainly be limited to a few centers that
are very active in interventional catheterization.112
Device Occlusion of Miscellaneous
Intracardiac Communications
In addition to the previously discussed ASD and VSD occlu-
sions, many other unusual or often unique intravascular
communications have been closed with ASD and VSD occlu-
sion devices, specific vascular plugs, and various coils. The
most notable of this type of use is the closure of the atrial
communication or fenestrations that are left purposefully in
the baffles of the caval-pulmonary procedures. A small 3- to
5-mm opening purposefully is created in the atrial baffle of
a caval-pulmonary artery repair of a single ventricle. This
defect allows a small right to left shunt of blood away from
the pulmonary circuit, which increases the systemic cardiac
output with this shunted blood. This augmentation is par-
ticularly important during the immediate postoperative
recovery period.113 The defect/shunt does leave the patient
cyanotic and with a potential for right to left embolization
of particulate material so that once the usefulness of the
increased systemic output is over, it is desirable to close the
defect. This is accomplished similar to the closure of an
ASD. Because of the small size and usually rigid baffle mate-
rial, the occlusion devices seat securely in these defects
although during the implant, the device often initially rests
at a very unusual angle. At the present time, the FDA allows
329
the use of the CardioSEAL device for these defects under
an HDE use and the use of the Amplatzer PFO occluder
for occlusion of the fenestrations in an investigational
protocol.
Similarly, the various occlusion devices have been used
in extenuating circumstances for closure of other nonpur-
poseful residual postoperative leaks including peripatch
leaks and even a few perivalvular leaks. The uses in these
lesions are so rare and so heterogeneous, that each case
usually is a new and unique procedure, which is performed
at the discretion of a physician skilled and experienced in
the use of the particular device and after an informed discus-
sion and disclosure with the patient. As these unusual and
rare uses occur, they will become accepted and more and
more of these patients will be spared unnecessary redo surgi-
cal procedures.
Occlusion of Extracardiac Intravascular
Communications
Patent Ductus Arteriosus
The patent ductus arteriosus (PDA) is a very common lesion
in childhood, and occasionally a PDA will slip by the pedi-
atric cardiologist and appear in adulthood. Commonly, the
PDA is small or moderate in size, and the main adverse
implications for the adult patient are endocarditis and the
eventual consequences of a lifelong left ventricular volume
overload. Although the risk of operative intervention for PDA
in pediatric patients generally is considered low, it is surgery,
and it involves the pain and morbidity of surgery and even
an occasional death, particularly in the elderly patient who
has more sclerotic vessels, heart failure, pulmonary hyper-
tension, or additional coronary artery disease. Surgery is
complicated further by calcification of the PDA in older
adults.
Interventional cardiologists have been occluding the
PDA nonsurgically for almost four decades. Porstmann
et al.114 first introduced a catheter technique for closure of
the ductus arteriosus in 1967, following which Rashkind et
al.90 introduced a more clinically useful double umbrella
device (USCI BARD, Glens Falls, NY), which began clinical
trials in 1981. Despite a successful FDA IDE clinical trial,
eventual approval by the FDA professional panel, and uni-
versal professional approval for use throughout the rest of
the world, the failure of the bureaucracy of the FDA to
finally approve the device for use in the U.S. forced the USCI
to abandon the device (and all pediatric devices) in 1995.
The Rashkind PDA device is no longer available anywhere
in the world.
The Rashkind PDA device demonstrated very effectively
that a correction of a congenital cardiac defect in the cathe-
terization laboratory was possible safely and effectively. With
the Rashkind PDA device the long sheath delivery system
for intravascular devices, which is still used today for many
devices, was introduced and perfected. Fortuitously, the
sudden withdrawal of this widely and successfully used non-
surgical cure of a lesion stimulated the imagination of inter-
ventional cardiologists to develop other devices for occlusion
of the ductus as well as other lesions.
330 chapter
Coil Occlusion
The first of these devices and techniques for PDA occlusion
that resulted from the void left after the withdrawal of the
Rashkind device was the GianturcoTM coil (Cook Inc., Bloom-
ington, IN) described by Cambier et al.115 for PDA occlusion.
Gianturco coils already were FDA approved for occlusion of
vascular structures.116 The Gianturco coils are lengths of
spring guidewire that have no safety core but are curled into
repetitive loops of a fixed diameter and have filaments of
nylon embedded in the coiled wire along their length. The
coils are available in wires of different diameters and with
various diameters of the loops of the coil. Initially and until
the later introduction of the 0.052-inch coil wire,117 only the
0.038-inch wires were sturdy enough for the occlusion of the
usual PDA. The coil is straightened into a length of spring
guidewire in a straight metal loader, which is used to intro-
duce it into the delivery catheter. The straightened coil is
advanced through the catheter by pushing it out of the loader
with a long standard spring guidewire of the same wire
diameter as the coil wire. When the coil is extruded out of
the end of the catheter, it coils like a small pigtail, forming
three to six circular loops depending on the initial length of
the coil wire and its manufactured diameter. Once any part
of the coil has been advanced past the tip of the catheter,
there is no way of withdrawing the standard Gianturco coil
back into the delivery catheter.
The use of Gianturco coil for PDA occlusion along with
multiple modifications of the coil and the techniques for its
delivery118–120 proliferated over a very short period of time,
and this method now has been accepted as one of the stan-
dard therapies for the small to moderate-sized PDA in the
U.S. and abroad.121 Coil occlusion of the ductus is most appli-
cable when the PDA has an aortic ampulla with a discrete
narrowing toward the pulmonary end. It is less likely to be
successful with either the very short or large and tubular
PDA. Fortunately, most PDAs are small to moderate with
some discrete stenosis. The Gianturco coils and techniques
offer the advantages of the ready availability of a variety of
sizes and the low cost of the coils.
The standard Gianturco coil can be delivered retrograde
from the arterial or prograde from the pulmonary arterial
approach. Very low profile, end-hole-only catheters are used
for the retrograde approach and allow the delivery of 0.038-
inch caliber coils through a 4 F or 5 F arterial sheath. The
retrograde coils usually are delivered using a free, noncon-
trolled release. When delivered prograde, the same free release
technique is possible, but more often the coil is grasped with
a 3 F bioptome for control and the combination is delivered
through a 5 F long sheath.122
All techniques for coil occlusion of a PDA require very
careful angiography of the ductus arteriosus with accurate
measurement of the narrowest and the widest diameter as
well as the length of the ductus. A coil is selected with coil
loops that are at least twice the diameter of the narrowest
area of the PDA.115 For the standard retrograde delivery, the
PDA is crossed from retrograde into the pulmonary artery
with an appropriate end-hole (only) catheter for the coil deliv-
ery. The coil is advanced through the catheter using a stan-
dard straight spring guidewire of the same wire diameter as
the coils as the pusher wire. One-half to three-quarter loops
12
of the coil are extruded out of the tip of the catheter, which
is positioned in the pulmonary artery just at the pulmonary
artery end of the narrowest portion of the ductus. The pusher
wire is fixed rigidly in this position against the tabletop while
the catheter alone is withdrawn into the descending aortic
off the pusher wire (and coil). This extrudes the remaining
two to four loops of coil from the delivery catheter into the
descending aorta/aortic ampulla of the ductus. The closure
rate with this technique is up to 97% in some series.123–125
Occasionally, there is some residual flow through the ductus,
which necessitates the placement of one or more additional
coils after a successful placement of the first coil. The proce-
dure for the additional coils is the same, with particular care
taken not to dislodge the first coil during the subsequent
catheter manipulations through the ductus. A disadvantage
of this technique is the lack of control with no ability to
withdraw the coil once the extrusion of the coil has just
started. This leads to occasional coil displacement or embo-
lization. Usually, the coil can be retrieved from the circula-
tion if the coil is badly placed or embolization occurs.126
Modifications of the coil delivery technique include
methods of attaching the delivery wire to the coil to enhance
delivery with the potential for retraction of the coil anytime
during the delivery if the position is not optimum. Outside
of the U.S., these JacksonTM coils are standard, approved
systems with specifically designed, effective screw attach-
ment and release mechanisms that have simplified the tech-
nique and made it more safe and effective.127 Unfortunately,
these exact systems are not available for clinical use in the
U.S. A different attach/release mechanism for the coils has
been introduced in the U.S.; however, the coil wires for this
system are smaller in diameter and there are fewer fibers on
each coil. As a consequence, these coils are less robust and
less occlusive and have not gained much popularity.
To increase the occlusion and stability of the coils, they
have been used with the simultaneous delivery of two (or
more) coils at the same time through separate catheters.128
The separate catheters can be from the same vessel approach,
or one catheter from the artery and one catheter from the
vein are used. In addition, a thicker, much more robust coil
of 0.052-inch wire has become available in the U.S. (Cook
Inc., Bloomington, IN). This coil by itself fixes in the ductus
much more securely,117 and along with the bioptome control
technique, which is described subsequently, has become the
preferred coil for the PDA occlusion.
In the U.S., a snare technique118 and a bioptome attach-
release mechanism119 were developed for controlling the
coil(s). With the snare technique, the 4 F or 5 F coil delivery
catheter is passed retrograde through the ductus arteriosus
into the main pulmonary artery similar to the free release
technique. A snare catheter is advanced from the femoral
vein into the pulmonary artery and used to snare the very
tip of the retrograde catheter in the main pulmonary artery.
The coil is then advanced through the retrograde catheter
until 1 mm of the tip of the coil is extruded out of the tip of
the delivery catheter into the main pulmonary artery. The
snare is allowed to slip to the tip of the retrograde catheter
in order to snare the exposed tip of the coil just as the nar-
rowed snare loop slips off the tip of the catheter. The coil
is fixed in its exact position by holding the tip of the coil
with the snare catheter while the retrograde delivery cathe-
 c ong e n i ta l h e a rt di se a se i n t h e a du lt
ter is withdrawn off the coil. A half loop of coil is held in
the main pulmonary artery by the snare, and the rest of the
coil is delivered onto the arterial side of the ductus ampulla.
If the positioning is not ideal even after the coil is fully
extruded, the coil can be pulled further into the ductus or
removed completely using the venous snare. Angiography is
performed while the coil is still held by the snare catheter.
If delivery of a second coil is necessary, the retrograde cath-
eter can be repositioned across the ductus and into the main
pulmonary artery while still having control of the first coil
already in the ductus with the snare in order to avoid dislodg-
ment of the first coil. Once the position of the coils are sat-
isfactory, the snare is opened carefully to release the coil.
Although a little more complex and time-consuming, and
although the procedure adds to the cost of the snare catheter,
this technique does allow better control of the procedure at
all stages.
The use of a 3 F bioptome to grasp the tip of the coil is
an even preferable system to control the delivery of the stan-
dard 0.052-inch coil to the ductus.119 The attachment site on
the coil is prepared by forcefully grasping the tiny welded tip
of the coil with a forceps and pulling this weld 1 mm away
from the remainder of the coil wire. The weld remains as a
small ball 1 mm away from the rest of the coil but attached
by a single strand of the basic fine wire, which makes up the
coil. The separated tip is grasped by the 3 F bioptome and the
coil is withdrawn out of the original loading tube into a short
length of 4 F sheath, which is comparable in length to the
loading tube and through which the bioptome has been
passed. The short sheath, in which the coil is grasped by the
bioptome, is introduced into the proximal end of a 4 F or 5 F
long sheath, which previously has been positioned across the
ductus. The long sheath can be positioned retrograde from
the aorta or, preferably, prograde from the pulmonary artery.
The appropriate loop (or number of loops) of coil is extruded
at one end of the ductus (depending on which direction the
long sheath was introduced from), the entire system is with-
drawn into the ductus, and then the bioptome is fixed in
place while the sheath is withdrawn off the remaining loop(s)
of coil at the opposite end of the ductus. Once the coil is in
the proper position, the bioptome is opened releasing the coil.
The bioptome allows the coil to be withdrawn or reposi-
tioned any time until the purposeful release from the
bioptome.
AmplatzerTM PDA Occluder
While the coils and coil delivery techniques were being mod-
ified and perfected for occlusion of the PDA, the Amplatzer
PDA occluder was developed, introduced into a clinical FDA
IDE trial, and eventually fully approved specifically for PDA
occlusion.129,130 This device uses the same nitinol wire mesh
and a similar expansion/fixation concept as the Amplatzer
ASD and VSD occluders. The Amplatzer PDA occluder con-
sists of a short, slightly tapered, tubular hub with a thin
2 mm larger rim or disk at its largest (aortic) end. The disk
creates a retention mechanism to help hold the device in
place. The Amplatzer PDA device is available in sizes of 5-4,
6-4, 8-6, 10-8, and 12-10 in the U.S. and two larger 14-12 and
16-14 sizes outside of the U.S. The larger number of the
labeled size indicates the diameter in millimeters of the hub
3 31
at its largest (aortic) end. Except in the very smallest device,
the hub tapers 2 mm in diameter from the largest to the
smallest end. In the smallest device (the 5-4), the taper of the
hub is only 1 mm. The hub is 5 mm long in the 5 device, 7 mm
long in the 6 and 8 devices, and 8 mm long in the 8 and 10
devices. Like the other Amplatzer devices, the PDA device
is stretched into a long thin braid of the nitinol material for
loading and introduction into the delivery sheath.
The device also is delivered through a 6 F to 8 F long
sheath, which previously has been positioned prograde from
the pulmonary artery across the PDA. The retention disk is
extruded in the descending aorta, the entire system is with-
drawn until the disk is seated in the aortic ampulla of the
ductus and then the sheath is withdrawn off the rest of the
device to expand and fix it in the ductus.
The Amplatzer PDA device used is at least 2 mm larger
than the smallest diameter of the ductus. The smallest Am-
platzer PDA device is the 5-4 device, which makes the Am-
platzer PDA devices suitable for the PDA which is larger than
2.5 mm with a characteristic conical configuration. The
Amplatzer PDA occluder now represents the standard
accepted therapy for the PDA that is larger than 2.5 to 3 mm
in diameter.
Gianturco-Grifka Vascular Occlusion Device
The Gianturco-Grifka Vascular Occlusion DeviceTM
(GGVOD) (Cook Inc.) was developed as another modification
of the spring coil wire for vascular occlusions. The GGVOD
consists of a long predetermined length of flexible spring
guidewire that in use is forcefully wadded into a small nylon
bag to form a dense, constrained mass of the coil wire. The
bags are of different diameters to correspond to the different
lengths of wire. All sizes of the GGVOD are delivered through
an 8 F long sheath system.
The GGVOD is applicable for the occlusion of larger,
tubular and higher velocity vascular communications.131 It
has FDA approval for occlusion of vascular structures and
has had limited use for PDA and other abnormal tubular
vascular structures. When used for occlusion of the PDA,
angiography of the lesion is essential to carefully measure
both the length and the diameter of the PDA. To use the
GGVOD, the diameter of the vascular structure must be
0.5 mm narrower and the length of the vessel 1.5 times the
length of the sack that will be used. The 8 F long sheath is
introduced prograde from the pulmonary artery, through a
tubular ductus, and the tip of the sheath is positioned well
into the descending aorta. The empty sack is advanced
through the sheath to the aortic ampulla, where it is partially
filled with coil. The sheath and sack are withdrawn into the
tubular portion of the ductus, toward but still within the
pulmonary end of the ductus. The sack is filled completely
with the specific length of spring wire. Once the surgeon is
satisfied with the position of the sack as well as the stability
and occlusion of the PDA, wire and sack are released from
the delivery catheter by the fairly complex attach/release
mechanism. The sack is totally removable until this pur-
poseful release from the delivery catheter. The GGVOD has
proven very effective for the long tubular PDA132 as well as
some other larger tubular abnormal vascular structures
including aortopulmonary collaterals.
332 chapter
Other Devices for PDA Occlusion
In addition to the Amplatzer PDA occluder, the various mod-
ifications of the coil, and the GGVOD, there are other devices
outside the U.S. specifically developed for PDA occlusion.
One of these is the Nit-OccludTM device [PFM (Produkte fur
die Medizin AG), Cologne, Germany], which is a more recent
modification of an earlier Duct-OccludTM device.133 The Nit-
Occlud device has had favorable results outside of the U.S.
and is in IDE trials in the U.S. at this time. The Nit-Occlud
device is a stiff, preformed, tight double coil of nitinol wire
that comes in various sizes to fit various sized and shaped
ductus. It also comes with an elaborate attach/release/
delivery mechanism that gives total control over the delivery
of the device until it is very purposefully released.
In addition to the various vessel occlusion devices previ-
ously described, a number of ASD/VSD occlusion devices
have been adapted for the closure of the large, atypical PDA
that add to the armamentarium available for the occlusion
of the PDA.
Occlusion of Other Abnormal Extracardiac
Vascular Communications
Embolization of abnormal or persistent arterial or arterio-
venous structures has been performed for over 30 years.116
Many materials and devices have been used for these periph-
eral occlusions, including the patient’s own clotted blood,
Gelfoam, colloidal plugs, glues, detachable balloons, and
coil occlusion devices. These embolization techniques
originally were developed and perfected by vascular radiolo-
gists to treat abnormal bleeding related to the gastrointes-
tinal tract and CNS, particularly in end artery vessels.
In patients with congenital heart disease, there frequently
are abnormal aorta-to-pulmonary collateral vessels or per-
sistent, surgically created, systemic-to-pulmonary artery
shunts associated with complex cyanotic lesions. It is ap-
propriate to occlude these vessels when there is competitive
flow between the collateral and the normal pulmonary
blood flow, particularly when the major defect has been or
is to be corrected.134 These communications historically
required surgical division during the corrective procedure
or even as a separate surgical procedure. When these
communications are closed surgically along with the
intracardiac repair, the closure of these defects significantly
prolongs the surgery and the recovery of the patient.
Occasionally, teenagers and adults with congenital heart
disease will develop hemoptysis from spontaneous bleeding
of these abnormal collaterals and will require urgent
intervention.
The Gianturco coils116 described previously are the most
commonly used device for occlusion of unwanted aorta-to-
pulmonary communications in patients with congenital
cardiac defects. For occlusion of abnormal tubular vascular
communications, the coil to be used should have a coil diam-
eter that is approximately 1.5 times the diameter of the
vessel to be occluded. The delivered coil wire should elongate
slightly, and in turn form an irregular mass of wire but not
a straight strand or a tight doughnut circle in the vessel to
be occluded. To deliver the coil, an end-hole-only catheter
12
with an internal diameter just slightly larger than the diam-
eter of the wire of the coil is positioned within the vessel as
near as possible to the site to be occluded. The Gianturco
coil occludes the vessel by the creation of a mass of the wire
and attached strands of nylon thread, which stimulate throm-
bus formation. Ideal vessels for Gianturco coil occlusion
have a discrete narrowing where the coil can be fixed in
place. Without a discrete stenosis, the coils have a potential
to migrate farther through the vessel, so that care must be
taken in the measurement of the vessel. Without a distal
narrowing, coils can be used only in vessels that, when dis-
tended, are less than 7 to 8 mm in diameter. It is often neces-
sary to place several coils in a larger vessel to achieve
complete occlusion.135 For vessels that are greater than 7 to
8 mm in diameter, coils may be used in conjunction with
other intravascular occlusion devices, especially where there
is no discrete stenosis.
AGA Medical Corp., in its line of Amplatzer occluders,
now has an AmplatzerTM Vascular Plug for occlusion of mis-
cellaneous abnormal vascular lesions.136 These, as the name
implies, are short cylindrical plugs. They are manufactured
from a weave of an even finer nitinol wire and have no reten-
tion disks at the ends and no polyester material within them
to enhance thrombosis. The Amplatzer plugs are available
up to 16 mm in diameter. Because of the differences in their
manufacture, the plugs can be delivered through smaller-
diameter long sheaths, but must be oversized in order to be
wedged tightly into vessels, and they do not occlude imme-
diately. The Amplatzer plugs are FDA approved and are avail-
able in the U.S.
Most abnormal aorta-to-pulmonary communications can
now be occluded with Gianturco coil137 or the Amplatzer
plug.138 The intracardiac or more specific ASD, VSD, or PDA
occlusion devices occasionally are used in the very large
vascular communications. Other lesions in which the various
vascular occlusion devices may be useful include arteriove-
nous fistulas, systemic coronary-cameral communications,
and pulmonary arteriovenous fistulas. In these lesions, it is
critical to advance the delivery catheter as distally as possi-
ble beyond branches of the vessel that supply more proximal
significant or vital tissues before considering device delivery.
It is helpful to be able to deliver the occlusion device at a
stenotic site or vessel to reduce the danger of more distal
embolization through the communication to a vital systemic
structure.
In very complex congenital heart lesions and particularly
in the older patient, unusual communications occur that
require occlusion. These include persistent left SVC to the
left atrium, persistent systemic-to-pulmonary artery shunts
in patients who had undergone tetralogy of Fallot or pulmo-
nary atresia repair, recurrent cephalad systemic venous to
caudal systemic venous shunts in patients who have opera-
tive Glenn procedures, persistent pulmonary venous-to-
systemic venous communications in patients who had had
some type of caval-pulmonary operations, and persistent
atrial communications in patients with right to left shunt
following repair of complex defects. All of these patients
have symptoms from their abnormal communications and
are at significantly greater risk for any further surgical inter-
vention. In any defect of this type, the nonsurgical transcath-
eter approach should be considered. Thoughtful and
 c ong e n i ta l h e a rt di se a se i n t h e a du lt
innovative interventions in these types of patients can sig-
nificantly improve their quality and length of life.
Miscellaneous Therapeutic
Catheter Procedures
Atrial Septostomy
The very first intracardiac therapeutic catheterization proce-
dure was the balloon atrial septostomy performed in 1966 by
Rashkind1 using his balloon septostomy catheter. This was
not only the first intracardiac therapeutic procedure to be
performed in the catheterization laboratory, but also the first
therapeutic catheterization procedure, which effectively
replaced a surgical procedure. The procedure was crude but
effective in creating an interatrial communication when
intracardiac mixing of systemic and pulmonary blood was
critical, and it is still in use today. The actual Rashkind
balloon septostomy has no use in the adult patient, but the
concept of creating atrial communication in the catheteriza-
tion laboratory is absolutely essential in many adult congeni-
tal patients.
Although the original septostomy procedure is strictly a
pediatric procedure and has not changed significantly over
the past four decades, the procedure has been elaborated on
in order to make the catheter septostomy applicable in adults.
The use of the catheter septostomy has been extended
to other lesions where mixing is needed through the
atrial septum to sustain life. Such lesions in the adult patients
include patients with failing, single ventricle, caval-
pulmonary repairs, inoperable complex lesions, and pulmo-
nary vascular disease. All of these patients benefit from
an atrial pop-off to improve cardiac output, to decrease
pulmonary congestion, or to decrease right heart failure.139
Blade Atrial Septostomy
The inability to create an adequate atrial communication
with balloon septostomy in children beyond the newborn
period led to the development of the ParkTM blade septostomy
catheter (Cook Inc., Bloomington, IN) and the blade septos-
tomy procedure.140 Indications for this procedure are similar
to those for balloon septostomy and have been further
expanded to include teens and adults. The Park blade septos-
tomy catheter is designed to initiate a cut in a thicker or
tougher atrial septum.141 A small blade at the distal end of
the catheter is controlled by a sliding wire that runs the
length of the catheter lumen from the proximal Tuohy™-type
hub to the blade at the distal tip of the catheter. When the
control wire is advanced, the blade extends out of the slot in
a metal pod at the end of the catheter and forms a triangle
extending off the shaft of the catheter/pod with the apex of
the triangle away from the catheter and the proximal edge
of the triangle sharpened. When the extended blade is with-
drawn, from left atrium to right atrium, the blade initiates
an incision in the atrial septum. This incision then is
extended with a balloon dilation procedure. The current Park
blade septostomy catheters include the PBS 300, on an 8 F
shaft. This catheter has a very sturdy 2-cm-long knife blade
recessed in a slot in the distal end of the catheter. It is the
333
only blade catheter that is sturdy enough for the thicker
septum in the adult congenital patient.
Indications for blade septostomy in the adult are patients
with inoperable complex congenital lesions with inadequate
venting of either atrium and patients with cor pulmonale
secondary to pulmonary vascular disease.139 In the presence
of the muscular atrial septum found in the adult, the balloon
pull-through septostomy is impossible to perform, and the
creation of an atrial septal communication always is begun
with the blade septostomy procedure even when a small,
preexisting ASD is present.
When a balloon dilation septostomy is performed first or
alone, it will stretch only a preexisting restrictive atrial com-
munication. When the defect is stretched, it causes a subse-
quent blade to distort and pull through the stretched orifice
and does not produce the desired initial cut. The PBS 300
blade septostomy catheter is introduced through a 9 F long
Mullins sheath that has been passed into the left atrium
through either a preexisting atrial communication, or prefer-
ably via a separate transseptal puncture adjacent to any pre-
existing atrial communication. The location of the blade in
the left atrium is verified on biplane fluoroscopy. The sheath
is withdrawn off the blade and well back into the low right
atrium/IVC.
With the blade apparatus positioned well into the left
atrium, the catheter is rotated until the blade points toward
the anterior chest wall and either to the patient’s right or left.
The blade is opened carefully to approximately a 45-degree
angle while verifying that it is not in the left atrial appendage
or in a pulmonary vein. The blade is locked in the open posi-
tion and the blade catheter is withdrawn slowly against the
atrial septum. Resistance is felt at the septum, and the blade
tends to rotate as it engages the septum. A continued firm,
slow, and controlled withdrawal of the catheter and blade is
performed until the blade snaps through the septum. Often
the entire septum (and heart!) is displaced caudally almost
into the IVC before the blade pulls through the septum.
When the blade pulls through the septum, it is important
that the open blade is not withdrawn any further into the
IVC after the incision is made. After the successful cut, the
blade apparatus is withdrawn back into the catheter shaft.
The blade catheter is reintroduced into the left atrium, and
the blade pull-through is repeated three to five times until
no further resistance is felt as the blade is withdrawn through
the septum. With each withdrawal the right or leftward angle
of the blade is changed slightly, while at the same time the
blade always is maintained facing anteriorly. After multiple
withdrawals of the blade are completed, the blade catheter is
replaced with a balloon dilation catheter that should be sig-
nificantly larger than the size of the desired opening. A
balloon dilation of the atrial septum is performed to enlarge
the opening created with the blade.
Balloon Dilation of an Atrial Defect Alone
Angioplasty balloon dilation of the atrial defect is used in
conjunction with a blade atrial septostomy or it can be per-
formed as the primary septostomy procedure in the adult
patient. Balloon dilation septostomy also is indicated when
there is compromised access from the IVC for a blade septos-
tomy. Balloon dilation of the atrial septum, however, is more
334 chapter
effective following an initial blade septostomy because even
a tiny initial incision will initiate a tear that will be extended
by the dilation.
To perform a balloon dilation of the atrial septum, an
end-hole catheter or a transseptal puncture is used to intro-
duce a stiff exchange wire through the atrial septum and out
into a left upper pulmonary vein. An angioplasty balloon is
chosen with a diameter at least twice the size of the desired
opening in the atrial septum. With the wire stabilized in this
position, the appropriate balloon dilation catheter is intro-
duced over the wire and advanced into the atrial septum. The
angioplasty balloon is partially inflated to visualize the
indentation on the balloon made by the restrictive septum.
Once the balloon is centered precisely within the septum, a
controlled inflation of the dilation balloon to its maximum
recommended pressure is performed. The balloon should be
observed closely on fluoroscopy during the inflation to be
sure that it is not squeezed out of the tight septum at its full
inflation. The procedure is repeated several times to ensure
the dilation has achieved maximal opening of the septum.
During the repeat inflations, no waist or indentation should
appear on the balloon even as the balloon is inflated initially.
In large adult patients, a single angioplasty balloon may not
achieve an adequate atrial septal defect due to balloon size
and pressure limitations. In these patients, venous access is
obtained from both groin areas, two separate sheaths are
introduced, and two stiff wires introduced into the pulmo-
nary veins for simultaneous balloon inflations of two angio-
plasty balloons side by side in the atrial septum. Once
completed, the balloon angioplasty catheters are removed
and the hemodynamics are repeated to be sure an adequate
septal opening has been achieved.
In most of the patients with complex lesions and restric-
tive mixing or inadequate venting, an attempt is made to
create the largest possible ASD by using the large blade and
double balloons. Occasionally multiple separate punctures,
blade withdrawals, and balloon dilations are performed. At
the other extreme, in patients with pulmonary vascular
disease or malfunctioning caval-pulmonary connections, a
very small defect (4 to 6 mm) is created initially, enlarging it
in 1-mm increments until the desired minimal systemic
desaturation is achieved.
The final means of creating a more permanent atrial
septal communication or a defect of a specific size is to
implant an intravascular stent in the atrial septum. For a
restricted opening, the stent is prepared on the table to
produce an area of restricted expansion.142 This procedure is
utilized in patients with pulmonary vascular disease and in
patients with a single ventricle or a failing Fontan caval-
pulmonary repair who have developed protein-losing enter-
opathy. A short stent with a strong wall and the capacity to
be dilated to a large diameter is necessary.
A restrictive stent must be prepared by hand on the table.
First the stent is expanded on a 10- to 12-mm balloon, the
balloon is deflated, and a heavy suture is woven in and out of
the struts/openings around the entire circumference of the
stent at its center. The stent with the suture around it is
crimped over a smaller balloon inflated to the diameter of the
desired septal opening and the suture is tightened over this
balloon. The smaller balloon is deflated, withdrawn from the
stent, and the stent/suture is mounted (crimped) onto a large-
12
diameter angioplasty balloon for delivery. The left atrium is
entered either through a preexisting opening or a new trans-
septal puncture. A stiff wire is positioned in the left upper
pulmonary vein, and a long sheath large enough in diameter
to accommodate the balloon/stent/suture combination is
positioned in the left atrium. Often, to pass the large sheath
through the tough septum, it is necessary to perform a
predilation of the septum with a smaller high-pressure
angioplasty balloon. Once the sheath is positioned in the left
atrium, the stent/balloon is advanced into the sheath, cen-
tered precisely on the septum, and dilated to the maximum
pressure of the dilation balloon. The stent should be centered
on the septum as accurately as possible using angiograms or
TEE, but because of the restriction at the center of the stent
and the toughness of the septum, these stents tend to self-
center with the inflation of the larger balloon. The ends of the
stent are expanded to the maximum diameter of the balloon,
and the balloon is deflated and withdrawn, leaving the dumb-
bell-shaped stent in the septum holding open the septal
opening at the desired restricted diameter.
Catheter Implant of Cardiac Valves
The most recent and one of the most exciting new therapeu-
tic catheterization procedures to appear is the transcatheter
implant of cardiac valves. A large number of adult congenital
heart patients who previously have undergone repair of tetral-
ogy of Fallot, pulmonary atresia with ventricular septal
defect, or truncus arteriosus now have wide-open pulmonary
valve regurgitation with right ventricular dilation and failure.
Many of these patients already have undergone one (or more)
repeated surgical interventions for the replacement of the
pulmonary valve with some type of conduit containing a
prosthetic pulmonary valve.
Bonhoeffer et al.,143 working with NuMED Inc. (Hopkin-
ton, NY), developed a stent-mounted pulmonary valve that,
after extensive animal testing, has been successfully
implanted percutaneously in humans. The initial delivery
system was very large but has been modified to a more practi-
cal size. At present the pulmonary stent/valve requires a
somewhat restrictive as well a regurgitant right ventricular
outflow tract in order to hold the valve in place. It is hoped
that this stent/valve will enter FDA IDE clinical trials in the
very near future. In addition to Bonhoeffer et al., other inves-
tigators are in various stages of developing other percutane-
ous implants for the pulmonary as well as the aortic valve.
Cribier et al.144 developed a modification of the stent/
valve concept for use in the aortic valve. The percutaneous
aortic valve is intended for use in the elderly adult with cal-
cific aortic stenosis/insufficiency. The valve itself, the deliv-
ery technique, and the indications for this valve currently
are being modified, but as these are perfected this valve may
have applicability for the adult patient with congenital aortic
valve disease who has developed dominant aortic regurgita-
tion secondary to prior surgical or catheter interventions or
just over time.
The percutaneous implant of cardiac valves is just in its
infancy but should continue to be very exciting over the next
few years and provide a considerably less traumatic reinter-
vention for these patients with severe pulmonary or aortic
valve regurgitation.
 c ong e n i ta l h e a rt di se a se i n t h e a du lt
Catheter Removal of Foreign Bodies
Transcatheter removal of intravascular foreign bodies is an
important part of the armamentarium of the interventional
cardiologist. The need for this intervention has been present
since the early days of intravascular catheterization145 and
has evolved into an essential and often complex intervention.
The incidence of iatrogenic intravascular foreign bodies has
increased due to the general increase in the use of indwelling
catheters and the increased number of therapeutic devices
being implanted in the catheterization laboratory—all of
which have a potential for embolization. Most, if not all, of
the foreign bodies within the vascular system are iatrogenic.
In the past, the majority of these foreign bodies were pieces of
indwelling intravenous tubing from chemotherapy, hyperali-
mentation, and neurosurgical shunts that were broken during
removal, leaving pieces floating in the circulation.146–148
Now, many of the foreign bodies are a consequence of inter-
ventional procedures, including occlusion coils that have
migrated or embolized, tips of catheters or wires, pieces of
balloon dilation catheters, umbrella occlusion devices, and
even intravascular stents. Most intravascular foreign bodies
can and should be removed in the cardiac catheterization
laboratory. A biplane catheterization laboratory is essential
for any foreign body removal, which in turn makes the con-
genital catheterization laboratory particularly well suited for
these retrievals. The key to the successful removal of foreign
bodies is the ability to localize the foreign body within the
vascular system in three dimensions using biplane fluoros-
copy. Without the use of the simultaneous fluoroscopic views,
the retrieval becomes a random “fishing expedition” that
uses inordinate amounts of fluoroscopy time and often ends
unsuccessfully.
There are a variety of catheter devices for the removal of
foreign bodies. These devices are commonly inserted through
a long sheath that must be of a sufficient diameter and stiff-
ness to allow the grasped foreign body to be withdrawn into
the sheath before withdrawal from the body. This occasion-
ally requires a 14 F or 16 F long sheath. An end-hole catheter
is manipulated to a location in the exact same vessel but
distal to the foreign body. A stiff or Super Stiff exchange
length guidewire is advanced and fixed distal to the foreign
body so that a large long sheath and dilator can be maneu-
vered over the wire to a location immediately adjacent to the
foreign body. The retrieval device is passed through the long
sheath so that the foreign body can be grasped and with-
drawn into the sheath for removal.
The mainstay of the retrieval devices is the snare cathe-
ter. Several snare catheters are available including simple
homemade snares that use a loop of standard 0.018-inch
spring guidewire looped through an end-hole catheter. The
more sophisticated commercial nitinol snare systems, which
include the GooseneckTM snare (Microvena Corp., White
Bear Lake, MN) and the EnSnareTM (MDTECH, Gainesville,
FL) now are used universally. The total and reproducible
memory of the nitinol snare loops of the commercially avail-
able snares represents significant advantages over the home-
made snares. The commercial snare catheters are only 4 F or
5 F end-hole catheters, which can be inserted through a short
sheath, a long sheath, or a 7 F end-hole guiding catheter that
has been positioned near the foreign body. The snare itself is
335
a wire with the fixed diameter loop. When it is advanced out
of the distal end of the snare catheter, it aligns at a reproduc-
ible acute angle to the shaft of the catheter. The proximal
end of the snare wire extends out of the proximal end of the
catheter for control of the loop from the proximal end.
The loop of the snare is advanced out of the tip of the
catheter and manipulated to encircle the foreign body by
moving the wire at the proximal end in and out while rotat-
ing the catheter. Once an object is grasped, the snare loop is
made smaller by advancing the catheter forward over the
proximal loop while holding the back end of the wire. With
the infinite memory of the nitinol snare loops, no matter
how many times the loop is advanced to open or is with-
drawn back into the catheter, it resumes its original shape
and orientation when reextruded. Another advantage is that
the snare loop has an offset at an angle from the shaft of the
catheter that has the same memory as the loop. This allows
the loop to pass around the object more easily as the open
snare is advanced rather than trying to catch it from the side
as the snare is withdrawn. For a snare to work, there must
be a free end or piece of the foreign body extending into the
lumen of the vessel/chamber so that the loop of the snare
can encircle it. This snare is most useful for the retrieval of
pieces of indwelling lines, pieces of catheters, or wire/coils.
Another frequently used retrieval device is the basket
device (Boston Scientific, Natick, MA, and Cook Inc., Bloom-
ington, IN). This is a catheter with a core wire system that
has a helix or basket of three or four strands of memory wire
at the distal end. The basket opens as it is extruded from the
catheter. There are several different designs of the baskets,
each of which are available in various sizes. When extruded
from the catheter, and as the basket opens, it is rotated as it
expands and encircles or entangles the foreign body. Several
wires of the basket must be able to encircle at least part of
the foreign body in order to trap it. When the catheter is
advanced over the open basket, the basket compresses as it
retracts into the catheter and in this way grasps the foreign
body securely. The basket device also is used for the retrieval
of pieces of catheter or other larger foreign bodies that have
a free end. The basket will not work unless at least one sepa-
rate wire of the basket can encircle or pass through the
foreign body and the combination then can be trapped by the
basket. This technique is essential in the retrieval and extrac-
tion of fractured pieces of embedded transvenous pacing
leads. The basket is also useful for embolized occlusion
devices including coils, umbrellas, or even stents—all of
which can be compressed at least partially by the basket.
Another essential retrieval device is the GrabberTM cath-
eter (Boston Scientific, Natick, MA). This 4 F catheter has
four tiny metal arms that when extended out of the tip of
the catheter move away from the center of the catheter as
small outward arcs positioned 90 degrees away from each
other. Each arm has a small 1-mm 90-degree inward bend at
its distal tip, which, when the arms are withdrawn into the
catheter, are forced together and overlap each other, creating
a very tight grip on anything positioned between the arms.
The Grabber has the advantage (and disadvantage) of grasping
anything directly in front of it and, in turn, not having to
encircle a foreign body before grasping it so that it can grab
the side of objects. This makes the Grabber uniquely useful
for grabbing objects embedded in the tissues with no free
336 chapter 12

ends such as occlusion devices and wads of coils. The major cover sharp parts of the device, it never should be withdrawn
disadvantages of the Grabber are that once an object is through the cardiac chambers/structures. When the foreign
grabbed it often cannot be released and the Grabber often body can be drawn into a peripheral vessel, it usually can be
will also grab adjacent tissues and retrieve small pieces of removed by a small cut-down over the peripheral vessel using
tissue along with the foreign body! Fortunately, this does not local anesthesia, rather than requiring a thoracotomy. Even
appear to cause any permanent sequelae. when a large foreign body has embolized to the lung, is
A cardiac Bioptome can be used as an alternative to grasp grasped and freed from its distal site, but cannot be with-
foreign objects in some circumstances. The advantage of a drawn sufficiently into the sheath to be drawn through the
bioptome is that it also can be used to grasp a side as well as heart, it can be maneuvered to and held in the main or proxi-
the ends of a small object. A limitation of the bioptome is mal branch pulmonary arteries where the surgeon has easier
that it must be manipulated so that its jaws open perpendicu- access to it. All of these possibilities should be considered in
lar to the object to be grabbed. The bioptome jaws also may preparation for foreign body removal.
not open widely enough to accommodate larger foreign
bodies, and once the object is grabbed, often the bioptome is
not strong enough to hold and withdraw the object. Another
Collaborative (Hybrid) Therapeutic
disadvantage of the bioptome is the difficulty and patience
Catheterization and Surgical Procedures
(and fluoroscopy) it takes to grab a small, moving object with
An added bonus to the new therapeutic catheterization pro-
such a small jaw.
cedures has been an increased collaboration between pediat-
A unique use of the bioptome is to grasp a part of a foreign
ric cardiologists and many of the more forward-thinking
body in order to free or stabilize it while it is being grasped
pediatric cardiac surgeons in the development of staged,
by a sturdier device. The bioptome is useful to grasp the
collaborative repairs of complex defects.110,149–151 One of the
center of a piece of catheter or wire that extends across a
earliest examples of this preplanned cooperation was the
vessel or chamber when no free end of the catheter/wire is
fenestrated Fontan patients, in whom the immediate surgical
accessible. Although retrieval may not be accomplished with
morbidity was reduced by purposefully leaving a residual
the bioptome, at least one end can be pulled free to allow it
ASD that could be closed in the catheterization laboratory
to be grasped by one of the stronger retrieval devices.
once the patient had recovered from the surgery.113 Another
Another retrieval device is the vascular retrieval forceps
notable example of this type of multistaged collaboration is
(Cook Inc., Bloomington, IN). This device has a very tiny
in patients with pulmonary artery atresia and VSD. Early in
angled and serrated jaw that extends out from one side near
the course of management, the surgeon creates a right ven-
the distal end of a very small 3 F catheter. It is operated much
tricle to pulmonary artery connection rather than the simpler
like the jaw operation on the CookTM bioptome catheter. This
to perform systemic to pulmonary shunt. The right ventricle
tiny device can be passed into or through a mass of foreign
to pulmonary artery connection provides the interventional
body that is wedged distally in a vessel. The grasping jaw is
cardiologist with early access to the pulmonary vessels in
opened and closed within or beyond the mass to catch part
order to dilate the small, deformed, pulmonary arteries and
of the object and pull it partially free, if not out of the vas-
to perform intrapulmonary stent implants in preparation for
cular system. The tiny tip and catheter also can be passed
the eventual more definitive repair.
under the middle of a catheter or wire that is against a vessel
The most extensive and notorious example of this col-
or chamber wall and used to pull the foreign material away
laborative effort is the proposed cardiology/surgery collabora-
from the wall. This device is useful both for small foreign
tion to complete the final IVC to pulmonary artery connection
objects and to dislodge or move larger objects initially into
of the caval-pulmonary single ventricle repair in the cathe-
more favorable positions for grasping with sturdier retrieval
terization laboratory rather than in the operating room.152
systems.
This requires the surgeon to do a preceding Glenn procedure
The AmplatzTM deflector wires (Cook Inc.) can be used in
(SVA to pulmonary artery anastomosis) in a very specific
a similar manner to the small jaws device to encircle, grasp,
manner to prepare the pulmonary artery for the eventual
and dislodge or secure foreign bodies that have no free ends.
completion of the IVC tunnel in the catheterization labora-
The tip of the straight deflector wire is advanced outside of
tory. This type of cooperation and its complementary benefi-
the end of the catheter and passed between the foreign body
cial results for the patient contribute to a far better outcome
and the vascular wall. The deflector system is activated,
for many of the extremely complex lesions.
which results in the foreign material being encircled by the
360-degree loop of the deflected tip of the wire. This loop of
wire is not very strong and is more useful for holding or Summary
securing the foreign body while it is grasped with a stronger
retriever. The therapeutic cardiac catheterization procedures dis-
The type and size of the foreign body, its location, the cussed in this chapter represent some of the greatest
time it has been in place, and the adequacy of access vessels advances in the treatment of patients with congenital heart
all will determine the success of foreign body retrieval. The disease since the advent of the first surgical corrections. The
larger foreign bodies certainly can be grasped within the procedures are performed with less immediate risk and cer-
vascular system but may be too large to be withdrawn into tainly far less acute trauma to the patient than from repeated
a sheath or otherwise completely out of the vascular system. surgical interventions. Even with the additional expense of
If a large, jagged foreign body such as an open occlusion the specialized catheters and devices and the added cost
device cannot be withdrawn into the large sheath enough to of the more extensive catheterization procedure, the direct
 c ong e n i ta l h e a rt di se a se i n t h e a du lt
costs of the therapeutic catheterization procedure are sig-
nificantly less than the costs for the comparable surgical
procedure. The savings in indirect expenses for the patient
and family may be even greater than the savings in direct
expense. With the interventional catheterization procedure,
the patient is away from home and work for only 1 or 2
days, compared to a week or two for the comparable surgical
procedure. Following the catheterization procedure, the
patient immediately returns home and returns to full activ-
ity. This compares to a minimum of a 4 to 8 weeks of con-
valescence following a major surgical procedure. With these
multiple advantages to the therapeutic catheterization pro-
cedures, many of the catheter procedures already have
replaced the surgical alternatives. With further develop-
ments and improvements in the catheter techniques, many
more nonsurgical corrections should be included in this
standard category of treatment within the next several
years.
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 1 Surgical Treatment
3 Magdi Habib Yacoub, Anselm Uebing,
Rosemary Radley-Smith, and
Michael A. Gatzoulis
General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
Specific Congenital Defects in the Adult . . . . . . . . . . . . 341
D
uring the 1980s and 1990s, there was a determined
effort to “correct” congenital heart disease during
infancy, usually within the first few days or weeks
of life,1–5 in an attempt to prevent secondary functional and
anatomic changes in the heart and other organs and to avoid
the stress of repeated hospitalization and surgery in older
children and adults. Despite this, a significant proportion of
patients with uncorrected congenital heart disease grow to
adulthood because of the relatively “benign” nature of the
condition or because they were not offered or they refused
surgical treatment. In addition, a number of patients who
have undergone palliative or supposedly corrective opera-
tions require further surgical treatment in adulthood. The
increasing number and the specific nature of these opera-
tions have created a new subspecialty of surgery for congeni-
tal heart disease.6–9 This chapter considers some of the
general features and specific conditions of congenital heart
surgery in the adult.
General Considerations
Congenital heart defects produce progressive changes in
cardiac form and function, as well as secondary effects
resulting from chronic systolic or diastolic overload10 that
can involve myocardial cells,11 the connective tissue frame-
work of the heart,12–14 or the microvasculature and endocar-
dium.15 These abnormalities are qualitatively different for
systolic and diastolic overload. Although many of these
changes initially have the potential to be reversed,16 they
may become irreversible if left uncorrected. Other cardiac
effects may involve progression or development of new
obstructive lesions, such as that observed in tetralogy of
Fallot,17 ventricular septal defect (VSD), or aortic outflow
obstruction in double-inlet ventricle with malposition of the
great arteries.18,19 Continued blood turbulence may affect the
structure and function of the atrioventricular (AV) or semi-
lunar valves, with thickening or calcification of the cusps or
dilatation of the annulus. Poststenotic changes in the great
arteries can lead to either dilatation or arterial wall changes
Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
as the result of turbulence or failure of development and
growth due to chronic reduction in flow. The pulmonary
vascular changes caused by an increase in flow and pressure
include medial hypertrophy and reactivity of smooth muscle
cells, functional and structural intimal changes,20 and even-
tual development of irreversible plexogenic lesions.21,22 The
rate at which such changes occur varies among different
conditions and among individual patients. Other changes
that may occur are the direct result of previous surgery,
which can produce distortion of vessels on intracardiac
shunting. Cerebral, hepatic, and renal function may be
affected by hypoperfusion, cyanosis, or embolism. Accurate
characterization of the extent and reversibility of secondary
changes is of special importance in planning the time and
type of surgical intervention in adults with congenital heart
disease.
Specific Congenital Defects in the Adult
Aortic Valve Stenosis
Congenital bicuspid aortic valve commonly results in pro-
gressive stenosis due to thickening and calcification of the
cusps (Fig. 13.1). Accurate measurement of the amount and
localization of calcification in the aortic valve can be made
using electron beam computed tomography.23,24 The amount
of calcium in the valve has been shown to be a predictor of
progression of the disease25 as well as an independent prog-
nostic indicator.26 Valve-conserving surgery is rarely possible
in adults, and therefore valve replacement is the most com-
monly performed surgical procedure. Advances in myocar-
dial protection and other intraoperative techniques have led
to a reduction in the perioperative mortality rates for both
initial and successive surgery to approximately 1% to 3%.27
The most important issue is the choice of a valve substitute,
which should match the characteristics of the valve to the
requirements of the patient.
Although a considerable amount of information is avail-
able about the performance and suitability of the different
3 41
342 chapter
FIGURE 13.1. Severe aortic stenosis of congenitally bicuspid
valve.
valve substitutes, this information is often incomplete, and
other factors, such as the experience, predictions, and bias of
the surgical team, cardiologist, and patient, can influence
the choice. There is increasing evidence that the normal
aortic valve performs a series of extremely sophisticated
functions that depend on the biologic properties of their
components.27–29 The use of a living valve substitute capable
of reproducing most or all of these functions can result in
clinical benefit in terms of both survival and quality of life.
The only current valve procedures capable of preserving
aortic valve viability in the long term are valve repair and
the Ross operation. Recent evidence strongly suggests that
both survival and exercise capacity are enhanced after the
Ross operation when compared to other valve substitutes.30
Recent progress in tissue engineering31 holds the promise of
making available a fully viable human valve in the not very
distant future. The available substitutes include prosthetic
valves and stented or unstented xenografts. Prosthetic valves
are the most commonly used valve substitutes and have the
advantages of ease of insertion and superior durability.
However, the need for continuous postoperative anticoagula-
FIGURE 13.3. Homograft aortic valve replacement: the two-suture-
line technique.
13
FIGURE 13.2. A stented xenograft valve: porcine bioprosthesis.
tion32 can lead to a small but significant morbidity and mor-
tality incidence,33 particularly in women during the
childbearing years.34 Stented xenografts offer the advantage
of predictability, ease of insertion, and low incidence of
thromboembolic complications. However, their durability is
limited, particularly in patients younger than 35 years. In
addition, the stent can become obstructive (Fig. 13.2), which
has negative implications for hemodynamic performance
and possibly for long-term left ventricular (LV) function.
Homograft valves are inserted in the subcoronary position
either via a two-suture-line technique 35,36 (Fig. 13.3) or as a
root replacement (Fig. 13.4) with reimplantation of the coro-
nary arteries.37,38 These valves have excellent hemodynamic
performance (Fig. 13.5), are virtually free of thromboembolic
complications, and have greater durability than xenografts,
particularly in children. However, their insertion is some-
what technically demanding, they are less readily available,
 su rgic a l t r e atm e n t 343

FIGURE 13.4. Homograft aortic valve replace-

ment with reimplantation of the coronary
ostia.

and they must be replaced after a period of time.39,40 Pulmo-

PCG nary autografts make use of the patient’s pulmonary valve
ECG to replace the aortic valve, with insertion of a pulmonary or
aortic allograft in the pulmonary position (Fig. 13.6).41–43 The
autograft is inserted in the aortic position using a two-suture-
line technique or as a root replacement. The latter technique
is more predictable with regard to achieving immediate com-
100 mmHg petence, but there is some concern about the late dilatation
AOP
of the autograft root. This problem, however, can be largely
LVP
0
prevented by technical modifications, particularly in rela-
tion to the lower suture line43 and the use of hypotensive
drugs during the immediate and early postoperative period.
Aortic stenosis
After aortic valve replacement Stenosis of the pulmonary homograft in the right ventricular
A using homograft outflow tract requiring reoperations occurs in 5% to 10% of
PCG patients following the Ross operation. However, this is com-
ECG pensated for by the considerable advantages of enhanced sur-
vival and quality of life mentioned earlier.

AOP
100 mmHg Subaortic Stenosis
Subaortic stenosis may be caused by muscular or fibromuscu-
0 LVP lar tissue, which may be mild at birth but can progress during
adulthood (Figs. 13.7 and 13.8).44–47 Adequate relief of obstruc-
tion can be achieved in almost all cases with transaortic exci-
sion of the obstructing tissue, starting from a point below the
After aortic valve replacement midportion of the right coronary cusp and extending laterally
Aortic stenosis using stented bioprosthesis
B toward the left fibrous trigone, clearing the angle between the
FIGURE 13.5. Simultaneous left ventricular pressure (LVP) (solid- muscular septum and the anterolateral attachment of the
state catheter) and M-mode echocardiogram show left ventricular anterior mitral leaflet with mobilization of both fibrous
wall movement and transventricular peak systolic gradient imme-
diately after aortic valve replacement with homograft (A) and stented trigones (Fig. 13.9) and thus restoring the dynamic nature of
xenograft (B). AOP, aortic pressure; ECG, electrocardiogram; PCG, the subaortic region (Fig. 13.10).48 Subaortic obstruction due
phonocardiogram. to hypertrophic obstructive cardiomyopathy (HOCM) can be
 Homograft

FIGURE 13.6. Pulmonary autograft

replacement in the aortic position; two-
suture-line technique. Pulmonary auto-
grafts as a root replacement (see Fig.
1. Excise pulmonary valve 2. Pulmonary valve to aorta 3. Homograft to pulmonary artery 13.4).

FIGURE 13.7. Left ventricular outflow tract obstruction due to subvalvular

muscular hypertrophy. IVS, interventricular septum; PW, posterior wall; i,
inferior; s, superior.

FIGURE 13.8. Echocardiogram shows the anterior component of the subaortic stenosis (A), post-
operative transesophageal echocardiogram of the left ventricular outflow tract (LVOT) during
systole and diastole (B), and the mobilized hinge mechanism of the right and left fibrous trigones
(C). Ao, aorta, LA, left atrium; LV, left ventricle; MV, mitral valve; RV, right ventricle.
 su rgic a l t r e atm e n t 345

FIGURE 13.9. Diagrams show the dif-

ferent steps of surgical relief of fixed sub-
aortic stenosis with mobilization of the
fibrous trigones (see text for details).

relieved by percutaneous alcohol ablation49 or with transaor- Coarctation of the Aorta

tic wide excision of the obstructive muscle. Currently, surgi-
cal myectomy is considered the gold standard for relief of
obstruction in HOCM.50 Mobilization of the fibrous trigones
may be necessary in some of these patients.48 A very small
minority of patients with tunnel-type obstruction requires
more radical procedures.51–53
Supravalvular Aortic Stenosis
Supravalvular aortic stenosis is usually associated with
hypoplasia of the ascending aorta. This condition can be
adequately treated by the insertion of a bifid (Fig. 13.11)54 and
trifoliate (Fig. 13.12)55 patch of autogenous pericardium or
Dacron.
On the right side, isolated infundibular stenosis can
usually be relieved through the pulmonary valve or through
a transverse ventriculotomy.
Uncorrected and recurrent coarctation56,57 or complications
related to previous repair,58 such as false aneurysms or hyper-
tension, can present in adult life. In these patients, an accu-
rate diagnosis of the exact anatomic lesion is necessary.
Magnetic resonance imaging or alternatively high-resolution
computed tomography is the preferred noninvasive imaging
technique to delineate the anatomy of the entire aorta (Fig.
13.13). Magnetic resonance imaging provides information
not only on the anatomy but also on the pressure gradients
across the coarctation and collateral blood flow.59–62 The use
of patch angioplasty has resulted in a high incidence of late
false aneurysms. The operation of choice is excision of the
lesion with direct end-to-end anastomosis; in some patients,
however, interposition of a Dacron graft or the use of a bypass
graft from the proximal to the distal segment may be neces-
sary, and possibly safer.

Muscular septum Membranous

septum

FIGURE 13.10. Diagrams show the

interaction between the mitral and aortic
orifices (B and C), with the two fibrous
trigones acting as a hinge mechanism for
the movement of the subaortic curtain Left fibrous
and anterior leaflet of the mitral valve trigone Right fibrous
during different phases of the cardiac Subaortic trigone
cycle and the structures surrounding the curtain
left ventricular outflow tract (A). A B C
346
FIGURE 13.11. (A,B) Repair of supravalvular aortic stenosis with a
patch of autologous pericardium.
Over the past one to two decades interventional tech-
niques have been developed both for pediatric and adult
patients with congenital heart disease.63,64 In many centers
primary stent implantation has nowadays replaced surgery
chapter 13
as treatment of choice for native or recurrent coarctation in
the adult.64 Furthermore, interventional implantation of an
endovascular stent graft has the potential to avoid repeat
surgery for para-coarctation aneurysms and is offered in spe-
cialized tertiary centers (Fig. 13.14).
However, there are ongoing concerns about balloon
angioplasty and stenting for young pediatric patients relating
to the common complication of aneurysm formation and the
relative narrowing of the stent with respect to somatic
growth, respectively.
Aortic Regurgitation
Severe aortic regurgitation in adults may be secondary to
congenital abnormalities of the aortic sinuses, sinotubular
junction, or cusps, and may be associated with VSD. Valve-
preserving reparative procedures are possible in a high pro-
portion of these patients65–71 and depend on a thorough
understanding of the anatomic and functional components
of the particular condition, factors that influence progression
and evolution of safe, predictable methods of surgical repair.
These principles are exemplified in repair of the syndrome
of dilatation of the right coronary sinus, VSD, and aortic
regurgitation67 (Figs. 13.15 and 13.16), as well as aortic regur-
gitation due to dilatation of the aortic sinus or sinotubular
junction in patients with connective tissue disorders, such
as Marfan’s syndrome72–75 (Fig. 13.17), or after the correction
of certain congenital malformations, such as truncus
arteriosus.76
Cusp extension with the use of fresh autologous or glu-
taraldehyde-treated or homologous pericardium dura mater
FIGURE 13.12. (A) The aorta is tran-
sected just distal to the area of maximal
stenosis. (B) Three incisions are made,
one into each sinus of Valsalva. (C) Res-
toration of normal aortic root geometry
by insertion of three patches. (D) End-to-
end anastomosis of the reconstructed
root of the ascending aorta. (E) En-
largement of the ascending aorta by an
additional patch.
 su rgic a l t r e atm e n t 3 47

A B C
FIGURE 13.13. Magnetic resonance imaging of an adult patient with native aortic coarctation showing the anatomic details (A–C) of the
aorta and collateral arteries.

FIGURE 13.14. Magnetic resonance imaging

of severe aortic coarctation before (left) and
after (right) primary stent implantation in an
adult patient.

FIGURE 13.15. Hemodynamic forces

that influence progression of the syn-
drome during early systole (A), late
systole (B), and diastole (C).
348 chapter 13

FIGURE 13.16. (A,B) Section in the

aortic root illustrates the placating
sutures used to close the ventricular
septal defect, elevate the annulus, reduce
the size of the sinus, and restore compe-
tence of the aortic valve.

A B

D
E

FIGURE 13.17. (A–E) Operative technique of the

valve-sparing operation used in this series (see text).
 su rgic a l t r e atm e n t
has been used with good initial results (Fig. 13.18).77–79
Although this technique can be used to tide patients over for
a period of time, relatively fast degeneration of the cusp
extension, especially in young individuals, limits its wider
use. The development of more durable materials, possibly
through tissue engineering, is needed for this method to
reach its potential.
Mitral Valve Disease
Congenital abnormalities of the mitral valve can present in
adulthood with severe regurgitation secondary to a cleft in
349
the anterior cusp or to cusp prolapse (Fig. 13.19) caused by
myxomatous degeneration.80–85 Valve repair is the procedure
of choice for these lesions and is appropriate for the majority
of patients. Accurate characterization of the anatomic lesion
is usually achieved with intraoperative echocardiography
(Fig. 13.20). Intraoperative testing of the mitral valve, using
a technique that subjects the valve to physiologic pressures
with a beating heart, allows selective repair of the responsi-
ble lesion (Fig. 13.21).
Congenital mitral stenosis secondary to a parachute
valve almost always presents in infancy or childhood. A
supravalvular membrane attached to the upper surface of the

C
A B D E

F G I J

A B H

C D

FIGURE 13.18. (A–H) Surgical tech-

nique of aortic cusp extension with
fresh autologous pericardium. G H
350 chapter
FIGURE 13.19. Top: Short-axis cut at the level of the left ventricular
outflow tract (LVOT) in a patient with an isolated cleft in the anterior
mitral valve leaflet. Note the cleft, indicated by two arrows pointing
toward the outflow tract, and not the right ventricle (RV). LA, left
atrium. Bottom: Short-axis cut at the level of the mitral valve (MV).
Note again the cleft indicated by the arrows, pointing toward the
outlet of the heart and not the right ventricle. A, anterior; IVS, inter-
ventricular septum; L, left; MV, mitral valve; P, posterior; R, right;
RVOT, right ventricular outflow tract.
FIGURE 13.20. (A,B) Typical features of mitral valve prolapse (MVP) as shown by intraoperative transesophageal echocardiography. AL,
anterior leaflet; LA, left atrium; LV, left ventricle; RA right atrium; RV, right ventricle.
13
FIGURE 13.21. Intraoperative testing of mitral valve repair. Note
use of bifurcated coronary line directing blood into the left ventricle
via the apex and into the aortic root proximal to the cross-clamp.
The mitral valve can be safely inspected in the beating heart.
mitral valve can present in late childhood or early adulthood
(Fig. 13.22).86 We have observed the progression of supraval-
vular membranes in adulthood. Although the membrane is
commonly fused to the atrial surface of the mitral valve
cusps, it is usually possible to excise it with preservation of
the valve. The left AV valve in ventriculoarterial discordance
is usually abnormal, with resulting progressive regurgitation
in adult life.87,88 These valves usually require replacement
and are very rarely suitable for repair. Furthermore, after
surgery, the regurgitation is usually associated with varying
degrees of dysfunction of the systemic morphologic right
ventricle.
 su rgic a l t r e atm e n t 3 51
13.23).89,90 In patients with advanced RV dysfunction in the
presence of severe LV dysfunction, a total cavopulmonary
shunt can be considered. In patients with advanced RV and
LV dysfunction, cardiac transplantation is indicated.

FIGURE 13.22. Congenital stenosing supravalvular membrane
attached to the atrial side of the mitral valve (mv). Note that in
contrast to the situation in cor triatriatum, the pulmonary veins
and left atrial appendage enter the left atrium (LA) proximal to or
above the supravalvular membrane. AO, aorta.
Tricuspid Valvular Disease
The most common congenital defects of the tricuspid valve
presenting in adulthood are the less severe forms of Ebstein’s
anomaly, with displacement of attachment of the posterior
and septal leaflets into the right ventricle, resulting in
varying degrees of tricuspid regurgitation, as well as RV and
LV dysfunction. Repair is possible in approximately two
thirds of the patients, with a variety of techniques (Fig.
Pulmonary Valve
Isolated pulmonary valvular stenosis occasionally presents
for the first time in adult life. Although the valve is thicker
and may be calcified, open valvotomy is usually possible.
Pulmonary valve replacement is rarely necessary. Recurrent
or residual pulmonary valvular dysfunction after previous
repair or angioplasty is uncommon except in patients with
tetralogy of Fallot who have received transannular patches
or previous insertion of a valve conduit for correction of a
variety of complex congenital anomalies.91 In these patients,
the calcified conduit could be adherent to the sternum and
therefore at risk of being injured during sternotomy. To avoid
this, profound hypothermia with femorofemoral cannulation
may be used. The preferred valve at both the first and second
operation is a pulmonary homograft, although both aortic
homografts and xenografts have been used with varying
degrees of success. Alternatively, percutaneous valve replace-
ment could be used.92
Percutaneous Valve Replacement
This is a rapidly progressing area that has captured the
imagination of both clinicians and patients. Several strate-
gies are being developed for all four valves.92 The most
successful to date is pulmonary valve replacement utilizing
a stent bearing a bovine jugular vein valve (Fig. 13.24).

FIGURE 13.23. Surgical technique. I:

Operative view. A, Anterior leaflet; C,
atrialized chamber; P, posterior leaflet;
S, septal leaflet. II: Anterior leaflet and
adjacent portion of posterior leaflet are
detached from the annulus. Leaflet
tissue is mobilized by cutting fibrous
bands attached to the ventricular wall.
Interchordal spaces are fenestrated if
obliterated. III: Longitudinal placation
of right ventricle by simple sutures
passed through the septal and posterior
leaflet remnants. Tricuspid annulus and
right atrium are plicated. IV: Anterior
and posterior leaflets are sutured to the
tricuspid annulus after clockwise rota-
tion (arrow) to cover the entire orifice
area. V: Prosthetic ring is inserted to
remodel the orifice and to reinforce
repair. Atrial septal defect is closed.
352 chapter
FIGURE 13.24. Pulmonary angiogram before percutaneous valve
replacement showing significant pulmonary regurgitation (upper
panels). After implantation of the valve (lower panels), contrast
The immediate and short-term results are good and the pro-
cedure offers the great advantage of avoiding or delaying
repeat surgical procedures in young patients. The long-term
results of these procedures, however, are still unknown but
could be greatly enhanced by advances in experience and
technology including the development of tissue engineered
valves that, at least in theory, could provide semipermanent
solutions.
Septal Defects and Anomalous Pulmonary Veins
Secundum Atrioseptal Defect
Secundum atrioseptal defect (ASD) can present in adulthood
and may be associated with atrial fibrillation, marked enlarge-
ment of the right ventricle and pulmonary arteries (Fig. 13.25),
and occasionally mitral valve prolapse. Varying degrees of
pulmonary vascular disease may occur later in life.
Nowadays, the majority of secundum ASDs can be closed
with a transcatheter approach. The latter, which is most
commonly performed with the Amplatzer septal occluder™
13
injection into to the pulmonary artery documents normal function-
ing of the new valve.
(AGA Medical Corp., Golden Valley, MN), is established as
a safe and effective alternative to surgical closure.93,94
However, transcatheter closure is not feasible if the ASD is
too large (without a sufficient rim around the defect) or if the
ASD is of sinus venosus or primum type. Therefore, ASDs
still need surgical closure with a pericardial or Dacron patch
to avoid tension on the slightly rigid tissues. The sudden
postoperative drop in flow through the markedly enlarged
pulmonary arteries may lead to intravascular thrombosis,
which may be prevented by postoperative anticoagulation for
a period of 1 month to 1 year, depending on the size of the
pulmonary arteries. Defects with echocardiographic evi-
dence of right heart dilatation, a pulmonary/systemic flow
ratio of more than 1.5, or both, should be closed electively to
prevent long-term complications. Even in older patients
(above 40 years) with large ASDs, closure of the defect
improves mortality from cardiovascular events such as pul-
monary or systemic embolism, deterioration or heart failure,
and overall mortality, and improves functional class.95
However, older patients remain at the risk of persistent or
newly developing postoperative arrhythmia (Fig. 13.26), and
 su rgic a l t r e atm e n t
FIGURE 13.25. Right ventricular enlargement associated with a
secundum atrial septal defect presenting in adult life.
for this reason, additional procedures targeting the arrhyth-
mia (maze procedure) should be considered at the time of
surgical closure of the defect.96–98
Atrioventricular Septal Defect
Patients with partial atrioventricular septal defects (AVSDs)
share the same hemodynamic burden of chronic right heart
FIGURE 13.26. Meier survival curve of freedom from late post-
operative atrial flutter/fibrillation.
353
volume overload with secundum ASDs, with the additional
hazard of left AV valve regurgitation. Patients with more
severe forms of left AV valve regurgitation tend to present
earlier. Repair of partial AVSD in adulthood, combined with
elective left AV valvuloplasty, carries a low operative risk
with an excellent long-term outcome and may reduce the
need for reoperation on the left AV valve.99
Patients with complete AVSDs, in contrast, develop
early pulmonary vascular disease, and although they may
still survive to adulthood without an operation, they develop
the Eisenmenger complex. Occasionally, the pulmonary
circulation in the older patient with complete AVSD is
protected by natural pulmonary stenosis or the early inser-
tion of pulmonary artery banding. Ideally, complete AVSD
should be corrected during the first year of life, including
those with tetralogy of Fallot, unless there are specific
contraindications.100
After repair of the AVSD, a significant number of patients
develop progressive left AV valve regurgitation. This is
usually secondary to separation of the two repaired compo-
nents of the reconstructed septal leaflet of the new left AV
valve and can be repaired by inserting extra sutures (Fig.
13.27). Occasionally, valvular tissue is deficient, necessitat-
ing valve replacement with a low-profile valve to prevent LV
outflow obstruction by the prosthetic valve. Subaortic steno-
sis can develop late after repair of AVSD. This is usually due
to turbulence produced by the abnormal attachment of the
left AV valve, resulting in the development of a discrete
fibrous shelf. Radical excision of the fibrous tissue is usually
sufficient to relieve the obstruction (see Subaortic Stenosis,
FIGURE 13.27. Reattachment of the two components of the recon-
structed septal leaflet of the left atrioventricular valve.
354
above). Occasionally, more complex forms of reconstruction
are required.
Anomalous Pulmonary Veins
Anomalous drainage of one or more pulmonary veins is occa-
sionally encountered in adult life. This may be isolated or
associated with a small ASD or specific syndrome of right
pulmonary hypoplasia (scimitar syndrome) (Fig. 13.28). As
in isolated ASD, the need for correction depends on the size
of the left-to-right shunt.
Ventricular Septal Defect
Small VSDs may be diagnosed in adulthood during routine
medical examination or during repeated episodes of infec-
tious endocarditis involving the tricuspid valve on the RV
wall. The defect may be closed after adequate treatment of
the endocarditis with intravenous antibiotics. Emergency
excision of the infected tissue and repair of the VSD during
the acute stage are indicated in patients with uncontrolled
infection or uncontrolled heart failure. There still is no
agreement about the management of small defects diagnosed
during routine medical examination. The risk for death or
major complications (i.e., endocarditis) is very small and
probably equal to the risk of surgical correction. Occasion-
ally, small defects present with RV outflow obstruction or
aortic cusp prolapse and aortic regurgitation. Resuspension
of the right coronary or noncoronary cusp often reveals a
larger VSD—partially occluded by the cusp—and may pre-
serve the aortic valve.67 Patients with large unoperated defects
present with advanced pulmonary vascular disease and are
considered for heart-lung transplantation or double-lung
transplantation, and repair of the defect (see later).
FIGURE 13.28. Hemianomalous pulmonary venous drainage in
association with right lung hypoplasia (scimitar syndrome).
chapter 13
Patent Arterial Ducts
Small patent ductus arteriosus diagnosed in adulthood
carries a relatively high risk for endarteritis (about 1% to 2%)
because of the turbulence created, which may produce endo-
thelial damage and infection; therefore, these defects should
be electively closed. In middle-aged patients, calcification
and aneurysmal dilatation around the area of the duct may
necessitate the use of cardiopulmonary bypass to handle the
additional lesion. The presence of a large patent ductus arte-
riosus in adults in usually associated with severe pulmonary
vascular disease, which may require heart-lung or double-
lung transplantation.
Coronary Artery Anomalies
Anomalies of the mode of origin or course of the proximal
coronary arteries can have a profound effect on myocardial
blood flow and can lead to severe ischemia or sudden death.
Although these anomalies are uncommon, familiarity with
the different anatomic types and with the exact mechanisms
involved in ischemia is essential if the treating clinician is
to recognize and effectively treat these potentially correct-
able conditions before they produce irreversible damage.
In addition, recognition of benign coronary anomalies
and aberrant vessels is important in planning surgical repair
of congenital heart disease. Anomalies occur in 10% to 30%
of cases of tetralogy of Fallot—most commonly, a prominent
conus artery arising from the right coronary artery or the
left anterior descending coronary or circumflex artery aris-
ing from the right aortic sinus or right coronary artery. If
the aberrant vessel crosses the RV outflow tract, it may be
jeopardized at the time of surgical repair. There are several
surgically important variations of coronary anatomy in
transposition of the great arteries (AV concordance, VA
[ventriculo-arterial] discordance) to be considered when per-
forming the arterial switch operation in an infant.101
Anomalous Origin of the Coronary Arteries From
an Inappropriate Aortic Sinus
Origin of the left coronary artery from the right coronary
sinus and, less commonly, the right coronary artery from the
left coronary sinus102 is known to produce sudden death or
episodic ischemia. The exact mechanism responsible has
been debated and was originally thought to be compression
of the proximal coronary artery by the pulmonary artery.
However, the most probable cause is compression of the
intramural segment of the anomalous coronary artery that
runs inside the aortic wall superficial to the intercoronary
commissure of the aortic valve. Clinical diagnosis of the
anomaly may be difficult, because objective evidence of isch-
emia may be lacking unless the patient undergoes repeated
stress exercise testing to reproduce the exact conditions nec-
essary to produce ischemia. Surgical treatment involves
removal of the intramural course of the artery by laying it
open into the lumen of the aorta, with careful reattachment
of the intima.102 This technique is effective, but there is a
risk of damaging the aortic valve or producing coronary dis-
section or obstruction by the intimal flaps. Alternatively, the
coronary artery can be bypassed, preferably using an arterial
graft.
 su rgic a l t r e atm e n t
Anomalous Origin of the Left Coronary Artery
From the Pulmonary Artery
This rare condition usually presents in infancy when pulmo-
nary vascular resistance decreases, with myocardial isch-
emia and LV failure. However, 10% to 15% of patients survive
into adulthood because an adequate circulation is established
between the right and left coronary arteries via intercoro-
nary collateral vessels.103–105 Adults may be asymptomatic or
present with myocardial ischemia or mitral regurgitation
due to papillary muscle dysfunction. Even if there is no
resting myocardial ischemia and ventricular function is
normal, repair is warranted because such patients remain at
risk of ischemia, syncope, and sudden death. Although
several surgical strategies for treating this condition have
been described,106–110 the operation of choice is to create a
two-coronary artery system by transplanting the anoma-
lously arising vessel from the pulmonary artery. A reliable
technique of anatomic correction of this anomaly with aortic
transfer of the coronary ostium to the middle of the left coro-
nary aortic sinus has been developed.111,112 The exact location
of the coronary ostium in the sinus could have important
implications for coronary flow.113 The technique consists of
limited mobilization of the pulmonary artery button bearing
the coronary orifice, followed by threading it through the
transverse sinus into the lumen of the aorta after making a
circular hole in the aortic sinus. The anastomosis is per-
formed from inside the aorta (Fig. 13.29). Mitral valve repair
FIGURE 13.29. Technique of anatomic correction of an anomalous
left coronary artery with transfer of the coronary ostium to the
middle of the left coronary aortic sinus.
355
may also be required. Survival after surgical repair depends
on the amount of ischemic myocardial damage and degree of
mitral regurgitation.
Coronary Artery Fistulas
Coronary artery fistulas consist of a heterogeneous group of
anomalies characterized by the presence of a fistulous tract
between part of the coronary artery tree and a low-pressure
chamber such as the right ventricle (40% of cases), the right
atrium (25%), the pulmonary artery (15%), and rarely, the
left atrium, pulmonary veins, or superior vena cava. In almost
all of these conditions, survival to adulthood is usual, but
longevity could be reduced. The evolution of the anomaly
and its clinical importance depend on several factors, includ-
ing the initial size and the exact location. Small fistulous
communications between the proximal left anterior descend-
ing or right coronary artery on one side and the pulmonary
artery on the other side usually cause trivial shunts and no
significant coronary steal and appear to remain very small
and therefore require no treatment. In contrast, large fistu-
lous tracts between one of the aortic sinuses near the coro-
nary orifice or from one of the large coronary arteries usually
continue to grow in size and length, becoming progressively
more tortuous.
The relationship between the fistulous tract and the coro-
nary artery system can be complex in that the portion of the
coronary artery proximal to the origin of the fistula can
markedly enlarge and appear to be part of the fistulous tract
but can be distinguished by the fact that it gives origin to
coronary artery branches and, to some extent, by its location,
which follows the normal course of the particular artery
affected. Definition of the exact location of the coronary
arteries to the fistulous tract is essential in planning the
appropriate corrective procedure. The objective is to remove
the fistulous tract in its entirety while preserving coronary
artery supply without ectatic segments. Attempts at defining
the exact cause of the fistulous tract and the associated coro-
nary orifice in relation to the fistulous tract can be deter-
mined at the time of operation after opening the fistulous
tract. Restoration of near-normal coronary anatomy (after
excision of the fistulous tract) can be accomplished via
various reconstructive procedures involving anastomosing a
flap or a button carrying the main coronary artery back to
the aorta, occasionally combined with arterial grafts to the
distal coronary branches. Distal interruption of the fistulas
is inadequate because it could result in recurrence through
rupture of the blind end into the same or another chamber
or progressive thrombosis involving some of the coronary
artery branches. Similarly, transcatheter closure may be
accompanied by such complications.114
Cyanotic Heart Disease
Tetralogy of Fallot
Uncorrected tetralogy of Fallot encountered in adulthood is
usually associated with many secondary changes, including
various degrees of RV fibrosis, acquired calcification or
atresia of the pulmonary valve, aortic valvular abnormalities
(regurgitation or annular calcification), and, occasionally,
356 chapter
dilatation of the aortic root and ascending aorta. In addition,
the possibility of coronary artery disease should be excluded
by angiography. Late repair is usually feasible but carries a
slightly higher risk.115–117 Such patients do not tolerate well
free pulmonary regurgitation, and the use of a valve in the
pulmonary position under these circumstances is advisable.
Previous palliative procedures, such as shunts, must be taken
down, with repair of any distortion or narrowing of the pul-
monary arterial tree produced by the shunt. The shunts of
Waterston and Pott require separation of the aorta from the
pulmonary artery, with reconstruction of both vessels, which
may be extensive in some patients. The use of extracardiac
conduits to relieve the RV outflow obstruction is required
more often than in the pediatric age group. Pulmonary or
aortic homografts118,119 are the preferred types of conduits
because of their superior hemodynamic performance and
durability compared with other types of conduits, such as
stented porcine xenografts,120 pericardial valve conduits, or
prosthetic valves.121
Residual or recurrent hemodynamic lesions leading to
RV dilatation are not uncommon in the adult patient with
previous repair of tetralogy of Fallot. These lesions should be
A B 600
PA
Flow volume (mL/s)
RV
–200
–400
A B
RV
LV
C D
FIGURE 13.30. (A) Diastolic right ventricular outflow tract cine
MRI image in patient with repaired tetralogy of Fallot with late
pulmonary regurgitation. (B) Flow map from through plane pulmo-
nary artery velocity map in the same patient showing significant
13
corrected before they produce irreversible changes. Pulmo-
nary regurgitation secondary to transannular patches, mal-
functioning monocusp, or complete conduit is well tolerated.
Pulmonary regurgitation, however, in the long term may
lead to reduced exercise capacity, RV dysfunction, arrhyth-
mia, and possibly sudden death.122 QRS duration from the
surface electrocardiogram relates to RV size; when it exceeds
180 ms, it becomes a sensitive and specific marker of sus-
tained ventricular tachycardia and sudden death late after
repair of tetralogy of Fallot.
Restoration of right ventricular outflow competence with
pulmonary valve implantation, therefore, should be consid-
ered when progressive RV dilatation and early dysfunction,
new-onset tricuspid regurgitation, or arrhythmia occurs or
the patient becomes symptomatic. Timely pulmonary valve
implantation leads to an improvement of right ventricular
function and clinical status.123
Magnetic resonance imaging has been established as the
method of choice for the noninvasive assessment of right
ventricular size, function, and mass and for quantifying pul-
monary regurgitation. It can be used for serial assessment of
the patient (Fig. 13.30).123–125
400
200
0
0 200 400 600 800 1000 1200
Trigger delay (ms)
* RPA
RVOT
LV
pulmonary regurgitation (35%). (C) Four-chamber cine image
showing dilated, hypertrophied right ventricle and tricuspid regur-
gitation (arrow). (D) Cine image showing discrete right pulmonary
artery stenosis (below asterisk).
 su rgic a l t r e atm e n t 357
If degeneration of an implanted homograft in the pulmo-
nary position occurs leading to pulmonary stenosis and
again regurgitation, nonsurgical percutaneous insertion of a
new pulmonary valve is now an option in selected special-
ized centers,126 as mentioned earlier (Fig. 13.24).
Progressive aortic root dilatation potentially leading to
aortic regurgitation can occur in a subset of Fallot patients,
operated and unoperated and may warrant aortic valve and/or
root replacement.127 There is fresh evidence that this is
caused by marked histologic abnormalities in the wall of the
aortic root and the ascending aorta.128

Tetralogy of Fallot with Pulmonary Atresia

A significant number of patients with tetralogy of Fallot with
pulmonary atresia survive into adulthood when there is pul-
monary blood supply through a set of true pulmonary arter-
ies supplied by a patent ductus arteriosus, a previously
constructed shunt, or multiple aortopulmonary collateral
arteries (MAPCAs). The intracardiac anatomy is usually
identical to that found in tetralogy of Fallot with atresia or
absence of the RV outflow tract. Aortic root dilatation is
often marked in these patients and may predispose to aortic
root rupture and sudden death.
Management of this condition depends largely on the
anatomy of the pulmonary circulation. The blood supply to
the different segments may be absent or may be taken by a
transpulmonary artery (connected to a central pulmonary
artery derived from the sixth arch), by an MAPCA, or by a
combination (dual blood supply).129 Accurate definition of all
the branches supplying the lung (Fig. 13.31) is essential to the
formulation of a plan for surgical treatment, consisting of FIGURE 13.32. Repair of pulmonary atresia with homograft conduit
one or, usually, more multiple stages of unifocalization130–132 from the right ventricle to the central pulmonary artery.
of the pulmonary arteries by direct anastomosis of the differ-
ent branches or interposition of segments of azygos vein or
Gore-Tex shunt combined with ligation of MAPCAs supply-
ing segments with dual blood supply. Total correction is per-
formed by closing the VSD and inserting a homograft conduit
from the right ventricle and the reconstructed pulmonary
artery tree (Fig. 13.32). In some patients with absent central
pulmonary arteries, unifocalization is not a real option; for
these patients, lung or heart-lung transplantation may be the
only recourse.

Transposition of the Great Arteries

FIGURE 13.31. Aortopulmonary collateral arteries in a patient
with tetralogy of Fallot and pulmonary atresia.
Uncorrected transposition is incompatible with survival into
adulthood unless there are additional lesions that ensure
adequate mixing of blood and possible protection against
pulmonary vascular disease. The most common such addi-
tional abnormalities are large VSDs with or without pulmo-
nary stenosis. Patients with transposition and large VSDs
develop severe pulmonary vascular disease at an earlier age
than those without transposition.133 In severely symptomatic
patients, heart-lung transplantation is the only treatment
option.134,135 The combination of transposition of the great
arteries, VSD, and pulmonary stenosis can be treated with
the Rastelli operation,136 which consists of redirection of
blood through the VSD to the RV outflow tract into the aorta
and insertion of an extracardiac conduit from the right ven-
tricle to the transected pulmonary artery (Fig. 13.33). The
Lecompte operation [redirection entre ventriculaire (REV)]
358 chapter
Pledgets
Pledgets
FIGURE 13.33. Use of a right ventricle to pulmonary artery conduit
in the Rastelli operation.
constitutes an alternative approach (Fig. 13.34).137 Incomplete
or L-transposition of the great arteries is usually associated
with AV and ventriculoarterial discordance (corrected trans-
position). In these patients, surgical treatment is commonly
required for left AV valve regurgitation and associated anom-
alies such as VSD and pulmonary outflow obstruction.
Adults with transposition of great arteries who have
undergone a previous atrial switch procedure (Mustard or
13
Senning) may present with arrhythmia or symptoms due to
stenosis of the systemic or pulmonary venous pathways or
RV dysfunction. Relief of baffle obstruction can be achieved
with baffle revision, enlargement of the pulmonary venous
atrium, or both.
Right ventricular dysfunction is common in adults after
atrial switch operation as the RV has to sustain systemic
pressure permanently. It seems that progressive structural
deterioration of the right ventricular myocardium takes
place after the atrial switch procedure. Fibrosis of the sys-
temic right ventricle detectable by late gadolinium enhance-
ment magnetic resonance imaging could be found especially
in older patients and relates not only to RV dysfunction but
also to clinical events such as arrhythmia or syncope, sug-
gesting prognostic importance of this finding (Fig. 13.35).138
Anatomic correction (takedown of the Mustard or
Senning procedure combined with an arterial switch) after
pulmonary artery banding (to retrain the left ventricle for the
systemic circulation) has been considered a “conventional”
option for patients with failing systemic right ventricles.139
However, there are very limited data on the use of this
approach in this group of patients. The future application of
this strategy will depend on the timing of the operations and
possibly on the use of strategies to induce physiologic hyper-
trophy as suggested by experimental studies.140 Deterioration
in RV function can ultimately affect LV structure and func-
tion through ventriculoventricular interaction.141
Tricuspid Atresia and Double-Inlet Ventricle
The conditions of tricuspid atresia and double-inlet ventricle
are characterized by severe hypoplasia or absence of one of the
FIGURE 13.34. Correction of transposi-
tion of the great arteries with ventricular
septal defect and pulmonary stenosis.
(A) View from right ventricular infun-
dibulectomy of the ventricular septal
defect and the portion of the interven-
tricular septum to be excised. (B) The
infundibular septum has been resected.
(C) The intraventricular baffle has been
sutured into place. (D) The pulmonary
bifurcation is passed anterior to the
ascending aorta. (E) The posterior rim of
the distal pulmonary trunk is sutured to
the top of the infundibulectomy. (F) An
anterior patch is sewn over the pulmo-
nary outflow tract.
 su rgic a l t r e atm e n t 359

A B

C D

FIGURE 13.35. Magnetic resonance imaging of a patient after right ventricle is severely dilated (A,C). There is extensive fibrosis
Mustard repair for transposition of the great arteries. Cine images of the right ventricular free revealed by late gadolinium enhance-
show thin myocardium of the right ventricular free wall and the ment magnetic resonance imaging (white areas in B and D).

ventricular chambers, rendering biventricular repair impos-
sible or impractical. These patients are considered for opera-
tions that direct systemic venous return to the lung.142–144
The original Fontan operation142 consisted of anastomosing
the right atrium to the pulmonary artery with interposition
of homograft values. These operations can be considered only
if pulmonary vascular resistance is low, the pulmonary arter-
ies are of adequate size, ventricular function is not signifi-
cantly impaired, and there is no AV valvular dysfunction.
Directing systemic venous return to the lung can also be
achieved by total cavopulmonary shunt,145,146 which avoids
the use of the atrium as a pumping chamber. This approach
has many advantages.
A total cavopulmonary connection (TCPC) can be estab-
lished by connecting the superior vena cava to the pulmo-
nary arteries (bidirectional cavopulmonary anastomosis) and
diverting the inferior vena cava return to the pulmonary
arteries either by a baffle within the right atrium (lateral
tunnel) or by an extracardiac conduit. The extracardiac total
cavopulmonary connection has become the Fontan modifi-
cation of choice in patients older than 3 years of age. This
technique preserves147,148 the hemodynamic benefits ascribed
to the total cavopulmonary anastomosis, yet avoids the
potential disadvantages of aortic cross-clamping and compli-
cations related to the intraatrial placement of baffles or
tunnels, including leaks, stenoses, arrhythmias, and throm-
boembolic complications in the systemic circulation.147,148
In patients with marginally elevated pulmonary vascular
resistance, the addition of a fenestration between the sys-
temic venous channel and the atrium has added substantially
to the safety of the operation.149 The fenestration can then
be closed by transcatheter insertion of an umbrella device,
providing balloon occlusion of the orifice does not cause
excessive rise in systemic venous pressure (>15 mm Hg).
In addition, protagonists of the extracardiac Fontan opera-
tion have advocated that the need for fenestration be
360 chapter 13

assessed after cardiopulmonary bypass is discontinued, when

hemodynamics can be accurately evaluated.149 Another
approach that we have used is the creation of a temporary
“fenestration” by a cruciate incision in the baffle that closes
spontaneously after a period of several weeks or months.
The judicious use of the Fontan operation has provided
good palliation for a large number of patients. There are still
concerns, however, regarding the very long-term results of
this procedure.150–152 Complications late after the Fontan
operation include atrial arrhythmias, decreased ventricular
function, increasing cyanosis, intraatrial thrombus forma-
tion, protein-losing enteropathy, liver dysfunction, and
finally multiorgan failure and premature late death. Many of
these complications are related to surgical pathways, atrial
distention, and unfavorable fluid dynamics mainly in atrio-
pulmonary connections. Fontan conversion to a total cavo-
pulmonary connection with concomitant arrhythmia surgery
is an option for these patients with a failing Fontan circula-
tion and can improve clinical status and exercise tolerance
and reduce arrhythmia propensity.153
Some patients can be adequately palliated by systemic-
to-pulmonary artery shunts, a Glenn anastomosis, or both
as a long-term solution.154 Survival rates for such selected
patients with definitive non-Fontan palliations may compare
favorably with those from published Fontan series. Arrhyth-
mia is a major cause of morbidity for these patients and
relates to both ventricular dysfunction and death. Another
serious complication of a Fontan-type operation is protein
losing enteropathy.155,156 This condition may respond to con-
version of the Fontan operation to total cardiopulmonary
correction or could necessitate heart transplantation.156

Heart-Lung Transplantation for Congenital

Heart Disease
Transplantation constitutes an effective form of treatment
for patients with congenital heart disease who develop irre-
versible myocardial damage or advanced pulmonary vascular
disease. These patients can experience specific anatomic and
functional changes related to congenital heart disease or
secondary to complex or less complex surgical treatment.
This point must be addressed if transplantation is to be suc-
cessfully accomplished.
Abnormalities of situs, such as situs inversus or situs
ambiguus, can be treated through technical modifications of
the transplant procedure (Fig. 13.36).157 Similarly, abnormal
pulmonary or systemic venous return, malposition of the
great arteries, and aortic artery anomalies can be corrected
with the use of donor tissue.
In patients with marginally elevated pulmonary vascular
disease (three to five units), cardiac transplantation can lead
to severe and acute failure of the thin-walled normal donor
right ventricle. In patients with potentially reversible pulmo-
nary vascular disease, such as those with long-standing pul-
monary venous hypertension due to chronic heart failure,
tests of reversibility, using pulmonary vasodilators158 such as
prostacyclin or inhaled nitric oxide, can be of value in decid-
ing whether orthotopic heart transplantation should be con-
sidered. In these patients, a large heart or a heart from a FIGURE 13.36. Technique of heart implantation in recipients with
abnormalities of situs inversus (A) and situs ambiguous (B).
domino procedure159 for a patient who requires heart-lung
transplantation for a condition causing some degree of pul-
 su rgic a l t r e atm e n t
monary hypertension can be valuable. Alternatively, hetero-
topic heart transplantation can be considered if the recipient
heart has a relatively healthy pulmonary ventricle capable of
supporting the pulmonary circulation.160,161
Heart-lung transplantation is the procedure of choice for
patients in whom both the heart and lungs are badly and
irreversibly damaged or malformed. In patients with severe
pulmonary hypertension, heart-lung or double-lung trans-
plantation is the procedure of choice. Although single-lung
transplantation with repair of the intracardiac lesion has
been successfully used in some patients,162 this approach has
the disadvantage of potentially dangerous ventilation perfu-
sion imbalance during bouts of acute rejection or infection
of the transplanted lung as the entire cardiac output contin-
ues to perfuse the transplanted lung, which is badly venti-
lated due to reduced compliance during these episodes.
Summary
Successful surgical treatment of congenital heart disease in
adults depends on a thorough understanding of the specific
anatomic and physiologic changes in that age group. Although
many advances have been made, there is still room for
improvement through specialization and research.
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SEC TION III

Valvular Heart
Disease
 1 Valvular Heart Disease:
4 Anatomic Abnormalities
Hugh A. McAllister, Jr., L. Maximilian Buja,
and †Victor J. Ferrans
Floppy Valve (Myxomatous Degeneration) and
Connective Tissue Dyscrasias . . . . . . . . . . . . . . . . . .
Endocrine and Metabolic Valvular Diseases. . . . . . . . . .
Collagen Vascular Diseases . . . . . . . . . . . . . . . . . . . . . . .
Congenital Valvular Heart Disease . . . . . . . . . . . . . . . . .
Key Points
• Floppy mitral valve is due to myxomatous degeneration
and can occur as an isolated entity or as a component of
Marfan’s syndrome or other connective tissue dyscrasias.
• Endocrine and metabolic conditions producing valvular
dysfunction include carcinoid heart disease, cardiac amy-
loidosis, ochronosis, mucopolysaccharidoses, lipid storage
diseases, hyperlipidemias, and gout.
• Collagen vascular diseases that produce valvular heart
disease include rheumatic valvulitis, rheumatoid valvu-
litis, lupus erythematosus valvulitis, and other related
conditions. Postinflammatory valvular disease is mani-
fested by fibrosis and commissural fusion leading to
incompetence and stenosis.
• The most common congenital malformation of heart
valves is the bicuspid aortic valve; these valves are prone
to progressive fibrosis, calcification, and stenosis.
• Infective endocarditis can develop on previously diseased
or normal valves and produce valvular incompetence and
embolization of infected thrombi.
• Complications of prosthetic heart valves include throm-
bosis of mechanical valves and degeneration and calcifi-
cation of bioprostheses.
Floppy Valve (Myxomatous Degeneration)
and Connective Tissue Dyscrasias
Although myxomatous degeneration has been described in
tricuspid, aortic, and pulmonary valves, the mitral valve is
most commonly involved, and the posterior leaflet is affected
more often and more severely than is the anterior leaflet.
Grossly, the most outstanding feature is marked increase in
†
Posthumously, Dr. Ferrans remains an author of this chapter. Dr.
Ferrans died in October 2001.
Infective Endocarditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
369 Prosthetic Heart Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
370 Conduits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
372 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
375
surface area of the affected leaflets (Fig. 14.1), which are
voluminous, hooded, and white; however, they transillumi-
nate with ease, especially before fixation. On sectioning, the
myxomatous consistency of the center of the leaflet is often
apparent on gross examination. Small foci of ulceration with
occasional superimposed thrombi may be noted on the atrial
surface of the affected mitral leaflet.1 The chordae tendineae
often are elongated and thin; however, some localized thick-
ening may be present at their insertions into the valve leaf-
lets (Fig. 14.2). Rupture of the chordae tendineae is common
in myxomatous degeneration of the mitral valve: less fre-
quently, myxomatous degeneration may result in aneurys-
mal dilatation and rupture of a mitral leaflet. Commissural
fusion is not a feature of the floppy valve. Because these
valves are predisposed to infective endocarditis, gross evi-
dence of this complication must be sought by the surgical
pathologist, so that appropriate sections can be obtained for
culture before fixation of the valve.
Microscopically, the spongiosa contains stellate cells
embedded in a matrix rich in proteoglycans. Characteristi-
cally, there is focal to extensive replacement of the normal
dense, homogeneous collagen of the fibrosa by this myxoma-
tous tissue. This histologic pattern is in contrast to that seen
in most valvular heart diseases, in which the spongiosa of the
leaflets is partially or completely replaced by dense fibrous
tissue. The collagen in the chordae tendineae may show
changes similar to those in the fibrosa. The atrialis of the
leaflet generally contains a variable degree of fibroelastic pro-
liferation, and superficial ulceration with microscopic fibrin
deposition is not uncommon. Unless there is superimposed
infective endocarditis, there is no evidence of inflammation
or vascularization. Ultrastructurally, there is focal loss of the
normal orderly cross-banding of collagen fibers. Microscopi-
cally, small areas of myxomatous degeneration may be found
near the free edges of normal or diseased valves and should not
be confused with the diffuse findings in floppy valves.
369
37 0 chapter
FIGURE 14.1. Floppy mitral valve. The most outstanding feature is
a marked increase in the surface area of the leaflets. They are volu-
minous, hooded, and white; however, they transilluminate with
ease. Commissural fusion is not a feature of the floppy valve.
Myxomatous degeneration of the cardiac valves, with
resulting insufficiency, often occurs in connective tissue
dyscrasias such as Marfan’s syndrome, osteogenesis imper-
fecta, cutis laxa, and relapsing polychondritis. This group of
diseases may also be associated with cystic medial degenera-
tion of the aorta. Adults with Marfan’s syndrome most com-
monly have myxomatous degeneration of the aortic valve; in
children, however, the mitral valve is more commonly
involved.2 The affected mitral and aortic leaflets contain an
accumulation of myxoid material mainly in the spongiosa.
Recent studies have shown the importance of matrix metal-
loproteinases in the pathogenesis of these lesions in the
Marfan syndrome.3 The Ehlers-Danlos syndrome is a hetero-
geneous group of several genetically distinct disorders of
connective tissue synthesis, which differ in major clinical
features, inheritance patterns, and biochemical defects. Car-
diovascular lesions have been described in types I to IV;
however, myxomatous degeneration and prolapse of the
FIGURE 14.2. Floppy mitral valve. The chordae tendineae are often
elongated and thin; however, some localized thickening may be
present at their insertion into the valve leaflets.
14
mitral valve appear to be more common in type III, the
benign hypermobile form.2 The most common valvular
lesion in osteogenesis imperfecta is aortic regurgitation;
mitral regurgitation and combined aortic and mitral regurgi-
tation are less common. The aortic regurgitation results from
dilatation of the aortic root and deformity of the valvular
leaflets, which become abnormally translucent, weak, and
elongated. Aneurysms of the sinuses of Valsalva also occur.
The mitral annulus is dilated, the mitral leaflets are attenu-
ated and redundant and tend to prolapse, and the chordae
tendineae may rupture.2 In cutis laxa, the most common
cardiac lesions involve the aorta, pulmonary artery, and pul-
monary veins; less commonly, there may be myxomatous
degeneration of the aortic or mitral valves.2 The aortic and
mitral valves are the cardiac valves most commonly involved
in relapsing polychondritis. Lesions may be microscopically
identical to those in the other connective tissue
dyscrasias.1
Endocrine and Metabolic Valvular Diseases
In carcinoid heart disease, there is either focal or diffuse
plaque-like thickening of valvular and mural endocardium
and, occasionally, of the intima of the great veins, coronary
sinus, pulmonary trunk, and main pulmonary arteries. The
fibrous tissue is atypical and limited in the majority of
instances to the right side of the heart. When the pulmonary
valve is involved, deposition is almost exclusively on the
arterial aspect of the valve cusps (Fig. 14.3). When the tricus-
pid valve is involved, however, the fibrous tissue is located
predominantly on the ventricular aspect, often causing the
leaflets to adhere to the adjacent ventricular wall.4 Similar
lesions may be observed in the mitral and aortic valves in
patients with a patent foramen ovale or a functioning bron-
chial carcinoid tumor.5 In some patients with predominant
right-side carcinoid heart disease, the mitral and aortic valves
also may be involved to a lesser degree. Microscopically,
these lesions contain fibroblasts, myofibroblasts, and smooth
muscle cells embedded in a distinctive stroma, which is rich
in collagen and proteoglycans but lacking in elastic fibers.
Blood vessels, often thick-walled, may be immediately adja-
cent to the valve leaflets. Lymphocytes and plasma cells are
frequently located adjacent to these blood vessels.
Histologically, similar valvular and endocardial lesions
have been described in patients taking methysergide6 and
ergot7; however, the mitral and aortic valves are most com-
monly involved in these cases. Similar valvular lesions have
been described in patients taking fenfluramine and phenter-
mine for appetite suppression.8
The heart valves are involved in 50% of patients with
cardiac amyloidosis. Valvular involvement is usually
minimal, but discrete nodules measuring from 1 to 4 mm in
diameter are occasionally present on the valves either in the
cusps or in the annulus.2 Rarely, valvular involvement is
diffuse, resulting in thick, rigid cusps and stenotic or regur-
gitant orifices (Fig. 14.4). The four cardiac valves are affected
with almost equal frequency.
All heart valves and valvular annuli, especially the mitral
and aortic valves, are sites of heavy pigment deposition in
patients with ochronosis.2 Although the pigment deposition
 va lv u l a r h e a r t d i s e a s e : a n a t o m i c a b n o r m a l i t i e s 371

FIGURE 14.4. Amyloid valve disease. Valvular involvement is

usually minimal; however, diffuse involvement, as illustrated in
this heart, can occur, resulting in thick, rigid cusps and stenotic or
regurgitant orifices.

extremely soluble and difficult to preserve. In addition, small

FIGURE 14.3. Carcinoid heart disease, pulmonic valve. Heavy
deposition of collagen, lacking in elastic fibers, occurs almost exclu-
sively on the arterial aspect of the valve cusps, resulting in pul-
monic stenosis (Movat pentachrome, ×25).
granular cells are present, which contain membrane-limited
electron-dense material associated with fragments of colla-
gen fibrils. The valve thickening is due to the presence of the
cells and to an increase in the amount of fibrous connective
tissue.
In Fabry’s disease, the glycosphingolipid is deposited
within the cardiac valves, occasionally resulting in valvular
dysfunction.2 The mitral and aortic valves are the two valves
that most commonly present clinical problems. There may

is most prominent at the bases of the mitral and aortic valves

and annulus fibrosus, the edges of the cusps may be rough-
ened and fused for 1 to 2 mm at their bases; the cusps may
be focally calcified. The ochronotic pigment appears blue-
black on gross examination and yellow-tan in histologic
sections. Infective endocarditis may occasionally be super-
imposed, especially when the valves are heavily calcified.
The cardiac valves may be involved in any of the muco-
polysaccharidoses, most frequently in Hurler’s syndrome
(mucopolysaccharidosis I).2 The valves are considerably
thickened, particularly the mitral valve; right-sided cardiac
valves are less severely affected than those in the left side of
the heart (Fig. 14.5). The valvular thickening is most pro-
nounced at the free margins, which have an irregular, nodular
appearance. The commissures are not fused. The chordae
tendineae of the atrioventricular valves are moderately short-
ened and thickened. Calcific deposits occur in the angle just
beneath the basal attachment of the posterior mitral leaflet
(mitral annular calcification), in the mitral leaflets, and in
the aortic aspect of the aortic valve cusps. The valves contain
FIGURE 14.5. Hurler’s syndrome, mitral valve. The valvular thick-
large, oval or rounded connective tissue cells (Hurler cells) ening is most pronounced at the free margins, which have an irregu-
filled with numerous clear vacuoles, which are the sites of lar, nodular appearance. The commissures are not fused. The
deposition of acid mucopolysaccharide.2 This material is chordae tendineae are moderately shortened and thickened.
37 2 chapter
be thickening of the valves with interchordal hooding, or
there may be attenuation of the chordae with thickening and
ballooning of the mitral valve. Commissural fusion is not a
feature of Fabry’s disease.
Type II hyperlipoproteinemia (familial hypercholesterol-
emia) exists in homozygous and heterozygous forms, which
differ in the severity and age of onset of clinical symptoms.
Aortic valvular disease is frequent in homozygous patients
but does not usually occur in heterozygous patients. The
aortic valve may be markedly stenosed by fibrous tissue,
deposits of foam cells, and cholesterol crystals in the cusps.
Thickening of the mitral valve, which results in both steno-
sis and regurgitation, and thickening of the pulmonary valve
and endocardium by foam cells also occur.2
Patients with gout most commonly develop dysfunction
due to hypertension secondary to renal damage; however,
tophi occasionally may be present in the heart, most com-
monly in the mitral valve and the endocardium of the left
ventricle and, less frequently, in the mitral annulus and
aortic and tricuspid valve leaflets.2,9 To establish the diagno-
sis histologically, appreciable amounts of uric acid must be
identified in the tophi to distinguish them from small
amounts of uric acid that my be deposited on previously
existing fibrocalcific lesions. Urate deposits are histochemi-
cally identifiable by fixation in absolute ethanol, followed by
staining by the De Galantha method.
Collagen Vascular Diseases
Rheumatic Valvulitis
Acute rheumatic fever produces a pancarditis; however, val-
vular involvement is responsible for the most important
long-term consequences. In the acute phase of rheumatic
valvulitis, the most conspicuous lesions are minute, translu-
cent nodules (verrucae) along the lines of closure of the valve
cusps (Fig. 14.6). These are most frequently observed in the
mitral and aortic valves, less often in the tricuspid, and rarely
in the pulmonary valve. They vary in diameter from less
than 1 mm to 3 mm and are located on the atrial surface of
FIGURE 14.6. Acute rheumatic valvulitis, mitral valve. Fibrinoid
necrosis is represented by minute, translucent nodules (verrucae), 1
to 3 mm in diameter, along the lines of closure.
14
the atrioventricular valves and on the ventricular surface of
the semilunar valves.4 Occasionally, a few verrucae may be
distributed elsewhere over the cusps. They are also charac-
teristically present on the chordae tendineae, especially
those of the mitral valve, and not infrequently, they extend
over the posterior leaflet of the mitral valve onto the endo-
cardium of the left atrium. The verrucae tend to conglomer-
ate on the corpora arantii of the aortic valve and extend in a
row along the semilunar cusps. Diffuse thickening of the
valves, except the pulmonary, is a less conspicuous but fre-
quent gross alteration.
Microscopically, the verrucae may have the appearance
of either thrombi, formed by the deposition of platelets and
fibrin on the surface of the valve, or extruded collagen that
has undergone fibrinoid degeneration. The region immedi-
ately adjacent to the vegetation shows marked proliferation
of fibroblasts, as well as edema and numerous lymphocytes.4
The inflammatory process is observed most frequently in the
auricularis layer of the atrioventricular valves and the ven-
tricularis layer of the semilunar valves. A nonspecific inflam-
matory process, which may involve the entire valve and ring,
consists of edema, increased numbers of capillaries, and a
variety of inflammatory cells (mainly lymphocytes; occa-
sionally polymorphonuclear leukocytes predominate).
Plasma cells, fibroblasts, and other mononuclear cells are
often present in variable numbers. Usually the valve also
contains Anitschkow and Aschoff cells, which may be
arranged in nodules or in rows and often surround foci of
eosinophilic fragmented collagen, fibrinoid, or both. Aschoff
cells may be multinucleated.10 These lesions are typically
accompanied by characteristic Aschoff nodules in the
myocardium.4,10,11
Gross alterations of the cardiac valves become more pro-
nounced as a result of recurrent rheumatic valvulitis. Thick-
ening, irregularity of the surfaces, and gross vascularization
are usually present. This thickening is usually most pro-
nounced in the distal third of the valve leaflets.4 The chordae
tendineae become thicker and shorter, with especially prom-
inent thickening at their insertions into the valve leaflets.
Verrucae in various stages of activity and healing may be
observed. In addition to being thickened, the aortic cusps
may be considerably shortened, with their free margins rolled
and inverted toward the sinus pocket. Fibrous adhesions
are commonly present at the commissures, and verrucae in
various stages of activity may extend across the commis-
sures of aortic cusps. In recurrent valvulitis, there is a higher
incidence of verrucae on the valves of the right side of the
heart, and microscopic observation reveals considerable
fibrosis, an apparent increase in elastic tissue, and inflam-
matory changes in various stages of activity.4,11 The fibrosis
and inflammation involve the rings as well as the leaflets.
This histologic pattern differs from that of acute valvulitis,
in which the thickening of the valves is the result only of
edema and inflammation. Also in contrast to the appearance
of acute valvulitis are numerous arteries with thick muscu-
lar walls in the ring and proximal portion of the valve.
In chronic rheumatic valvulitis, the alterations described
in recurrent valvulitis are most advanced. Usually, the
diffuse thickening and fibrosis of the valves have resulted in
loss of elasticity and in narrowing of the orifice (Fig. 14.7).
Thickening, fusion, and shortening of the chordae tendineae
 va lv u l a r h e a r t d i s e a s e : a n a t o m i c a b n o r m a l i t i e s
FIGURE 14.7. Chronic rheumatic aortic stenosis. Diffuse thicken-
ing and fibrosis of the valves with commissural fusion resulting in
marked aortic stenosis. Also note the extensive poststenotic dilata-
tion of the ascending aorta.
of the mitral valve are usually pronounced (Fig. 14.8). In
addition, focal deposits of calcium salts may be present.
These deposits may be extensive and may project to the atrial
and ventricular surfaces, causing further distortion. Ossifi-
cation, complete with hematopoiesis, may occur, causing
further distortion.11 Verrucae are less frequent in chronic
valvulitis than in recurrent valvulitis and are broad and flat.
Active inflammation is less pronounced in chronic than in
recurrent valvulitis and usually consists of scattered foci of
perivascular cuffing with lymphocytes. The grossly apparent
thickening is due to an increase in fibrous and elastic tissue
throughout the entire leaflet including the rings and the tips
of the valves. The fibrous connective tissue is usually homo-
geneous and hyaline. These valves are vascularized by capil-
laries and thick-walled vessels, which are most numerous in
the superficial layers. The verrucae no longer consist of mate-
rial showing fibrinoid necrosis, but are organized and contain
FIGURE 14.8. Chronic rheumatic mitral stenosis. Note the thick-
ening, fusion, and shortening of the chordae tendineae, as well as
diffuse thickening and fibrosis of the valves, with commissural
fusion. The left atrium is enlarged and contains a mural
thrombus.
37 3
fibroblasts and collagen fibers. As chronicity progresses, the
number of fibroblasts decreases, and the verrucae become
dense, hyalinized scars.
Rheumatoid Valvulitis
Rheumatoid granulomas may occur in any of the cardiac
valves but are most common in the mitral and aortic valves.12
Involvement may be focal or diffuse and is usually most
prominent in the midportion or base of the valve (Fig. 14.9).
The chordae tendineae are usually uninvolved, but occasion-
ally, they may be fibrotic and shortened. Commissural fusion
is rare. Rheumatoid nodules are most commonly located
within the valve leaflets and are enclosed by fibrous tissue;
rarely, a rheumatoid nodule may erode the surface of the
valve, so that the necrotic center of the nodule communi-
cates with a cardiac cavity (Fig. 14.10). In these unusual
occurrences, there may be superimposed thrombus or infec-
tive endocarditis. Verrucae of fibrinoid necrosis, common in
rheumatic valvulitis and systemic lupus erythematosus, are
not a feature of pure rheumatoid valvulitis.
Lupus Erythematosus Valvulitis
Lupus erythematosus valvulitis (atypical verrucous endocar-
ditis of Libman and Sacks) is recognized as a specific valvular
abnormality occurring in systemic lupus erythematosus.
Any valve may be involved, but the mitral and tricuspid
valves are most often affected (Fig. 14.11). The verrucae may
be located on either side of a valve cusp but most frequently
are present on the ventricular surface of the posterior mitral
leaflet or in the valve ring; involvement of the anterior mitral
leaflet is infrequent. The lesions have no special tendency to
occur along the free edge of the valves and may be scattered
on the chordae tendineae and atrial or ventricular mural
endocardium. The lesions are small, usually ranging in size
from 1 to 4 mm in diameter, but rarely may reach a diameter
of 8 to 10 mm. They are sterile, dry, granular pink vegetations
that may be single or multiple in conglomerates.4 Histologi-
cally, the verrucae consist of a finely granular, eosinophilic,
FIGURE 14.9. Rheumatoid valve disease, mitral valve. Involvement
may be focal or diffuse, as in this case, and is usually most promi-
nent in the midportion of the base of the valve. The chordae tendin-
eae are usually uninvolved, and commissural fusion is rare.
374 chapter
FIGURE 14.10. Rheumatoid valve disease, mitral valve. Rheuma-
toid granulomas with extensive contiguous fibrosis involve the base
and midportion of a mitral valve. Another rheumatoid granuloma is
present in the adjacent subvalvular myocardium (Hematoxylin and
eosin, ×75).
fibrinoid material, which may contain hematoxylin bodies.
In a general sense, these hematoxylin bodies are the tissue
equivalent of the lupus erythematosus cell of the blood and
bone marrow.4 The verrucous endocardial lesions result from
degenerative and inflammatory processes of the endocar-
dium and deeper layers of the valves. An intense valvulitis
is present, which is characterized by fibrinoid necrosis of the
valve substance and is often contiguous with the vegetations.
Exudative and proliferative cellular reactions are present in
the deeper layers of the valve. Healing of these lesions may
produce foci of granulation tissue, which develop into focal
fibrous thickening in the valves or in the mural endocar-
dium. Rarely, bacterial endocarditis may be superimposed on
the Libman-Sacks lesions.12
Other Collagen Vascular and Related Diseases
Valvular lesions in scleroderma are distinctly rare; the most
common lesion is nonbacterial thrombotic endocarditis. In
patients with thrombotic thrombocytopenic purpura, non-
bacterial thrombotic endocarditis frequently is present. In
14
both diseases, the cardiac valves most commonly involved
are the mitral and the aortic.12 Valvulitis is most unusual in
Wegener’s granulomatosis. The mitral valve is most com-
monly involved by the inflammatory process, which may
result in subsequent fibrosis with commissural fusion resem-
bling rheumatic mitral stenosis.13 Primary valvulitis is not a
feature of dermatomyositis. Diseases that may result in val-
vulitis but are manifested most commonly by aortitis include
syphilis, ankylosing spondylitis, psoriatic arthritis, Reiter’s
syndrome, and granulomatous aortitis.
Lesions Resembling Collagen Vascular
Disease Valvulitis
Although not collagen vascular diseases, three entities that
may result in fibrous thickening of the cardiac valves and
thickening and fusion of chordae tendineae are Whipple’s
disease, endomyocardial fibrosis with eosinophilia, and radi-
ation-induced disease. In Whipple’s disease, the valve most
commonly involved is the mitral, and then the tricuspid and
the aortic valves.14 The gross deformity closely resembles
that seen in chronic rheumatic heart disease, with diffuse
thickening and fibrosis of the valve leaflets and chordae ten-
dineae and rolling of the free edges of the leaflets (Fig. 14.12).
Microscopically, the valve substance contains large macro-
phages filled with granules that are positive for the periodic
acid-Schiff reaction; these granules are identical to those
found in the epithelial cells of the small intestine in patients
with this disease. Proliferating fibrous tissue and chronic
inflammatory cells are commonly associated with the peri-
odic acid-Schiff–positive macrophages. Scattered rod-shaped
bodies, measuring 1.5 to 2.0 μm in length and 0.2 to 0.4 μm
in diameter, are present intracellularly and extracellularly.
These bodies, as well as membrane-bound masses of fibrillar
material within the macrophages, are identical to those
described in jejunal biopsies of patients with Whipple’s
disease14 and are thought to represent bacteria (Tropheryma
FIGURE 14.11. Lupus erythematosus valvulitis (atypical verrucous
endocarditis of Libman and Sacks), mitral valve. The lesions repre-
sent fibrinoid necrosis as sterile, dry, granular vegetations that may
be single or multiple in conglomerates. They have no special ten-
dency to occur along the free edge of the valves and may be scattered
on the chordae tendineae and atrial or ventricular mural
endocardium.
 va lv u l a r h e a r t d i s e a s e : a n a t o m i c a b n o r m a l i t i e s
FIGURE 14.12. Whipple’s disease, mitral valve. The gross defor-
mity closely resembles that seen in chronic rheumatic valve disease,
with diffuse thickening and fibrosis of the valve leaflets and chordae
tendineae and rolling of the free edges of the leaflets.
whippelii), which are known to be associated with this
disease.15 In endomyocardial fibrosis with eosinophilia, the
valves most commonly involved are the mitral and the tri-
cuspid, with a lesser incidence of aortic valve involvement.
There is fibrous thickening of endocardium, with superim-
posed fibrin thrombus beneath either the posterior mitral
leaflet or the posterior or septal tricuspid leaflet. These leaf-
lets become adherent to the underlying mural endocardium,
which results in regurgitation.16 The aortic valve cusps are
occasionally thickened by vascularized fibrous tissue, which
is superimposed on the ventricular aspects of the cusps. The
commissures of the aortic valve may become fused by fibrous
tissue with superimposed fibrin thrombus. Eosinophilic leu-
kocytes in varying numbers are usually present at the periph-
ery of the fibrous lesions.
Rarely, patients receiving mediastinal irradiation may
develop lesions of the cardiac valves.17,18 The valves most
commonly involved are the tricuspid and the mitral, fol-
lowed by the aortic and the pulmonary. The fibrous valvular
thickenings are focal, and the anterior tricuspid leaflet and
the anterior mitral leaflet are usually more markedly involved
than are the posterior leaflets. The chordae tendineae also
may be focally thickened by fibrous tissue.
Congenital Valvular Heart Disease
The most common congenital malformation of heart valves
is the bicuspid aortic valve. Unless it is the site of associated
dysplasia, this valve is not inherently stenotic, although it
frequently becomes stenotic in later life. Stenosis is second-
ary to fibrosis and calcification of the cusps and usually not
to fusion of the commissures, as is seen in rheumatic aortic
stenosis.19 Classically, the calcific deposits form nodules at
the base of the cusps in the sinuses of Valsalva and extend
to, but frequently do not involve, the free edge of the valve
cusps (Fig. 14.13). In addition, there are foci of calcification
and extensive fibrosis within the substance of the cusps.
375
Commissural fusion is usually minimal, involves only one
commissure, and is only rarely extensive.17,20 Another
common reason for surgical excision of a bicuspid aortic
valve is infective endocarditis. The moderately high inci-
dence of infective endocarditis in patients with bicuspid
aortic valves is well known. Therefore, each of these valves
must be examined closely by the surgical pathologist for
superimposed infective endocarditis, and if suspicious lesions
are noted, sections must be taken for microbiologic culture
before fixation.
The quadricuspid aortic valve is far less common than
the bicuspid valve. The most frequent indication for surgical
excision of these valves is aortic insufficiency. Most com-
monly, one of the cusps is rudimentary; however, the gross
and microscopic appearance of the valves is usually other-
wise normal.21 Quadricuspid pulmonary valves rarely cause
cardiac dysfunction unless there is associated dysplasia of
the valve or a coexisting congenital cardiac defect. As in
quadricuspid aortic valves, the fourth cusp is usually small
and rudimentary, with the remaining cusps appearing mor-
phologically normal.21
Valve dysplasia may affect any of the cardiac valves, most
frequently the aortic valve; however, 25% of patients have
multiple valve involvement.22 The dysplastic changes may be
severe and extensive, so that the entire valve is distorted, or
mild and focal, so that valve function is not impaired. A
dysplastic stenotic pulmonary valve is frequently present in
patients with Noonan’s syndrome. The dysplastic semilunar
valve may be unicuspid, bicuspid, or tricuspid; failure of
development of the commissures also may occur, resulting
in a dome-shaped valve. Stenosis is secondary to the marked
thickening of the individual valve cusps. The spongiosa of
the dysplastic valve is quite cellular and composed primarily
of small spindle cells resembling fibroblasts, set in an acid
mucopolysaccharide matrix and haphazardly arranged
bundles of collagen.1 This loose connective tissue encroaches
on and often replaces the ventricularis and fibrosa of the
valve cusps. The majority of involved cusps consist entirely
of this loose connective tissue; however, remnants of the
ventricularis and fibrosa, interrupted by accumulations of
FIGURE 14.13. Bicuspid aortic valve. Stenosis is secondary to fibro-
sis and calcification of the midportion and hinge of the cusps and
usually not to fusion of the commissures, as is seen in rheumatic
aortic stenosis.
376 chapter
abnormal loose connective tissue, are often found at the base
of the cusps. Inflammation and calcification are not features
of the dysplastic valve. The abnormal valve tissue of the
dysplastic or incompletely differentiated valve resembles the
embryonic connective tissue of the cardiac valves in 8- to
12-week-old fetuses.22
Infective Endocarditis
The relative frequency of involvement of the cardiac valves
is similar for infective endocarditis and rheumatic heart
disease: mitral, aortic, aortic and mitral, combined tricuspid,
and pulmonary valves, in decreasing order of frequency. The
tricuspid and pulmonary valves are not commonly involved,
with the notable exception of intravenous drug abusers. In
many cases of combined aortic and mitral involvement, the
anterior leaflet of the mitral valve appears to be infected by
regurgitation-induced deposition of organisms from the
aortic vegetation. Lesions usually originate on the atrial
surface of the atrioventricular valves and the ventricular
surface of the semilunar valves and vary from tiny granular
or flat vegetations to large polypoid masses. They may be
single or multiple and may be firm or soft, but are usually
friable. Grossly, they may appear yellow-white to red or
brown.23 The affected valve exhibits destruction and loss of
tissue. Valvular ulceration, perforation, or formation of aneu-
rysm of the valve may occur. Rupture of chordae tendineae
is common. Infection may spread into the contiguous struc-
tures, resulting in annular or myocardial abscesses or aneu-
rysms of the sinuses of Valsalva. Microscopically, the
vegetations are composed of masses of necrotic tissue, fibrin,
platelets, erythrocytes, leukocytes, and organisms. Classi-
cally, there is a superficial zone of fibrin, organisms, and
leukocytes; an intermediate zone of amorphous necrotic
material; and a basal zone of granulation tissue extending
from the substance of the valve. Small foci of calcification
are common.
Bicuspid aortic valves or valves with acquired deformities
are most frequently involved in infective endocarditis;
however, the disease may develop in previously normal
valves, including the pulmonary and tricuspid valves, espe-
cially in patients over 60 years of age. In previously normal
valves, the lesions tend to be larger, and tissue destruction
is more extensive. Staphylococci and gram-negative organ-
isms are more likely to be the etiologic agents than in the
case of infection of deformed valves, in which Streptococcus
viridans is the most common organism encountered. Infected
but previously normal valves often show marked necrosis
and inflammation, which are less common findings in
infected, previously scarred valves.
Although streptococci and staphylococci are the most
common microorganisms responsible for infection, a wide
variety of bacteria and fungi have been recovered from
patients with infective endocarditis. Candida species in par-
ticular are recovered from addicts and patients with pros-
thetic heart valves. Gram-negative bacilli account for only a
small percentage of infections, despite the relative frequency
of gram-negative bacteremia, and are more likely to be
encountered in addicts or in patients with prosthetic heart
14
valves. Rarely, infections are due to other organisms, such as
meningococci, pneumococci, gonococci, Brucella, Hae-
mophilus, Corynebacterium, mycobacteria, rickettsiae, and
Aspergillus and other fungal species.24 Fungal vegetations, in
particular, tend to be large and friable, with a tendency to
produce embolization. Because fungal endocarditis is fre-
quently indolent clinically, it is important for the surgical
pathologist to obtain appropriate special stains on any throm-
boembolus removed from a systemic artery. Any valve
removed surgically that has gross lesions suggestive of infec-
tive endocarditis should have sections taken for microbio-
logic culture before fixation. Merely taking a swab of the
surface of the valve for culture is not adequate. Indeed, even
if the valve appears grossly normal, patients in whom the
clinical history or physical findings suggest the possibility
of infective endocarditis should have sections of the valve
taken for culture.
Healing of vegetations may occur as a result of therapy
or spontaneously, without antimicrobial therapy.23 These
healed vegetations often result in multiple, calcified, polyp-
oid lesions on the surface of the valve. Contracture of scar
tissue may further reduce the surface area of the valve. The
healed vegetations in the heart valves or chordae tendineae
are similar in gross appearance to those with active infec-
tion.23 Occasionally, well-circumscribed defects with smooth
edges remain in the heart valve after the healing of perfora-
tions that resulted from infective endocarditis. Usually, the
etiology of these morphologic abnormalities cannot be iden-
tified, especially if there is no known antecedent infection.
Histologic study rarely helps to resolve these issues because
the alterations resulting from the healing of the inflam-
matory process tend to be similar in their end-state
appearance.23
Prosthetic Heart Valves
Types
Prosthetic heart valves in current use can be classified into
two major groups: rigid-framed (mechanical) valves and
tissue valves (bioprosthesis). Rigid-framed valves are of three
types: (1) valves with a centrally placed occluder (ball or
disk), which moves up and down in a metal cage and allows
only lateral blood flow; (2) valves with a tilting disk, which
permits semicentral flow; and (3) valves with two hinged,
semicircular plates (St. Jude type), which allow central flow.
Tissue valves include (1) fresh and variously treated homo-
grafts, (2) human dura mater or fascia lata valves, (3) bovine
pericardial valves, and (4) porcine aortic valves. The metal
and plastic mounting frames and the preimplantation chemi-
cal treatments vary from one type of tissue valve to another.
Tissue valves without supporting frames (unstented porcine
and human homograft valves) also are being used clinically.
Knowledge of the frames and treatments is necessary to
interpret morphologic findings in tissue valves. Radiographs
may be useful in the identification and evaluation of
explanted valves.25–27 Essential for the evaluation of any pros-
thetic valve is knowledge of the length of time the valve was
in place and the specific reason for its removal.
 va lv u l a r h e a r t d i s e a s e : a n a t o m i c a b n o r m a l i t i e s
Complications
Certain complications are common to all types of prosthetic
heart valves. Among these are thrombosis, embolization,
infection, dehiscence of the valvular ring, paravalvular leak,
disproportion, turbulent flow, and hemolysis. Complications
limited to rigid-framed prostheses28,29 are related to wear and
fracture of mechanical components, resulting in interference
with proper motion of the occluder (and sometimes also in
embolic phenomena), whereas complications peculiar to
tissue valves28,29 are related to calcification or breakdown of
the prosthetic tissue leaflets. Degenerative changes also
develop in homograft human tissue valves.30,31
Complications Common to All Types of
Prosthetic Valves
Thrombus formation in mechanical prostheses is most
common at the base of the struts forming the cage. From this
area, thrombi can spread and interfere with motion of the
occluder, with seating of the occluder on the orifice, or with
blood flow. These thrombi can undergo organization, become
infected, or be sources of emboli. Ball valves with cloth-
covered cage struts are less likely to form thrombi than are
those with uncovered struts. Tissue valves are least likely to
form large thrombi, although aggregates of platelets do
develop on their surfaces. Thrombi can splint the cusps of
bioprostheses and render them stenotic.32,33 Thrombi removed
from prosthetic heart valves must be examined (by histology
and by culture) for evidence of infection.11 Dehiscence of a
valvular ring must be regarded as due to infection until
proved otherwise. Paravalvular leaks most frequently result
from a prosthesis having been sutured to a ring that is heavily
calcified or weakened (as occurs in patients with Marfan’s
syndrome or other connective tissue disorder). Anemia and
renal hemosiderosis are typical findings in hemolysis pro-
duced by prosthetic heart valves.
Disproportion is caused by prosthetic heart valves that
are too large for the chambers in which they are placed. This
can result in interference with movement of the poppet, as
in the case of large ball valves placed in a small ascending
aorta (particularly in patients with combined mitral and
aortic valve disease in whom the aortic root is usually not
dilated) or in a small left ventricle (as in patients with com-
bined mitral and aortic stenosis in whom the left ventricle
is hypertrophied but not dilated). If a porcine bioprosthesis
is improperly placed in the mitral orifice, one of its struts
may obstruct the left ventricular outflow tract. In the case
of the double valve replacement, the prosthetic mitral valve
may be inadvertently placed in such a way as to interfere
with proper seating of the poppet of the prosthetic aortic
valve. Disproportion also may result from normal growth of
the heart of a child in whom a small prosthetic valve was
implanted at an early age.
Complications Limited to Rigid-Framed
(Mechanical) Prosthetic Valves
Turbulent blood flow produced by caged-ball prostheses may
lead to diffuse endocardial fibroelastotic thickening and to
intimal proliferation in the ascending aorta, sometimes with
37 7
extension of the thickening into the coronary arterial ostia.
Degeneration (variance) of the silicone rubber poppet was
common in the caged-ball prostheses implanted before 1967.
This complication, which resulted from surface abrasion and
lipid infiltration, has not been reported in the metallic hollow
poppet. Wear of a caged disk, causing “grooving” and disk
cocking, has been described in most caged-disk prostheses.
Disk cocking remains a potential problem with all caged-
disk valves, and it may be totally unrecognized as a cause of
fatalities. Wear of the cloth covering on the struts and the
orifice occurred in some of the older models of completely
cloth-covered caged-ball prostheses, but strut cloth wear has
not been reported in the newer Starr-Edwards model with
metal tracts. Dislodgment of caged disks and poppets has
been reported in association with wear of these components
or with fracture of struts.
Complications Limited to Bioprosthetic
(Tissue) Valves
The various types of bioprosthetic heart valves developed
since the 1970s have the following characteristics in common:
collagen is their major structural component; they are
mounted (except for some of the homografts) on metal and
plastic stents; the incidence of clinical episodes of thrombo-
embolism is lower with these valves than with rigid-framed
valves; and they have problems of long-term durability
because they can become stenotic as a result of calcification
or regurgitant due to alterations in collagen.34
Porcine Aortic Valves
Porcine aortic valves treated with a low (<1%) concentration
of glutaraldehyde (to crosslink tissue protein, to sterilize the
tissue, and to eliminate problems of antigenicity) and
mounted on flexible stents have become a widely used type
of valvular bioprosthesis. During the first 5 years after
implantation, these values usually have excellent function,
although they can de velop extensive anatomic changes.
After the first 5 years, appreciable incidences of calcification
and cuspal damage become evident. Calcific deposits develop
more frequently and earlier in children and young adults
than in older individuals and also are more frequent in
patients with chronic renal disease.22,32 Cuspal perforations
have no relation to patient age.
A bioprosthetic heart valve removed because of dysfunc-
tion should be first examined for evidence of infection, per-
foration, or calcification, and cultures should be taken as
indicated by clinical or anatomic findings; then it should be
radiographed and photographed before the cusps are detached
from the frame for histologic sectioning. These valves are
fragile and should be handled only by the mounting frame to
avoid producing artifactual damage to the cusps. Connective
tissue stains and stains for calcium are useful in evaluating
these valves. Transmission electron microscopy provides the
best method for studying the collagen, and scanning electron
microscopy is the method of choice for examining the
surfaces.
Histologically, porcine aortic valves are composed of the
following three layers, which also are recognizable in the
37 8 chapter
bioprosthesis even after having been in place for long periods
of time: (1) the ventricularis, which faces the ventricular
cavity when the valve is in its anatomic position and which
contains collagen and abundant elastic fibers; (2) the spon-
giosa, which is the proteoglycan-rich middle layer, and (3)
the fibrosa, which contains densely packed collagen but only
small, scanty elastic fibers and which faces the aortic wall.
Proteoglycans are lost from the spongiosa during commer-
cial processing and soon after implantation of the biopros-
thesis, leaving empty spaces that gradually are filled with
deposits of plasma proteins. The surfaces of porcine valvular
bioprostheses usually do not become endothelialized,
although they may be covered by macrophages, multinucle-
ated giant cells, platelet aggregates, and small fibrin deposits.
Polymorphonuclear leukocytes are very scanty or absent
unless infection is present. Macrophages show little ten-
dency to invade the bioprosthetic tissue, and there is no
evidence that immunologic rejection plays a role in its
deterioration.
Calcific deposits usually develop in association with col-
lagen in foci of loss of proteoglycans and with surface
thrombi, especially in the region near the commissures; they
form yellow, plaque-like or raised lesions.35 Calcific deposits
also develop in the aortic wall just adjacent to the cusps and
in cardiac muscle cells in a muscular shelf extending from
the ventricular septum into the base of the right coronary
cusp of the porcine aortic valve. This cusp is larger than the
others, and its base is less translucent. Calcific deposits can
also be associated with perforations, perhaps because colla-
gen adjacent to those deposits undergoes severe mechanical
stresses.35 The collagen in bioprostheses undergoes a time-
dependent process of degeneration, which may be related to
material fatigue and many result in perforation of the cusps.
Perforations in porcine valves occur most frequently near the
basal attachment of the cusps. In pericardial valves, particu-
larly those implanted in the mitral position, cuspal tears are
likely to involve the free edge near the attachment to the
post. It has been suggested that such tears begin at the attach-
ment suture. Infection of porcine valvular bioprostheses
differs from that of rigid-framed valves; it is likely to involve
the cusps (rather than the sewing ring), is less likely to result
in formation of a ring abscess, and usually extends into the
collagen in the cusps.34 The incidence of infection in the two
types of valves appears to be similar.
Other Bioprosthetic Valves
Fresh, antibiotic-sterilized, freeze-dried, and chemically
treated aortic valve homografts (allografts) have been used
infrequently in the United States. However, cryopreserved
aortic valve allografts have been used more extensively in
recent years.30,31 In contrast to glutaraldehyde-treated bio-
prostheses, allografts tend to become covered with a fibrous
sheath of host origin. These valves become completely acel-
lular, and apoptosis has been shown to play an important role
in the loss of the valvular cells.36 Complications of allograft
valves include calcification, cuspal rupture, and fibrous
retraction of the edges of the cusps. Autologous fascia lata
valves implanted without any chemical treatment have had
a very poor record of durability and a high incidence of degen-
eration, thrombosis, calcification, and fibrous contraction of
14
the cusps. Their use has been completely discontinued.
Human dura mater valves preserved by glycerol treatment
have been used extensively in Latin America. Bioprostheses
made of glutaraldehyde-treated bovine pericardium have also
been used as substitute cardiac valves. Both dura mater and
pericardium consist of dense collagenous sheets with sparse
elastic fibers. Their layered structure is easily distinguish-
able histologically from that of porcine aortic valves. Com-
plications of pericardial and dura mater valves are similar to
those of porcine valves, consisting mainly of calcification
and cuspal dehiscence.28
Conduits
Conduits composed of various synthetic materials have been
used to correct hypoplasia or atresia of the pulmonary artery.
Valveless conduits were first used; subsequently, conduits
containing mechanical (Björk-Shiley) valves were employed
but were found to be prone to valvular thrombosis. More
recently, extensive use has been made of pulmonic conduits
with bioprosthetic (porcine or pericardial) valves; in addition,
left ventricular apical-aortic conduits have had limited use
for correction of tunnel aortic stenosis.28 The most frequent
complication of conduits is obstruction, which can result
from one or more of the following causes: (1) muscular com-
pression of the proximal end of the conduit during ventricu-
lar systole, (2) accumulation of thrombotic or fibrous material
(fibrous peel) in the wall of the conduit, (3) compression of
the conduit by the sternum, (4) calcific or thrombotic steno-
sis of the bioprosthesis, and (5) stenosis at the distal end (the
most common cause of obstruction) because of the small size
of the artery at the anastomotic site.
Summary
Valvular heart disease can result from a spectrum of degen-
erative and inflammatory conditions. Floppy mitral valve
due to myxomatous degeneration occurs as an isolated entity
or as a component of Marfan’s syndrome or other connective
tissue dyscrasias. Several endocrine and metabolic condi-
tions can produce valvular diseases, including carcinoid
heart disease and cardiac amyloidosis. Collagen vascular dis-
eases commonly produce valvular heart disease, and these
include rheumatic valvulitis, rheumatoid valvulitis, lupus
erythematosus valvulitis, and other related conditions. The
bicuspid aortic valve is the most common form of congenital
valvular heart disease. Infective endocarditis can develop on
previously diseased or normal valves. Prosthetic heart valves
include mechanical valves and bioprostheses. Characteristic
pathologic changes influence the suitability of the different
prostheses for individual patients.
References
1. Pomerance A, Davies MJ. The Pathology of the Heart. Oxford:
Blackwell Scientific, 1975.
2. Ferrans VJ. Metabolic and familial diseases. In: Silver MD, ed.
Cardiovascular Pathology. New York: Churchill Livingstone,
1991:1973.
 va lv u l a r h e a r t d i s e a s e : a n a t o m i c a b n o r m a l i t i e s
3. Segura AM, Luna RE, Horiba K, et al. Immunohistochemistry
of matrix metalloproteinases and their inhibitors in thoracic
aortic aneurysms and aortic valves of patients with the
Marfan’s syndrome. Circulation 1998;98(suppl II):II331–II337.
4. Baggenstoss AH, Titus JL. Rheumatic and collagen disorders of
the heart. In: Gould SE, ed. Pathology of the Heart and Blood
Vessels. Springfield, IL: Charles C. Thomas, 1968:701.
5. McAllister HA Jr. Pathology of the heart in endocrine disor-
ders. In: Silver MD, ed. Cardiovascular Pathology. New York:
Churchill Livingstone, 1991:1181.
6. Redfield MM. Ergot alkaloid heart disease. In: Hurst JW, ed.
New Types of Cardiovascular Diseases: Topics in Clinical Car-
diology. New York: Igaku-Shoin Medical, 1994:63–76.
7. Redfield MM, Nicholson WJ, Edwards WD, Tajik AJ.
Valve disease associated with ergot alkaloid use: echocardio-
graphic and pathologic correlations. Ann Intern Med 1992;
117:50–52.
8. Connolly HM, Cresy JL, McGoon MD, et al. Valvular heart
disease associated with fenfluramine-phentermine. N Engl J
Med 1997;337:581–588.
9. McAllister HA Jr. Pathology of the cardiovascular system in
chronic renal failure. In: Lowenthal DT, Pennock RL, Likoff W,
et al., eds. Management of Cardiovascular Disease in Renal
Failure. Philadelphia: FA Davis, 1981:1.
10. Ferrans VJ, Butany JW. Ultrastructural pathology of the heart.
In: Trump BF, Jones RT, eds. Diagnostic Electron Microscopy,
vol 4. New York: Churchill Livingstone, 1983:319.
11. McAllister HA Jr, Ferrans VJ. The heart and blood vessels. In:
Silverberg SJ, ed. Principles and Practice of Surgical Pathology.
New York: Churchill Livingstone, 1991:787.
12. McAllister HA Jr. Collagen diseases and the cardiovascular
system. In: Silver MD, ed. Cardiovascular Pathology. New
York: Churchill Livingstone, 1991:1151.
13. Fauci AS, Wolff SM. Wegener’s granulomatosis and related dis-
eases. Dis Mon 1977;23(7):1–36.
14. McAllister HA Jr, Fenoglio JJ. Cardiac involvement in Whip-
ple’s disease. Circulation 1975;52:152–156.
15. Eck M, Muller-Hermelink HK, Harmsen D, Kreipe H. Invasion
and destruction of mucosal plasma cells by Tropheryma whip-
pelii. Hum Pathol 1997;28:1424–1428.
16. Olsen EGJ, Spry CJF. The pathogenesis of Loffler’s endomyocar-
dial disease, and its relationship to endomyocardial fibrosis.
Prog Cardiol 1979;8:281.
17. Roberts WC, Dangel JC, Bulkley BH. Nonrheumatic valvular
cardiac disease: a clinicopathologic survey of 27 different
conditions causing valvular dysfunction. Cardiovasc Clin
1973;5:333–446.
18. McAllister HA Jr, Hall RJ. Iatrogenic heart disease. In: Cheng
TO, ed. The International Textbook of Cardiology. New York:
Pergamon, 1986:871.
19. Cheitlin MD, Fenoglio JJ, McAllister HA Jr, et al. Congenital
aortic stenosis secondary to dysplasia of congenital bicuspid
37 9
aortic valves without commissural fusion. Am J Cardiol
1978;42:102–107.
20. Fenoglio JJ, McAllister HA Jr, DeCastro CM, et al. Congenital
bicuspid aortic valve after age 20. Am J Cardiol 1977;
39:164–169.
21. Davia JE, Fenoglio JJ, DeCastro CM, et al. Quadricuspid semi-
lunar valves. Chest 1977;72:186–189.
22. Hyams VJ, Manion WC. Incomplete differentiation of the
cardiac valves. A report of 197 cases. Am Heart J 1968;76:
173–182.
23. Titus JL. Infective endocarditis, active and healed. In: Edwards
JE, Lev M, Abell MR, eds. The Heart. Baltimore, MD: Williams
& Wilkins, 1974:176.
24. Freedman LR. Endocarditis updated. Dis Mon 1970;26(3):
1–71.
25. Silver MD, Datta BN, Bowes FV. A key to identify heart valve
prostheses. Arch Pathol 1975;99:132–138.
26. Steiner RM, Flicker S. The radiology of prosthetic heart
valves. In: Morse D, Steiner RM, Fernandez J, eds. Guide to
Prosthetic Cardiac Valves. New York: Springer-Verlag,
1985:53.
27. Butany J, Ahluwalia MS, Munroe C, et al. Mechanical heart
valve prostheses: identification and evaluation. Cardiovasc
Pathol 2003;12:1–22.
28. Lefrak EA, Starr A. Cardiac Valve Prostheses. East Norwalk,
CT: Appleton & Lange, 1979.
29. Zeien LB, Klatt EC. Cardiac valve prostheses at autopsy. Arch
Pathol Lab Med 1990;144:933–937.
30. Dagenais F, Cartier P, Voisine P, et al. Which biologic valve
should we select for the 45- to 65-year-old age group requiring
aortic valve replacement? J Thorac Cardiovasc Surg 2005;129:
1041–1049.
31. Koolbergen DR, Hazekamp MG, de Heer E, et al. The pathology
of fresh and cryopreserved homograft heart valves: an analysis
of forty explanted homograft valves. J Thorac Cardiovasc Surg
2002;124:689–697.
32. Platt MR, Mills LJ, Estrera AS, et al. Marked thrombosis and
calcification of porcine heterograft valves. Circulation 1980;
62:862–869.
33. Croft CH, Buja LM, Floresca MZ, et al. Late thrombotic obstruc-
tion of aortic porcine bioprosthesis. Am J Cardiol 1986;57:
355–356.
34. Ferrans VJ, Tomita Y, Hilbert SL, et al. Evaluation of opera-
tively excised prosthetic tissue valves. In: Waller BF, ed. Pathol-
ogy of the Heart and Great Vessels. New York: Churchill
Livingstone, 1988:311.
35. Hilbert SL, Ferrans VJ, McAllister HA Jr, Cooley DA. Ionescu-
Shiley bovine pericardial bioprosthesis: histologic and ultra-
structural studies. Am J Pathol 1992;140:1195–1204.
36. Hilbert SL, Luna RE, Zhang J, et al. Allograft heart valves: the
role of apoptosis-mediated cell loss. J Thorac Cardiovasc Surg
1999;117:454–462.
 1 Aortic Valve Disease
5 Blase A. Carabello
Aortic Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
Diagnostic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385
Aortic Regurgitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
Key Points
• Calcific disease is the major cause of aortic stenosis.
• Bicuspid aortic valves lead to aortic stenosis in approxi-
mately one half of patients who are born with them.
• The classic symptoms of valvular aortic stenosis, angina,
syncope, and dyspnea represent a major inflection in the
natural history of the disease and indicate the need for
surgical correction, and in the absence of surgical therapy
an increased risk of sudden death.
• The mainstay of diagnosis of valvular aortic stenosis
is the echocardiogram, which, together with Doppler,
provide an excellent estimate of the severity of valvular
aortic stenosis.
• Patients with low cardiac outputs and some valvular
aortic stenosis and those with severe valvular stenosis
and reduced left ventricle (LV) function can often be
distinguished by a dobutamine infusion test with
echocardiography.
• Aortic regurgitation is caused by pathology of the aortic
valve leaflets or of the aortic root.
• An Austin Flint murmur (apical diastolic rumble) indi-
cates severe aortic insufficiency.
• Vasodilators may reduce LV volume or delay the develop-
ment of symptoms in patients with aortic regurgitation
(AR).
• Surgical correction of AR is needed when the amount
of regurgitation is severe and either symptoms of conges-
tive heart failure (CHF) or angina develop or with evi-
dence of decline in LV function, for example, a fall in the
LV ejection fraction (LVEF) below 0.55 or the LV is unable
to contract down to 50 to 55 mm Hg at the end of
systole.
• Acute AR, such as occurs following perforation of an
aortic leaflet by infective endocarditis, is a potentially
life-threatening emergency that often requires very early
surgical correction.
• Appetite-suppressant drugs may cause pulmonary hyper-
tension and left ventricular valvular lesions, including
aortic and mitral valve insufficiency.
Obesity Drugs, Valvular Heart Disease, and
Pulmonary Hypertension . . . . . . . . . . . . . . . . . . . . . . 389
Aortic Stenosis
Etiology
The causes of aortic stenosis (AS) and our understanding of
them have evolved substantially over the past four decades.
Although rheumatic heart disease was once a major cause of
aortic stenosis in the developed world, today rheumatic
disease is exceedingly rare in those countries. Instead cal-
cific disease is now the major cause of AS. Previously con-
sidered to be a degenerative disease, it is now clear that the
process is much akin to atherosclerosis.1–3 The initial plaque
of AS resembles that of coronary artery disease (Fig. 15.1).1
Risk factors such as hyperlipidemia, hypertension, and evi-
dence of systemic inflammation are held in common by both
AS and coronary disease.2 The presence of aortic sclerosis,
the earliest phase of AS in which no hemodynamic distur-
bance is yet present, is associated with increased cardiac
mortality.4 Since the valve abnormality is too slight to cause
untoward events, it is presumed that the aortic sclerosis pre-
sages subsequent coronary events. Finally a body of data is
amassing that shows that hepatic hydroxymethylglutaryl
coenzyme A (HMG CoA) reductase inhibitors (statins), com-
monly used agents in treating coronary disease, are also
beneficial in retarding the progression of AS.5,6 Results of
randomized clinical trials are pending.
Another common cause of AS is bicuspid aortic valve.
This common congenital abnormality, which occurs in about
1% of the United States population, leads to AS in about half
the patients born with it. When AS occurs in such patients
it usually develops in the fifth and sixth decades of life, 20
to 30 years earlier than occurs in previously normal tricuspid
aortic valves. It is thought that in both bicuspid and tricuspid
valves, the etiology of AS, when it occurs, is similar to that
of atherosclerosis.
Occasionally, congenital aortic stenosis is detected for
the first time in adulthood. This disease differs somewhat
from the acquired disease discussed above. In congenital AS,
there is usually extensive concentric hypertrophy and
3 81
382 chapter 15

Disruption of endothelium
and basement membrane on
aortic side of leaflet

Lipide
Lipide
Lipide Lipide
T cells
Macrophages Lipide Lipide
Lipide
Lipide
Lipide Lipide Lipide

Lipide
Displacement of Fibrosa
elastic lamina Lipide
Fine, stippled
mineralization Ventricularis

FIGURE 15.1. A schematic representation of

the early lesion of aortic stenosis emphasizes
the presence of macrophages and lipids similar
Ventricular side of leaflet (intact endothelium) in nature to the plaque of coronary disease.

supernormal ejection performance.7 Sudden death is possibly malizing afterload, concentric LVH helps to maintain normal
more frequent in the absence of symptoms in congenital ejection performance. Paradoxically, LVH may be pathologic
versus acquired AS, although data to support this are sketchy. instead of compensatory. In general, in heart disease, LVH is
Finally, because the leaflets are joined at the commissures associated with adverse events.12–14 In addition, LVH may also
instead of being heavily calcified, balloon valvotomy may
produce excellent relief of congenital AS,8 a result rarely seen
in acquired AS.

Pathophysiology and Its Relation to Symptoms

As discussed below, the development of the classic symp-
toms of AS—angina, syncope, or dyspnea (and other symp-
toms of heart failure)—represent a dramatic inflection in the
natural history of the disease with little risk of sudden death
in the asymptomatic state and extreme risk once symptoms
have developed. Thus an understanding of the intertwining
of symptoms with the disease’s pathophysiology is key in
understanding the disease.

Pressure Overload
Normally the aortic valve offers little resistance to forward
flow. Once open, pressures on both sides of the valve are
virtually identical (Fig. 15.2A).9 Near equalization of systolic
pressures in the left ventricle (LV) and aorta remains until
the aortic valve area becomes less than half of its normal 3
to 4 cm2. However, as valve stenosis worsens, a pressure gra-
dient between LV and aorta develops (Fig. 15.2B). This gradi-
ent represents the additional pressure work (pressure
overload) that the LV must develop in order to propel blood
across the narrowed valve.
Although occasionally debated, there is general consen-
sus that a major compensatory mechanism for accommodat-
ing the pressure overload is the development of left ventricular
hypertrophy (LVH). Left ventricular ejection performance is
determined by preload, afterload, and contractility. One
expression for afterload is wall stress (σ) = p × r/2th, where p
is the LV pressure, r is the LV radius, and th is the LV thick-
ness. As the pressure term of this Laplace equation increases FIGURE 15.2. (A) Simultaneous left ventricular and aortic pressure
in the numerator, it can be offset by concentric LVH that tracings from a normal subject are shown. (B) The pressure gradient
increases the thickness term in the denominator.10,11 By nor- across a stenotic aortic valve.
 a o r t i c va lv e d i s e a s e
be responsible in part for some of the symptoms of AS, symp-
toms that presage morbidity and mortality.
Angina
When angina occurs, it indicates myocardial ischemia that
develops when myocardial oxygen demand outstrips oxygen
supply. As noted above it would be expected that many AS
patients would also have coronary artery disease, and this is
so in about half of AS patients.15,16 However, many patients
with AS who experience angina have normal epicardial
arteries invoking another cause for angina. In part, angina
in such patients is due to diminished coronary blood flow
reserve.17 Normal subjects can increase coronary blood flow
six- to eightfold during stress, an increase necessary to meet
the oxygen demands of increased workload. However, patients
with AS have reduced coronary blood flow reserve of only
two- to threefold, a deficit related to LVH. The exact mecha-
nism of this deficit is unknown but is thought to be second-
ary to the reduced capillary density per gram of myocardium.
A second mechanism of reduced flow reserve in LVH is that
elevated filling pressure that often accompanies it com-
presses the endocardium during diastole (when coronary
blood flow occurs), in turn impeding blood flow.18 While
reduction in coronary blood flow reserve must in some way
play a role in the angina of AS patients, it is not the complete
explanation because many patients with severe LVH do not
have angina. In fact, wall thickness, valve area, pressure
gradient, and other hemodynamic factors have failed to
predict when patients with AS will develop angina. The
measurable hemodynamic parameter best associated with
angina occurrence is diastolic filling time.19 During every
cardiac cycle the heart expends energy during systole when
coronary blood flow ceases incurring an oxygen debt. This
debt is repaid by coronary blood flow during diastole. The
ratio of systolic ejection period (debt period) to diastolic
filling time (repayment period) appears to be the best predic-
tor of when angina might develop.
Syncope
Syncope is the temporary loss of consciousness. Cardiac
syncope occurs when blood flow to the brain is inadequate to
maintain satisfactory perfusion. The mechanism of syncope
in AS is not well established, although many theories abound.
When syncope does occur in AS it almost always does so
during exercise. In normal subjects and in those with AS,
exercise causes vasodilatation and reduced total peripheral
resistance. Blood pressure is the product of total peripheral
resistance and cardiac output. In normals, cardiac output
increases more than total peripheral resistance falls during
exercise so that blood pressure increases. However, it is
thought that in patients with AS who develop syncope, cardiac
output is restricted by the narrowed aortic valve. Thus periph-
eral resistance decreases during exercise while cardiac output
is fixed so that blood pressure must fall, in turn leading to
syncope in some cases. In other cases, because pressure gradi-
ent is proportional to the square of the cardiac output, high
LV pressure during exercise is postulated to cause a vasode-
pressor response, in turn leading to syncope. In still other
cases, exercise-induced atrial or ventricular arrhythmias may
cause reduced cardiac output and syncope.
383
Congestive Heart Failure
Heart failure is often classified as deriving from systolic
dysfunction, diastolic dysfunction, or both. In AS both por-
tions of the cardiac cycle are usually abnormal. Diastole is
usually divided into the isovolumic relaxation phase, the
rapid filling phase, and atrial contraction. All may be abnor-
mal in AS. In AS and in conditions causing concentric LVH
in general, the isovolumic relaxation phase is delayed.20
During this active phase of myocardial relaxation, calcium
is pumped back into the sarcoplasmic reticulum reducing
actin-myosin interaction. Calcium removal is slowed in
LVH, presumably due in part to reduced SERCA 2 activity.21
In turn this delays the onset of the early rapid filling phase,
shortening the filling time.
During active filling, the pressure-volume relationship is
shifted upward and to the left (Fig. 15.3).20,22 Thus for any
given filling volume, filling pressure is increased, reflecting
the increased stiffness of the hypertrophied chamber. Stiff-
ness is increased because the left ventricular wall is thicker
than normal and because the collagen content of the myo-
cardium is increased. Slowed early relaxation together with
a stiffer myocardium result in increased LV filling pressure
that is referred to the lungs, resulting in pulmonary conges-
tion. Increased myocardial stiffness also results in greater
than normal dependence on atrial contraction for adequate
ventricular filling. Thus patients with AS are especially
dependent on their left atrial “kick” and may decompensate
rapidly if atrial fibrillation occurs.
Systole is also often abnormal in patients with AS. The
major determinants of systole are preload, afterload, and
contractility. The last two of these properties are often
disordered in AS. As noted above, LVH is thought to be a
compensatory mechanism that helps normalize afterload,
enhancing LV systolic performance. If the amount of hyper-
trophy that developed were just enough to offset the increased
100
80
Stress (kdyne/cm2)
60
40
controls
AS pre
20 AS early post
AS late post
0
0 0.3 0.4 0.5 0.6 0.7
Strain
FIGURE 15.3. Myocardial stiffness (stress vs. strain) is shown for
control subjects and aortic stenosis patients before, and early and
late after aortic valve replacement (AVR). Prior to surgery, myocar-
dial stiffness is greater in aortic stenosis (AS) than in normal sub-
jects. Early after AVR stiffness increases because the muscle
elements of the myocardium regress more quickly than the stiffer
collagen elements. Eventually, stiffness returns to normal.
384
pressure term in the Laplace equation, ejection performance
should be normal, and frequently it is. However, in some
cases the LVH is inadequate to normalize wall stress and
thus afterload increases, reducing ejection fraction (Fig.
15.4),23 in turn leading to congestive heart failure. Interest-
ingly, in some cases (especially in children and older women)
the hypertrophy that develops seems in excess of that needed
to normalize wall stress, stress is reduced, and ejection frac-
tion is actually increased.7,24 Although this phenomenon is
beneficial for systolic performance, the increased wall thick-
ness impairs diastolic filling.
Although in some cases, reduced systolic performance is
due to increased afterload, noted above, in other cases con-
tractility is reduced.23 Currently, the exact mechanisms
responsible for reduced contractility in the face of concentric
LVH are uncertain. Myocardial ischemia due to reduced
coronary blood flow,16 abnormal calcium handling,25 and
abnormalities of the myocardial cytoskeleton 26 have been
implicated.
Natural History
As shown in Figure 15.5, the onset of symptoms in AS is a
critical turning point in the natural history of the disease.27–29
The asymptomatic patient has a nearly normal prognosis, yet
once the classic symptoms of angina, syncope, or dyspnea
develop, survival is abruptly reduced. In fact, taken as a
whole, once these symptoms develop, mortality is about 2%
per month. Following the development of angina, about 50%
.6
.5
Ejection fraction
.4
.3
.2
150 200
250 300 350 400
σ dynes × 10 3/cm 2
FIGURE 15.4. Afterload (wall stress,σ) is plotted against ejection
fraction for aortic stenosis patients in heart failure. In some cases
(circles) the reduction in ejection fraction is accounted for by
increased stress. In other cases (×’s) ejection fraction is reduced more
than can be accounted for by elevated afterload, implying reduced
contractility.
chapter 15
Onset severe
100
symptoms
Angina
Synope
Latent period Failure
80 (increasing obstruction,
% survival
myocardial overload)
0 2 4 6
60
Average survival (yr)
40
20
Average death
age
40 50 60 70 80
Age (yr)
FIGURE 15.5. The natural history of AS is shown, demonstrating
a dramatic reduction in survival once symptoms develop.
of such patients succumb in 5 years. If syncope occurs, 50%
survival is 3 years, whereas the patient with dyspnea or other
symptoms of heart failure has a 50% survival of only 2 years
without aortic valve replacement. Thus a careful probing
history is crucial in managing the patient with AS.
Physical Examination
The physical examination of the patient with AS is quite
instructive as to the severity of the disease. The apical
impulse is usually not displaced but is sustained and force-
ful. The carotid upstrokes are classically delayed and reduced
in volume (parvus et tardus; Fig. 15.6).30 By placing one hand
on the patient’s forceful apical beat with the other hand on
the patient’s reduced carotid upstroke, the examiner can
deduce the severity of the obstruction between left ventricle
and the vasculature. The murmur of aortic stenosis is a sys-
tolic ejection murmur radiating to the neck. Thus S1 is heard
followed by a short quiet period as the LV develops enough
pressure to initiate ejection at which time the murmur com-
mences. As the severity of AS worsens, the murmur peaks
progressively later in systole until it becomes maximal just
before S2. In some cases the murmur is loudest in the aortic
area, decreases over the sternum, and increases again over
the LV apex (Gallavardin’s phenomenon), misleading the aus-
cultator into thinking that two murmurs, one of AS and a
second of mitral regurgitation, are present. The murmur of
AS may be quite loud and accompanied by a thrill. Paradoxi-
cally, as the disease severity worsens, the murmur becomes
softer as less stroke volume is delivered to the valve by a
progressively impaired LV.31 Thus a soft murmur by itself
should not be taken to indicate that the disease is mild. In
most cases the second heart sound becomes single as the
aortic component from a dysfunctional valve is lost. Today,
450
Carotid pulse
tracing
FIGURE 15.6. A normal carotid upstroke (left) is compared to the
carotid upstroke of a patient with aortic stenosis (right).
 a o r t i c va lv e d i s e a s e
detection of AS usually occurs before severe LV dysfunction
develops. Thus paradoxic splitting of S2 due to delayed emp-
tying of a severely weakened LV, which was noted in older
texts, is now rare.
Diagnostic Testing
The electrocardiogram (ECG) and chest x-ray may give clues
to the presence of AS, but these modalities are rarely diag-
nostic. The ECG typically demonstrates the pattern of LVH,
although severe AS may exist without such evidence. The
chest x-ray may show a boot-shaped heart consistent with
concentric LVH. Occasionally the calcified aortic valve is
seen in the lateral view. However, the mainstay of diagnosis
is the echocardiogram with Doppler interrogation of the
aortic valve. While in severe disease two-dimensional (2D)
echo demonstrates a thickened, immobile, heavily calcified
valve, it is the Doppler examination that can fairly precisely
quantify stenosis severity. Because flow equals the area
times the velocity, bloodstream velocity must increase when
it reaches the narrowed aortic valve. Sound waves transmit-
ted from an ultrasound transducer collide with the accelerat-
ing red blood cells that compress the sound waves, increasing
their frequency. This increase is detected by the transducer
that now acts as a receiver, converting the difference between
the frequency sent and the frequency received into a velocity
that in turn can be converted into a pressure gradient or valve
area.
Because almost all patients with AS are old enough to be
at risk for coronary disease and because AS and coronary
artery disease hold risk factors in common, most patients
with AS should undergo cardiac catheterization to perform
coronary angiography prior to aortic valve replacement
(AVR), although this test may be replaced by multislice com-
puted tomography (CT) scanning in the future. While several
studies have examined the use of nuclear imaging as a non-
invasive test to detect the presence of coronary disease,
nuclear studies in the presence of AS have not been accurate
enough to supplant angiography prior to AVR.32,33 In most
cases the severity of the AS has been assessed accurately
noninvasively prior to catheterization, obviating the need to
obtain a pressure gradient using simultaneous recording of
LV and aortic pressure (Fig. 15.2). However, in a minority of
cases, AS severity is still unclear at the time of catheteriza-
tion, necessitating evaluation of the valve invasively. In that
case, valve area is calculated using the Gorlin formula,34
employing measured cardiac output and direct pressure mea-
surement. In recording the gradient it is crucial that the
catheters be placed in the proper position with one catheter
well inside the body of the LV and the second catheter placed
in the ascending aortic to avoid errors in pressure measure-
ment.35 However, the need to use two catheters can be
avoided by using instead a double-lumen or double-trans-
ducer catheter or by a carefully recorded catheter pullback
in patients in sinus rhythm.
Medical Therapy
For asymptomatic patients with AS, no medical therapy is
indicated other than antibiotic prophylaxis for bacteremia-
causing procedures. Once patients develop symptoms,
surgery is necessary to prevent death (see below). Thus the
385
only indication for medical therapy in this disease is in the
case of symptomatic patients in whom surgery cannot be
performed because of existing comorbidities. In such cases
diuretics can be used with caution to treat congestive heart
failure, and nitrates may be used to relieve angina. Vasodila-
tors may be helpful in severe heart failure but must be used
with extreme caution to avoid hypotension.36 In a recent
study, nitroprusside improved hemodynamics in patients
with pulmonary edema. This agent is believed to be useful
not because it reduces afterload (which is fixed by the ste-
notic valve) but by reducing LV end diastolic pressure. This
action of the agent may improve coronary blood flow, enhanc-
ing LV function.
Timing of Surgery
Asymptomatic patients with severe AS have a good prognosis
with a minimal risk of sudden death or other complications
until symptoms develop.27–29 Thus as noted above, the onset
of symptoms represents a crucial demarcation point in the
natural history of the disease and indicates the need for
prompt AVR because AVR dramatically improves outcome.37
In some patients symptomatic status may be hard to ascer-
tain even after obtaining a careful history. In such patients
a carefully performed exercise test may be quite helpful38,39
in confirming symptom status. While exercise testing is
clearly contraindicated in symptomatic patients, the proce-
dure is becoming more widely accepted in patients in whom
symptomatic status is uncertain. Such patients are likely to
exercise anyway, and the development of symptoms during
formal testing or evidence of less than expected exercise
tolerance indicates a high risk for requiring AVR in the near
future.
When symptoms are present, the question arises as
to whether the patient’s AS is severe enough to be their
cause. While no “critical” valve area is agreed upon, because
symptoms appear at a wide variation in the valve area,40 in
general, if the valve area is <1.0 cm2 or if the mean gradient
exceeds 50 mm Hg or if peak jet velocity exceeds 4.0 m/s,
severe AS is usually present and the patient’s symptoms
are logically attributable to it. Because reduced cardiac
output reduces gradient, severe AS may be present in patients
with heart failure and lower gradients. However, in most
such patients, the ratio of outflow tract velocity to velocity
at the aortic valve is <0.25, another index of severe aortic
stenosis.
Asymptomatic Patients with Severe
Aortic Stenosis
Although stenosis severity is important in the progression to
symptoms, no valve area or gradient has been shown to cause
symptoms by itself. Not surprisingly, then, some patients
develop severe asymptomatic AS. While the short-term prog-
nosis in such patients is excellent without surgery, there is
still a small but definite risk of sudden death.29,41 Obviously
there is also a small but definite risk of morbidity and mor-
tality related to aortic valve replacement and to complica-
tions resulting from the presence of a prosthetic valve.42–47
Thus the clinician is faced with a dilemma. Whether the
strategy is surgery in the absence of symptoms or watchful
waiting, there is a small but definite risk. While there is no
386 chapter 15

definite solution to the problem, one strategy is to use the Patient survival (%)
results of exercise testing as noted above. For the truly
100
asymptomatic patient who performs well on the treadmill,
there is no compelling reason to proceed with AVR. If symp-
toms are manifest during the test, or if there is hypotension Group I, valve replacement
75
or arrhythmia, early AVR should be considered. The diffi-
culty in knowing how best to manage the asymptomatic
patient with severe AS has led to an interest in biomarkers. 50
Recent studies have found elevated B-type natriuretic peptide Group II, valve replacement
(BNP) in some asymptomatic patients with severe AS. In one
20 Group I, medical treatment
study elevated BNP greatly increased the risk of symptom
onset in the year following the initial test.48
Group II, medical treatment
0
Aortic Valve Replacement in Patients with
Reduced Ejection Fraction 0 50 100
Follow-up (months)
As shown in Figure 15.4, in some AS patients with low ejec-
FIGURE 15.7. The outcome of low-gradient, low-ejection fraction
tion fractions, reduced ejection performance is due to the patients is shown. Patients with inotropic reserve treated with AVR
afterload excess caused by high systolic LV pressure and had the best results by far.
limited hypertrophy inadequate to normalize wall stress. In
such patients AVR causes a prompt reduction in afterload,
ejection fraction returns to or toward normal, and prognosis
revascularization also has AS. When the AS is severe, obvi-
is excellent.23 However, in other patients, those with a low
ously both are corrected during the same surgery. A more
transvalvular gradient, ejection fraction is depressed below
problematic situation arises when the patient requiring
that which can be attributed to afterload mismatch. In this
bypass surgery has milder AS, AS of severity that by itself,
case there is severe LV muscle dysfunction and outcome fol-
would not be a reason to perform AVR. On the one hand,
lowing AVR is much less favorable. However, some such
concomitant AVR adds surgical risk and exposes the patient
patients may improve dramatically following AVR,49–51 and
to the risks of harboring a prosthetic valve. On the other
the obvious clinical challenge is to judge which low gradient,
hand, leaving significant valve disease behind at the time of
low ejection fraction patients are likely to benefit from
coronary revascularization may result in a second operation
AVR.
in the near future if the patient’s AS progresses rapidly. It
The first task is to divorce true aortic stenosis from a
appears that for patients with moderate AS and a gradient of
condition sometimes referred to as aortic pseudostenosis. In
>30 mm Hg or an aortic valve area of <1.3 cm2, AVR should
the former case severe valve disease has led to severe LV
be performed at the time of coronary (or other heart) surgery.57
dysfunction, a low output, and a low gradient. In the second
For gradients of <10 mm Hg, AVR should be avoided. In the
condition, a ventricle weakened from another cause such as
middle ground, with gradients between 10 and 30 mm Hg,
coronary disease is unable to open a mild to moderately ste-
valve morphology at echocardiography may be helpful, pro-
notic valve to its full aperture. In both cases the valve area
viding an impetus toward AVR for heavily calcified immo-
at rest will be quite reduced. However, in true stenosis, when
bile appearing valves.
cardiac output is increased by exercise or inotropic infusion,
the gradient increases in tandem and the valve area increases
only slightly.52–55 In pseudostenosis when cardiac output is The Elderly Patient with Aortic Stenosis
increased, the gradient does not increase proportionately and
It is well known that elderly patients, even those in their
as a consequence calculated valve area increases substan-
nineties, may have an excellent result following AVR. Indeed
tially, often to >1.0 cm2. Because such patients do not have
age-corrected survival following AVR for AS is normal for
severe aortic stenosis as the cause of their heart failure, they
patients over the age of 65.58 Nonetheless, the elderly patient
are unlikely to benefit from AVR.
is subject to a host of comorbidities that affect outcome.59–61
For the patients with severe aortic stenosis and low gradi-
In recommending AVR for the elderly patient, the co-pres-
ent and low ejection fraction, response to dobutamine infu-
ence of coronary disease, neurologic deficits, and renal and
sion is an important indicator of prognosis. As shown in
pulmonary dysfunction all worsen prognosis and must be
Figure 15.7, if dobutamine infusion increases cardiac output
taken into consideration. Especially in this age group, the
by >20% (with inotropic reserve, group I), prognosis follow-
patient’s expectation of outcome and lifestyle must be con-
ing AVR is much better than similar patients treated medi-
sidered in choosing AVR therapy.
cally and much better than those patients without inotropic
reserve (group II) treated medically or with AVR.56
The Percutaneous Approach to Aortic Stenosis
The Patient with Mild to Moderate Aortic
Although balloon aortic valvotomy (BAV) is useful in chil-
Stenosis Undergoing Coronary Revascularization
dren with congenital AS, the calcified lesion of acquired AS
As noted above, AS and coronary disease are likely to be in the adult does not respond well to BAV. After a modest
manifestations of the same pathologic process and thus often acute reduction in stenosis severity,62,63 restenosis recurs
coexist. Not infrequently, a patient who requires coronary usually within 6 months and BAV has not been shown to
 a o r t i c va lv e d i s e a s e
alter the high mortality of symptomatic AS.64 Thus BAV is
reserved only as a palliative measure for patients in whom
AVR is impossible because of comorbid conditions.
Percutaneous aortic valve replacement is being examined
as a therapy for AS. After the native valve is dilated by expan-
sion of a large balloon, a stented bioprosthesis is deployed
into the aortic annulus. Although residual calcium deposits
existing from the native valve may restrict seating, leading
to mild aortic regurgitation, the initial results in patients in
whom surgical AVR was contraindicated are promising.65
Aortic Regurgitation
Etiology
Aortic regurgitation (AR) is caused by pathology of either the
valve leaflets or the aortic root. As noted above, bicuspid
aortic valve is a common congenital abnormality often asso-
ciated with aortic stenosis. However, in other cases this same
387
defect may lead to aortic regurgitation. In such cases there
is usually concomitant dilatation of the proximal aortic root
leading to valve cusp separation and incompetence. While
such expansion was often labeled “poststenotic” dilatation
when even mild AS was present, it is now recognized that
abnormalities inherent in root composition are responsible
for its dilatation.66 Such dilatation (annuloaortic ectasia) may
also be seen in patients with tricuspid aortic valves and is
associated with aging and hypertension. Other causes of
aortic regurgitation include infective endocarditis aortic dis-
section, Marfan syndrome, rheumatic fever, and collagen
vascular disease, especially ankylosing spondylitis. Appe-
tite-suppressant drugs have also caused both aortic and
mitral valvular insufficiency (see later in the chapter).
Pathophysiology and Its Relation to Symptoms
As shown in Figure 15.8,67 AR imparts a volume load on the
left ventricle, as the cardiac output that regurgitates into the
LV during diastole must be compensated for by an increase

AOP 120/80
AOP 130/70
60 cc

Forward 100 cc
stroke Forward
EDV = 150 cc stroke EDV = 170 cc
volume
100 cc volume ESV = 50 cc
60 cc 120 cc EF = 0.71
ESV = 50 cc RF = 0.50
EF = 0.67
LVEDP = 10 mm Hg
LVEDP = 50 mm Hg

A B

100 cc AOP 190/60 75 cc AOP 170/60

Forward Forward
stroke EDV = 250 cc stroke EDV = 300 cc
volume 200 cc ESV = 50 cc volume 150 cc ESV = 150 cc
100 cc EF = 0.80 75 cc
RF = 0.5 EF = 0.50
RF = 0.50

LVEDP = 12 mm Hg LVEDP = 25 mm Hg

C D
FIGURE 15.8. The pathophysiologic stages of aortic regurgitation
(AR). Normal physiology (A) is contrasted with acute AR (B). In acute
AR little left ventricle (LV) dilatation has occurred so that total
stroke volume and forward stroke volume are reduced. The large
filling volume due to the AR is thrust into a small LV resulting in
high LV filling pressure. (C) Compensatory left ventricular hyper-
trophy (LVH) has developed. Cardiac enlargement now allows normal
forward stroke volume and LV filling pressure. The large total stroke
volume results in a wide pulse pressure that is responsible for many
of the signs of AR. (D) Muscle dysfunction has developed, resulting
in increased end systolic volume, reduced forward stroke volume,
and elevated LV filling pressure. LVEDP, left ventricular end-
diastolic pressure.
388
in total stroke volume. However it must be recognized that
this large compensatory total stroke volume increases pulse
pressure and systolic pressure. Thus the volume overload of
AR is also associated with a significant pressure overload. In
fact, systolic wall stress in AR may be as high as occurs in
AS and the lesion more typically thought of as a pressure
overload.68,69 Accordingly, LV wall thickness in AR is greater
than normal as the ventricle remodels to accommodate the
increased pressure demands on the LV.70 This combined pres-
sure and volume overload causes LV mass in AR to be the
greatest of all the valvular heart diseases.
Aortic regurgitation may be tolerated in the compensated
state for years. Compensation is provided by ventricular
remodeling (Fig. 15.8) whereby the enlarged LV can pump
enough extra stroke volume to maintain adequate perfusion
even during exercise. At the same time the enlarged LV can
accommodate the increased filling volume of the LV at fairly
normal filling pressure, preventing pulmonary congestion.
Eventually, however, eccentric hypertrophy fails to compen-
sate for the volume overload and concentric hypertrophy fails
to normalize systolic wall stress, both acting in concert to
reduce cardiac output. In turn, increased residual LV volume
and diastolic dysfunction lead to elevated LV filling pressure.
At this point in the course of the disease, CHF symptoms
may appear.
While much less common in AR than in AS, angina may
occur with normal epicardial coronary arteries. Angina is pre-
sumed to be caused by the reduced coronary flow of reserve
of LVH together with reduced diastolic aortic pressure for
driving coronary flow. This same reduction in diastolic pres-
sure may occasionally be associated with syncope.
Rare symptoms of AR include flushing episodes, carotid
artery pain, and an annoying awareness of the heartbeat.
Physical Examination
The physical examination of the patient with AR is rich with
dynamic findings. Palpation of the precordium finds an
active point of maximum impulse, displaced downward and
to the left. The diastolic blowing murmur typical of AR is
heard best over the left upper sternal border when the patient
100
Percent of patients asymptomatic
80
with normal LV function
60
40
Sudden death
20 Onset of symptoms
Onset of asymptomatic
LV dysfunction
0
6 0 82 4
10 12
Time (years)
FIGURE 15.9. The natural history of AR is shown. The onset of
symptoms or LV dysfunction occurs at a rate of about 4.5%/year.
chapter 15
is sitting upright and leaning forward. A diastolic rumble
may also be heard at the apex. This murmur (Austin Flint)
arises from the mitral valve. Its origin is thought to be due
to either relative mitral stenosis, as LV filling from the aorta
tends to close the mitral valve in diastole, or the aortic jet
striking and vibrating the mitral valve. In either case the
presence of an Austin Flint murmur usually indicates severe
AR.
The large total stroke volume and widened pulse pressure
of AR generate myriad signs. These include de Musset’s sign
(bobbing of the head in cadence with the heartbeat), Duro-
ziez’s sign (a to-and-fro bruit over the femoral artery when it
is compressed by the bell of the stethoscope), Quincke’s pulse
(plethora and blanching of the nail bed when traction is
placed on the nail), and Corrigan’s pulse (rapid upstroke and
brisk downstroke of the carotid pulse). Perhaps the most reli-
able indicator or severe AR is Hill’s sign, which is augmenta-
tion of systolic pressure in the leg by >40 mm Hg more than
in the arm.
Therapy
Medical Therapy
As noted above, aortic regurgitation increases left ventricular
afterload. Thus it is logical that afterload reduction therapy
might be advantageous. In fact several studies have shown
either reduction in LV volume or a delay to onset of symp-
toms when vasodilators were added to the regimen.71–74 In
most cases vasodilators were administered to asymptomatic
patients with normal LV function. Recently nifedipine
administered to patients already manifesting LV dysfunction
provided a long-term mortality benefit following AVR even
though the drug had been discontinued following surgery.75
The mechanism of this benefit is unknown. Which vasodila-
tor is the best agent to use is unknown because no direct
comparison of chronically used agents has ever been made.
While use of vasodilators in this disease of high afterload is
logical, such use should be weighed against preliminary
reports of failed long-term benefit.76
Surgical Therapy
Aortic regurgitation, like all valvular heart diseases, is a
mechanical problem that requires a mechanical solution.
Although a minority of regurgitant aortic valves can be
repaired, for the most part the mechanical solution for AR
is AVR. Thus as with AS, surgery should be timed to avoid
unnecessary patient-years of risk from a prosthetic valve
complication, but must be timed early enough to avoid the
risk of persistent LV dysfunction following AVR. The natural
history of several AR is shown in Figure 15.9.77 The average
risk of developing symptoms or asymptomatic LV dysfunc-
tion is about 4.5% per year. Thus many patients can tolerate
severe AR for a decade or more without negative sequelae.
However, once more than mild symptoms occur78 (Fig. 15.10)
or if LV dysfunction develops and is allowed to persist, the
prognosis is reduced.79–83 While the exact definition of LV
dysfunction is unclear, the prognosis diminishes when LV
ejection fraction falls below 0.55 or when the LV is unable to
contract down to 50 to 55 mm Hg at the end of systole. It is

100
Overall survival (%)
80
60
40
20
FIGURE 15.10. Outcome of patients 0
with AR and reduced ejection fraction
(left panel) and normal ejection fraction
(right panel) is shown. In either case,
advanced symptoms greatly reduced I-II n = 99 95 95 93 91 85 71 67 57 47 35 45 41 41 41 40 34 31 25 20 15 14
survival following AVR. III-IV n = 54 47 42 42 39 36 31 26 19 14 10 51 45 43 40 38 32 24 21 20 12 11
presumed that these benchmarks represent evidence of sig-
nificant LV dysfunction. Thus AVR should be performed in
AR patients if even mild symptoms occur or if there is evi-
dence of LV dysfunction as noted above. Following surgery,
reduction in afterload allows LV ejection fraction to improve,
especially if LV dysfunction has been present for less than
15 months.78,84
Acute Aortic Regurgitation
Acute severe aortic regurgitation (AR), such as might occur
following the perforation of an aortic leaflet by infective
endocarditis, is a potentially life-threatening emergency that
is often underrecognized. Treated medically, this disease has
up to 75% mortality while surgical intervention reduces risk
to 25% or less. Recent analysis clearly favors early surgery
in such patients.85 In acute severe AR, the unprepared small
LV must accept a large regurgitant volume, in turn increas-
ing LV diastolic filling pressure. At the same time, diastolic
aortic pressure falls due to increased run-off of blood into the
LV. The net result is reduced driving pressure for coronary
blood flow, potentially leading to myocardial ischemia,
setting up a vicious cycle of reduced coronary flow leading
to reduced LV function leading to reduced coronary flow, etc.
Of concern is that this pernicious physiologic state is diffi-
cult for the clinician to recognize. As noted above, the physi-
cal examination of the patient with chronic AR is very
dynamic, based on increased total stroke volume and pulse
pressure. However, in acute AR, there has been no time for
LV dilatation; thus most of the findings of chronic AR are
absent. Instead the murmur of AR is short and unimpressive
because rapid LV filling at high pressure reduces the gradient
for AR. Also rapid LV filling from AR causes early closure of
the mitral valve so that s1 is soft. Yet if preclosure of the
mitral valve is confirmed echocardiographically, the progno-
sis without AVR is dire.86 While medical therapies to stabi-
lize the patient are often attempted, they usually fail.
Vasodilators used to decrease the amount of AR also reduce
systemic blood pressure in patients who are often hypoten-
sive to begin with. Pressor agents with vasoconstrictor prop-
erties increase the amount of AR and thus are deleterious.
On the other hand, delay in performing AVR because of fear
that the replacement valve will become infected is unjusti-
fied because reinfection even with valve insertion within 48
hours of a positive blood culture is extremely rare, especially
when a homograft is inserted.87 Thus in acute AR, extreme
a o r t i c va lv e d i s e a s e 389
82 ± 5%
73 ± 7%
Class 40 ± 8%
I-II 40 ± 9%
III-IV
p < .0001 p = .023
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Years
vigilance for the earliest evidence of heart failure must be
practiced, and steps toward AVR must be initiated as soon as
such evidence is recognized.
Obesity Drugs, Valvular Heart Disease,
and Pulmonary Hypertension
Fenfluramine and Phentermine
The appetite-suppressants dexfenfluramine and the combi-
nation of fenfluramine and phentermine (Fen/Phen) have
been associated with an unanticipated outbreak of valvular
heart disease associated with their administration.88 Pulmo-
nary hypertension occurs in association with another appe-
tite suppressant, aminorex fumarate.89 Aminorex (Menocil)
resembles epinephrine and amphetamine in chemical struc-
ture, and its toxic effects have been attributed to the release
of norepinephrine and other catecholamines.90 Aminorex
became available in 1965 in Austria, Germany, and Switzer-
land, and in the next 7 years the incidence of pulmonary
hypertension increased by approximately 10-fold.89 Pulmo-
nary hypertension in humans associated with aminorex use
often progresses, but it may regress when the drug is discon-
tinued. Fen/Phen usage has also been associated with the
development of pulmonary artery hypertension.91
In the mid-1990s, more than 18 million prescriptions
were filled for Fen/Phen, mainly for overweight women.91
There had already been occasional reports of pulmonary
hypertension in association with the use of fenfluramine92
and phentermine alone.93 Connolly et al.88 from the Mayo
Clinic had already published a series of patients taking Fen/
Phen who had developed left ventricular valvular lesions,
most frequently aortic insufficiency, but also mitral insuffi-
ciency that was sometimes severe enough to require surgical
valve repair or replacement. The cardiac valve lesions in
patients who have taken Fen/Phen are very similar to those
seen in patients with metastatic carcinoid tumors, and both
appear to be a consequence of very high serotonin concentra-
tions in the blood.93,94 It appears that selected appetite sup-
pressant drugs, such as Fen/Phen, diminish the ability of the
lungs to extract serotonin from the circulation.95 It has been
speculated that (1) an inherited susceptibility to aminorex
and fenfluramine predisposes individuals to vasoconstric-
tion and obliterative pulmonary vascular lesions predomi-
nantly in the precapillary muscular arteries and arterioles of
390 chapter
the lungs; and (2) impaired clearance by the lungs of biologi-
cally active substances, such as serotonin, enables toxic con-
centrations of the agent to reach and damage LV heart valves,
leading to aortic or mitral valvular regurgitation.91
Based on data showing the prevalence of abnormal valve
regurgitation of approximately 30% in 291 patients treated
with dexfenfluramine, dexfenfluramine phentermine, or fen-
fluramine-phentermine as compared to 2% in controls, fen-
fluramine and dexfenfluramine were withdrawn from the
market in 1997.96,97 Efforts to identify the incidence of aortic
or mitral valve regurgitation in patients using dexfenflura-
mine have suggested that 7.6% of patients using dexfenflu-
ramine and 2% of controls develop at least aortic or mitral
insufficiency, with mild AR being the most frequent lesion.96
Other factors also related to the development of valvular
heart disease in these patients include older age, higher blood
pressure, and shorter time from discontinuation of the
drug.96
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 1 Pulmonary and Tricuspid
6 Valve Disease
Otto M. Hess, Urs Scherrer, Pascal Nicod, and
Blase A. Carabello
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
Key Points
• Pulmonary regurgitation secondary to dilatation of the
valve ring in patients with severe pulmonary hyperten-
sion and in those with severe mitral valve disease is the
most common pulmonary valvular abnormality.
• Tricuspid stenosis is usually rheumatic in origin, but it
is also seen in patients with carcinoid heart disease.
• Tricuspid regurgitation is seen with dilatation of the
right ventricle, tricuspid annulus, right atrial myxoma,
endocarditis, carcinoid syndrome, Ebstein’s anomaly, and
myxomatous degeneration of the tricuspid valve leaflets
and supporting structures.
Pathophysiology
Acquired pulmonary valve disease is extremely rare. Occa-
sionally, rheumatic inflammation may be seen, but this
rarely leads to serious deformity. Infective endocarditis and
leaflet destruction of the pulmonic valve may be observed in
drug addicts. Thickening or retraction of the pulmonary
valve leaflets has also been described in patients with carci-
noid syndrome.1 Finally, low-pressure pulmonary regurgita-
tion may be observed in patients with dilatation of the
valvular ring, as in idiopathic dilatation of the pulmonary
artery, in connective tissue disorders, or after valvotomy for
pulmonary stenosis.
By far the most common disorder is pulmonary regurgita-
tion secondary to dilatation of the valvular ring in patients
with pulmonary hypertension or severe mitral valve disease.
This disorder, called high-pressure pulmonary regurgitation,
is usually overshadowed by the underlying disease and is
characterized by a high-pitched diastolic murmur (Graham
Steell’s murmur).
Tricuspid stenosis is usually rheumatic in origin and is
typically accompanied by mitral stenosis. It is also seen in
patients with carcinoid syndrome. A reduction in tricuspid
valve area to less than 1.5 cm 2 is usually associated with an
Natural History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
Medical/Surgical Treatment . . . . . . . . . . . . . . . . . . . . . . . 395
increase in right atrial pressure. Severe tricuspid stenosis is
present if valve area is less than 1 cm2. Under these circum-
stances, right atrial pressure increases to 10 mm Hg or greater,
and venous congestion with peripheral edema and ascites
occurs.
Tricuspid regurgitation can be relative or organic. By far,
the most common cause is relative tricuspid regurgitation
secondary to dilatation of the right ventricle (RV) and the
tricuspid annulus, often associated with pressure or volume
overload of the RV. Organic tricuspid regurgitation is usually
more severe and may be caused by right atrial myxoma,
endocarditis, carcinoid syndrome, Ebstein’s anomaly, or
myxomatous degeneration of the tricuspid valve leaflets and
supporting structures.
Physiologic pulmonary or tricuspid regurgitation in
normal individuals is common and can be found in 80%
(pulmonary) to 95% (tricuspid valve) of all subjects.
Physical Examination
Pulmonary Valve Disease
Physical findings of pulmonary regurgitation vary according
to the presence or absence of pulmonary hypertension. The
carotid pulse is usually normal unless cardiac output is
decreased. Jugular venous pressure may be normal or
increased when tricuspid valve disease or RV failure is
present. A prominent A wave can be seen with pulmonary
hypertension. A parasternal RV impulse may be present, and
a pulsatile pulmonary artery may be felt in the second left
intercostal space. On auscultation, the pulmonary compo-
nent of S2 is usually normal and delayed, causing variable
wide splitting of S2. If significant pulmonary hypertension
is present, P2 becomes louder with narrow splitting of S2.
An ejection click and an S3 may be heard. The regurgitant
murmur, in the absence of pulmonary hypertension, follows
S2 in a crescendo-decrescendo pattern with a medium pitch
and is best heard in the third and fourth left intercostal
393
394 chapter 16

spaces.2,3 When pulmonary hypertension is present, the

murmur becomes decrescendo and has a higher pitch, similar
to that of aortic insufficiency.
When pulmonary stenosis is associated with pulmonary
regurgitation, a thrill may be felt in the second left intercos-
tal space. An ejection click is usually not heard in acquired
mixed pulmonary stenosis and regurgitation. A systolic cre-
scendo-decrescendo murmur is found in the second left para-
sternal intercostal space, with delayed peaking. Typically,
murmurs of pulmonary valve disease increase with inspira-
tion or with inhalation of amyl nitrite.

Tricuspid Valve Disease

Tricuspid Stenosis
The physical findings of tricuspid stenosis are often obscured
by the concomitant presence of stenosis or regurgitation of
other valves. The most prominent finding is the presence of
a large A wave in the jugular veins of patients who are in
sinus rhythm (Fig. 16.1).4 The distinction from pulsating
carotid arteries can be made by concomitant palpation of the
upstroke of the carotid pulse, which follows the jugular A
wave. In patients with atrial fibrillation, jugular turgescence
may be accompanied by a slow y descent, owing to an impair-
ment of RV filling in early diastole.5
Palpation is usually normal unless associated valvular
disease is present. Occasionally, a thrill may be felt over the
left lower sternal border, and pulsation of the right atrium
may be detected in the right parasternal area. FIGURE 16.2. (A) Right-sided venous pulse pressure (VP) in a 39-
S2 may be narrowly split, with little respiratory variation year-old patient with tricuspid regurgitation. There is a prominent
V wave, followed by a rapid y descent. A phonocardiogram (Phono)
as a result of impaired RV filling. An opening snap is often reveals a holosystolic murmur. (B) Right-sided venous pressure in a
difficult to differentiate from that of mitral stenosis but may 26-year-old patient without heart disease. The A wave is typically
occur later in diastole. The diastolic murmur after the taller than the V wave. Both the x and the y descents can be seen.
opening snap is usually of low frequency, or on occasion, of ECG, electrocardiogram.
higher frequency and decrescendo. It is maximal over the

lower left sternal border. In patients with sinus rhythm, a

presystolic murmur may be heard and can be differentiated
from that of mitral stenosis by an earlier appearance, a
crescendo-decrescendo pattern, and termination before S1.4
The murmur of tricuspid stenosis and the opening snap
typically increase in intensity with deep inspiration (Car-
vallo sign). All other maneuvers that cause an increase in
cardiac output, such as leg raising, exercise, and inhalation
of amyl nitrite, also increase the intensity of the murmur
and the opening snap, whereas the Valsalva maneuver and
sudden standing position decrease their intensity.

FIGURE 16.1. Right-sided venous pulse pressure in a 39-year-old
patient with tricuspid stenosis. The A wave is predominant, and the
y descent is decreased. On the phonocardiogram, a diamond-shaped
presystolic rumble can be appreciated. P waves on the electrocardio-
gram are suggestive of right atrial enlargement.
Tricuspid Regurgitation
Tricuspid regurgitation is often associated with pulmonary
hypertension or other valvular lesions. Prominent jugular V
waves may be seen in the neck (Fig. 16.2).5–7 They should be
differentiated from the A wave of tricuspid stenosis by their
slower upstroke and their appearance after the carotid pulse
and in association with the second heart sound. They may
be accompanied by a pulsatile liver and signs of RV failure.
The y descent is also present. The RV impulse may be promi-
nent and hyperdynamic. A systolic right atrial impulse may
 p u l m o n a r y a n d t r i c u s p i d va lv e d i s e a s e
FIGURE 16.3. Phonocardiographic recording (Phono) in a patient
with tricuspid regurgitation. There is a marked inspiratory increase
of the intensity of the murmur (Carvallo sign), followed by a third
heart sound. The right atrial (RA) pressure recording shows no
inspiratory fall in pressure, whereas right ventricular (RV) systolic
pressure increases during inspiration. ECG, electrocardiogram.
rarely be felt in the right parasternal area. On auscultation,
P2 may be increased in presence of pulmonary hypertension.
A prominent S3 that increases with inspiration may be heard.
The murmur is usually holosystolic and located in the lower
left parasternal area but may be heard over the lower sternum
and the subxiphoid area. Occasionally, it may be early sys-
tolic, particularly in the presence of acute tricuspid regurgi-
tation, or limited to midsystole or even late systole.
Sometimes, a diastolic flow rumble may be heard, as a result
of increased diastolic flow across the tricuspid valve.
The murmur typically increases with deep inspiration
(Carvallo sign) as a result of increased venous return (Fig.
16.3) and decreases with the Valsalva maneuver. However,
this inspiratory increase in the intensity of the murmur may
be lacking in the presence of markedly elevated venous
pressure.
Natural History
The natural history of pulmonary and tricuspid valve disease
is dependent on the underlying disorder. Acquired pulmo-
nary valve disease is extremely rare. Pulmonary or tricuspid
regurgitation due to infective endocarditis may be seen in
drug addicts or after surgical interventions. In the absence
of pulmonary hypertension, tricuspid regurgitation is usually
well tolerated for many years. However, when pulmonary
hypertension and tricuspid regurgitation coexist, right-sided
congestive heart failure, with reduced cardiac output and
painful congestive hepatomegaly, may occur.8 In patients
with combined tricuspid regurgitation and mitral valve
disease, the natural history is usually determined by the
latter.
395
Medical/Surgical Treatment
Mild tricuspid or pulmonary valvular insufficiency does not
require specific therapy other than antibiotic prophylaxis
against subacute bacterial endocarditis before dental work or
surgery. Hemodynamically significant tricuspid or pulmo-
nary insufficiency in the presence of pulmonary hyper-
tension is best treated with vasodilators and unloading
interventions, such as angiotensin-converting enzyme inhib-
itors, nifedipine, hydralazine, and prazosin, with or without
nitrates. In the absence of important pulmonary arterial
hypertension, the use of the same vasodilators with an ino-
tropic agent, such as cardiac glycosides, may be useful, espe-
cially if atrial fibrillation is present. With severe tricuspid or
pulmonary valvular insufficiency and RV failure, surgical
replacement or repair of the leaking valve may be required.
Hemodynamically important valvular pulmonic or tricuspid
stenosis with associated limiting symptoms is treated by
valvuloplasty or sometimes by surgical replacement or repair
of the valve.
The reader is referred to the Web sites of the American
College of Cardiology (ACC) (www.acc.org) and the Ameri-
can Heart Association (AHA) (www.americanheart.org) for
the ACC/AHA Guidelines for the Management of Patients
with Acute Myocardial Infarction.
Acknowledgments
This chapter was adapted from the corresponding chapter in
the previous edition.
References
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komplex? Schweiz Med Wochenschr 1953;83:4.
2. Nemickas R, Roberts J, Gunnar RM, Tobin JR. Isolated con-
genital pulmonic insufficiency: differentiation of mild from
severe regurgitation. Am J Cardiol 1964;14:456.
3. Bousvaros GA, Deuchar DC. The murmur of pulmonary regur-
gitation which is not associated with pulmonary hypertension.
Lancet 1961;2:962.
4. Perloff JK, Harvey WP. Clinical recognition of tricuspid steno-
sis. Circulation 1960;22:346.
5. Messer AL, Hurst JW, Rappaport MB, et al. A study of the venous
pulse in tricuspid valve disease. Circulation 1950;1:388.
6. Schilder DP, Harvey WP. Confusion of tricuspid incompetence
with mitral insufficiency: a pitfall in the selection of patients
for mitral surgery. Am Heart J 1957;54:352.
7. Amidi M, Irwin JM, Salerni R, et al. Venous systolic thrill and
murmur in the neck: a consequence of severe tricuspid insuf-
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8. Braunwald E. Heart Disease, 5th ed. Philadelphia: WB
Saunders, 1997.
 1 Mitral Valve Diseases
7 Maurice L. Enriquez-Sarano and
Robert L. Frye

The Normal Mitral Valve . . . . . . . . . . . . . . . . . . . . . . . . . 397 Mitral Regurgitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407

Mitral Valve Prolapse. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402

Key Points free edge and a central clear zone toward the base. The ante-
rior leaflet occupies only one third of the circumference of
• The predominant cause of mitral stenosis is rheumatic
the annulus but is longer than the posterior leaflet so that
heart disease.
the leaflet apposition (coaptation) is along an upward concave
• The most frequent ECG abnormality with mitral stenosis
curve resembling a smile. The anterior leaflet is attached by
is atrial fibrillation.
a fibrous connection to the aortic annulus (intervalvular
• The occurrence of atrial fibrillation (or atrial flutter) in
fibrosa). The posterior leaflet is attached to the mitral annulus
the patient with atrial fibrillation requires anticoagula-
above which the valve tissue is a continuation of left atrial
tion initially by heparin followed by coumadin and often
endocardium. The separations between leaflets (the commis-
of treatment aiming at control of rapid ventricular
sures) are anterolaterally and posteromedially positioned.2
response using digoxin, beta-blockade, and calcium-
The posterior leaflet is composed of three scallops, antero-
channel blockade.
lateral (P1), medial (P2), and posteromedial (P3). The anterior
• Guidance by transesophageal echocardiography (TEE) is
leaflet has no scallops but the zones coapting with the pos-
useful to rule out atrial thrombus before cardioversion.
terior scallops are similarly called A1 to A3. The leaflets are
• Prolapse of the mitral valve is a fall below its normal
thin, pliable, and have no inertia so that full opening is
position, and billowing (bulge beyond its normal place) of
obtained immediately in diastole. The leaflets are attached
the mitral valve is an abnormal movement of the mitral
to chordae tendineae by their tip (primary) or their body
valve during systole beyond its normal position and into
(secondary). The chordae are attached to the two papillary
the left atrium.
muscles (anterolateral and posteromedial), which provide
• Often mitral valve prolapse is a progressive disease with
chordae to both leaflets at and around each commissure.3
flail leaflets and chordal rupture being found in older
The papillary muscles are attached to the left ventricle (LV)
patients.
wall. The mechanisms ensuring competence of the mitral
• Mitral insufficiency is an organic mechanism if there is
valve are the preclosure following atrial contraction, which
intrinsic mitral valve disease or a functional mechanism
allows the leaflets to approximate before the ventricular con-
if the valve is structurally normal but regurgitates due to
traction; the orientation of the anterior leaflet, parallel to the
an extravalvular abnormality.
flow, which slides on its ventricular surface in systole; and
• Surgical correction of mitral regurgitation (MR) is indi-
the coaptation on rough zones of the atrial surface, creating
cated in patients with severe MR and symptoms or with
strong but passive friction resistance when the leaflets are
reduced LV systolic function.
apposed. The leaflets are composed of four layers: auricularis,
• Prevention of infective endocarditis using the appropriate
spongiosa, fibrosa, and ventricularis.
antibiotic prophylaxis is necessary in patients with MR.
The auricularis is composed of collagen and elastic tissue
• The most frequent cause of mortality after surgical cor-
and is continuous with the endocardium of the left atrium.
rection of MR is left ventricle dysfunction due to chronic
The spongiosa is situated between the auricularis and fibrosa
irreversible myocardial damage.
layers and is formed by a loose connective tissue. The fibrosa
constitutes the basic support for the leaflet and is composed
The Normal Mitral Valve of thick collagen. This layer is continuous at its base with
the mitral annulus and the intervalvular fibrosa and at its
The mitral valve has two leaflets (Fig. 17.1) attached at their free edge with the chordae tendineae. The ventricularis is a
bases to a fibrous annulus and by their free edges to their thin layer of collagen and elastic tissue that covers the ven-
chordae tendineae.1 Each leaflet has a rough zone toward the tricular aspect of the fibrosa and is continuous beyond the

397
398 chapter
FIGURE 17.1. Anatomic ventricular view of a normal mitral valve.
The commissures (C) are closed by a narrow band of valvular tissue.
Ant Leaf, the anterior leaflet, the longest and narrowest; Post Leaf,
the scallops of the short but widest posterior leaflet; PM, the two
papillary muscles situated in regard to the commissures and distrib-
uting chordae to the corresponding parts of both leaflets. Chordae
are indicated by arrows.
posterior leaflet with the left ventricular endocardium and
is part of the fibrosa.4
Mitral Stenosis
Pathophysiology
The predominant cause of mitral stenosis (MS) is rheumatic
heart disease. The valvular lesions produced by the rheu-
matic process in patients with MS are characterized by com-
missural fusion, which directly cause the stenosis.5 There is
also tissue retraction of leaflets and chordae tendineae, fusion
of chordae, and ultimately postinflammatory calcification,
which combined determine the feasibility of interventional
or surgical treatment.5 The commissural fusion is responsible
for the reduction of mitral orifice size during diastole and
also for the loss of physiologic valvular reserve (larger open-
ing with larger flow) characterized by fixed mitral orifice
irrespective of blood flow.6,7 The major hemodynamic con-
sequence of MS is left atrial (LA) pressure elevation, which
when greater than 25 to 30 mm Hg is responsible for transuda-
tion of fluid into the pulmonary interstitial space. Left atrial
pressure is determined by the transmitral diastolic pressure
gradient, governed mostly by the orifice area and also by dura-
tion of diastole and stroke volume transported through the
orifice.8,9 Tachycardia decreases diastolic time and for a given
stroke volume augments transmitral diastolic flow rate, pres-
sure gradient, and LA pressure.10 Increased stroke volume for
any given diastolic filling period (such as with pregnancy or
anemia) increases transvalvular velocity linearly with flow,
but as pressure gradient is a square function of velocity, may
lead to marked LA pressure elevation.11
When the mitral orifice (normally 4 to 6 cm2) is reduced
to 2 to 2.5 cm2 (mild MS), LA pressure is normal under resting
conditions, but may increase abnormally with excess blood
flow or heart rate changes. With orifices of 1.5 to 2.0 cm2
(moderate MS), LA pressure, mildly elevated at rest, may
17
increase markedly with sustained exercise. When the mitral
orifice is <1.5 cm2 (moderately severe to severe MS), LA pres-
sure is augmented at rest, and pressure gradients of more
than 10 mm Hg can be observed. Such patients have often
reduced cardiac output and dyspnea during mild exercise or
even at rest. For any given orifice area, previously asymptom-
atic patients may suddenly become symptomatic if they
become pregnant, infected, or anemic or develop atrial fibril-
lation with rapid ventricular response.
Left atrial response to MS with chronic elevation of LA
pressure is characterized by LA dilatation, which in turn is
a compensatory mechanism normalizing LA compliance12
and activating natriuretic peptides.13 However, LA dilatation
may also have deleterious consequences with reduced blood
flow and increased local coagulability,14,15 which may lead to
thrombus formation and with reduced electrical stability
which may lead to atrial fibrillation. Also, increased LA
transport function plays an important hemodynamic role in
MS. Left atrial contraction augments end-diastolic mitral
blood flow and maintains stroke volume despite reduced
orifice area. Occurrence of atrial fibrillation, even with
acceptable ventricular response, is responsible for approxi-
mately a 20% decrease in cardiac output. Therefore, mainte-
nance of sinus rhythm is important for the well-being of
patients with MS. Conversely, left ventricular dysfunction is
not a major concern in MS. Although ejection fraction may
be reduced, it is mostly an unloading phenomenon, is usually
not progressive, and has modest effects on outcome.16
Pulmonary vascular response to chronically elevated LA
pressure leads to increased pulmonary vascular resistance
and excessively elevated pulmonary pressure, which in turn
may lead to right ventricular dilatation, tricuspid annular
dilatation, and functional tricuspid regurgitation, and ulti-
mately may lead to global heart failure.17
Mitral stenosis is a progressive disease with progressive
commissural fusion leading to a reduced valve area, which
is amplified by periorificial calcifications and by subvalvular
obstruction to flow due to chordal fusion and retraction.18
Natural History
The natural history from the initial rheumatic fever episode
to the development of MS is reputed to be slow, taking a
decade or much longer in developed countries, whereas in
developing countries19 the disease may progress more
rapidly,20,21 and severe MS may already be present in early
adolescence.22 This difference may be due to differences in
utilization of antibiotics, recurrent carditis, virulence of bac-
terial strains, or genetic factors, but is attested to by differ-
ences in age at intervention in various world regions. This
reduced MS development in developed countries has resulted
in a major decline in the prevalence of MS requiring medical
attention.
The natural history of patients with established MS and
medically managed has been defined by retrospective studies
conducted in the 1950s and 1960s.23,24 Mitral stenosis is a
progressive disease with a slow, lifelong course that is ini-
tially asymptomatic and subsequently punctuated by acute
complications or evolving into symptoms development.
Once mitral stenosis has become symptomatic, it takes
approximately 5 to 10 years for most patients to progress
 m i t r a l va lv e d i s e a s e s
from mild to severe disability. In these natural history
studies, survival has been analyzed according to the develop-
ment of symptoms, but information regarding the influence
of mitral valve area, LA size, or pulmonary pressure is
lacking. Ten years after diagnosis in asymptomatic or mini-
mally symptomatic patients, rates of mortality and of new
symptoms are 20% and 40%, respectively. In the presurgical
era, 5-year mortality rates were 38% in mildly symptomatic
patients and 85% in severely symptomatic patients. The
cause of death in these series was heart failure in 60% to
70% and thromboembolism in 20% to 30%.
Clinical Evaluation
The diagnosis of MS may be based on abnormal physical
examination or Doppler echocardiography with symptoms
either absent or nonspecific, such as fatigue or chest pain.
Most patients are diagnosed with MS because of exertional
dyspnea and more rarely because of complications such as
pulmonary edema, hemoptysis, global heart failure, atrial
fibrillation, or an embolic event (Table 17.1).
The general appearance of patients with critical MS, the
“facies mitralis” with malar cyanosis, is now exceptionally
observed. Inspection of jugular veins may show prominent
A waves in patients with pulmonary hypertension and in
sinus rhythm or large V waves in patients with severe func-
tional tricuspid regurgitation. Jugular vein distention, periph-
eral edema, and liver enlargement appear in patients with
heart failure. Precordial palpation may reveal a right ven-
tricular heave in patients with right ventricular dilatation, a
palpable S2 with severe pulmonary hypertension, and at the
apex a palpable S1 and rarely a diastolic thrill found while
the patient lies on the left side.
Auscultation reveals25,26 a characteristically S1 accentu-
ated (due to the mitral thickening and wide closure move-
ment with elevated LA pressure), but which may be normal
or reduced with decreased leaflet mobility. S2 is usually
normal, but with pulmonary hypertension accentuation of
the pulmonary component may be noted. An opening snap
follows S2, is best heard at the apex, and is usually high-
pitched but may be attenuated when valve excursion is
limited by thickening or calcification. However, it rarely
disappears and it may be the only auscultatory finding in
TABLE 17.1. Clinical syndromes of mitral stenosis (MS) presentation
Edematous MS
Presentation 20–30-year-old; no symptoms
until pulmonary edema
Physical examination Loud S1 and OS
Loud rumble
ECG Sinus; LA enlargement
Chest x-ray Small heart; LA enlarged
Echo-Doppler Small MVA, large gradient;
no MR; no calcification
Follow-up Balloon mitral valvuloplasty
LA, left atrium; MR, mitral regurgitation; MS, mitral stenosis; MVA, mitral valve area; OS, opening snap; PBMV, percutaneous mitral balloon valvuloplasty;
RA, right atrium; TR, tricuspid regurgitation.
399
patients with markedly reduced cardiac output. The time
interval between A 2 and the opening snap is an indicator of
LA pressure and is most often 0.08 second with mildly ele-
vated LA pressure. Intervals <0.06 and >0.10 second suggest
respectively severe and minimal LA pressure elevation.
Thus, the A 2 opening snap interval, best measured by pho-
nocardiography (or estimated at the bedside on physical
examination), is an indirect measure of MS severity. A dia-
stolic rumble can be best heard while the patient lies on the
left side; it follows the opening snap and decrescendo, and
displays presystolic accentuation in sinus rhythm. With a
smaller mitral valve area the rumble is more holodiastolic,
and with a higher gradient it is more intense. However, a
holodiastolic rumble may be present in mild mitral stenosis
and tachycardia. The diastolic rumble may be difficult to
hear with increased heart-skin distance (obesity or emphy-
sema) but may be of low intensity with low cardiac output-
low gradient. With markedly reduced output in patients with
calcified leaflets of reduced mobility, MS may be silent, and
the only clue to the presence of MS may be a faint opening
snap. Systole is usually silent, but a systolic murmur (apical,
early systolic with mild mitral regurgitation or xiphoid with
inspiratory accentuation with tricuspid regurgitation) may
be heard. An associated diastolic murmur may be heard
along the left sternal border either due to pulmonary insuf-
ficiency (Graham Steell’s murmur) with severe pulmonary
hypertension or due to the frequently associated aortic regur-
gitation. Thus, it is usually possible to obtain a strong clini-
cal impression of severe MS with loud and holodiastolic
rumble with a thrill, short A 2-opening snap interval, loud S2,
and tricuspid regurgitant murmur, but all these signs can be
observed with moderate stenosis and increased cardiac
output due to pregnancy, infection, or anemia.
The most frequent ECG abnormality is atrial fibrillation.
In sinus rhythm a prolonged P wave is due to LA enlarge-
ment. With pulmonary hypertension, a P pulmonale (tall P2,
P2 > P3 > P1), a right axis deviation of QRS, and a tall R wave
in V1 with negative T’s in V1 to V3 may be observed.
The chest radiography may show LA dilatation, creating
a double contour, widening of the carina, and LA appendage
dilatation along the left sternal border. While the heart
size is usually normal, marked LA, right atrial, and ventric-
ular dilatation may result in frank cardiomegaly. With
Fibrotic MS Silent advanced MS
40–50-year-old; mild dyspnea 70–90-year-old
with exertion Class IV CHF
Audible S1 and OS Soft OS
Moderate rumble No rumble, decreased S1
Pulsatile liver
Atrial fibrillation Atrial fibrillation
Marked LA and RA enlargement Marked cardiomegaly
Small MVA, modest gradient at Critical MS with massive calcification
rest, MR present; commissural Severe pulmonary hypertension and TR
calcifications
PBMV or surgery depending on MVR
MR and calcification
400 chapter
FIGURE 17.2. Echocardiographic long-axis view of the mitral valve
in a patient with mitral stenosis. The large arrows indicate the
leaflet tip thickening, typical of rheumatic mitral involvement and
the small arrows indicate the diastolic hockey-stick deformation
due to the restriction of movement of the anterior leaflet due to
commissural fusion. Left atrium (LA) is markedly enlarged with
normal left ventricular (LV) size suggestive of severe stenosis. Ao,
aorta. Note the associated thickening of the aortic valve, suggestive
of rheumatic disease.
pulmonary hypertension, pulmonary trunk and branch dila-
tation and cephalization of the pulmonary circulation are
present and often associated with interstitial markings of
pulmonary edema and pleural effusion.
Doppler echocardiography is the core test allowing posi-
tive diagnosis and assessing the severity and morphology of
MS. Imaging shows the features of rheumatic disease (Fig.
17.2) with valvular thickening (predominant early on leaflet
tips), retraction, and reduced mobility (particularly of poste-
rior leaflet). Mitral stenosis diagnosis is based on doming of
the anterior leaflet, direct planimetry of the stenotic mitral
orifice, and increased diastolic velocity (and gradient) through
the mitral valve.27 Assessing MS severity can rely on several
methods. First, mitral orifice planimetry (Fig. 17.3) in the
Area = 1.5 cm2
Scale
RV
LV
Planimetered
mitral orifice
FIGURE 17.3. Echocardiographic short-axis parasternal view in a
patient with mitral stenosis. The image is obtained at the leaflet tip
to allow planimetry of the mitral orifice. RV and LV, right and left
ventricle.
17
FIGURE 17.4. Doppler measurement of mitral transvalvular gradi-
ent in a patient with severe mitral stenosis in sinus rhythm. The
transvalvular velocity is in excess of 2 m/sec and the mean gradient
is calculated at 13.8 mm Hg.
short axis view is simple but requires delicate positioning at
the tip of the mitral funnel.28–30 The value of three-dimen-
sional echocardiography is currently being evaluated,31 and
may improve with enhanced image quality. Second, Doppler
allows measurement of the transvalvular gradient (Fig. 17.4)
and the pressure half-time method of measurement of the
mitral valve area (Fig. 17.5) uses the velocity decay in early
diastole and is most frequently used,32 but may be affected
by associated aortic regurgitation33 or alterations of LV and
LA compliance, particularly after balloon valvuloplasty.34
Third, the continuity equation measures the orifice area as
the ratio of the aortic stroke volume to the mitral stenotic
jet time velocity integral by Doppler. It may be affected by
underestimation of stroke volumes or by frequent presence
of aortic regurgitation. Fourth, the proximal isovelocity
FIGURE 17.5. Doppler measurement of the mitral valve area by the
pressure half-time method. The slope of deceleration of the trans-
mitral velocity indicates a pressure half-time of 223 ms, which
calculates a mitral valve area of 1.0 cm 2.
 m i t r a l va lv e d i s e a s e s
surface area (PISA) method uses color flow imaging of the
flow convergence proximal to the mitral orifice to measure
transvalvular flow (Fig. 17.6), the ratio of which to transval-
vular velocity provides the orifice area.35,36 Complex angular
correction tends to limit its accuracy and reproducibility.
Because all of these methods have a notable range of error, it
is prudent to use two or more methods and average them to
estimate the mitral diastolic valve area.
An important measure of MS severity is the mean trans-
valvular gradient, measured by continuous-wave Doppler
(Fig. 17.4) as the average of multiple beats. The mean gradient
should be interpreted carefully depending on cardiac output
(lower gradient with reduced output) and heart rate (increased
gradient with higher rate). If necessary, assessment of mean
gradient with exercise (using a graded recumbent bike proto-
col)37 or dobutamine stress38 shows rapid and marked gradi-
ent increase related to the heart rate and output increase in
severe MS. Assessing MS morphology relies on the complete
description of leaflets, commissures, chordae, and papillary
muscle.39 The valve score is a number between 4 and 16 (from
lightest to most severe alteration) obtained by summing the
scores between 1 and 4 for the leaflets’ thickening, lack of
mobility, and calcification, and for subvalvular alteration.40
Scores above 8 to 10 are usually considered as precluding
balloon valvuloplasty.41 Calcification location and severity
assessment is crucial, because minor or unicommissural cal-
cifications do not limit valvuloplasty, while bicommissural,
diffuse, or severe calcifications usually preclude good results
of valvuloplasty.42,43 Presence and severity of mitral regurgi-
tation (MR) are assessed by color flow imaging, if necessary
using transesophageal echocardiography (TEE) in patients
with uncertain transthoracic assessment. The presence of LA
thrombus, particularly in the appendage, is assessed by TEE
before valvuloplasty and in patients with recent thromboem-
bolic complications.44,45 Echocardiography should also dif-
ferentiate true MS with commissural fusion from mitral
obstruction due to protrusive mitral annular calcification,
FIGURE 17.6. Doppler echocardiographic measurement of the
mitral valve area using the proximal flow convergence (proximal
isovelocity surface area, PISA) method in a patient with mitral ste-
nosis. The color flow image (left) is obtained with an upward shift
of the baseline allowing the measurement of the radius of the flow
convergence (double-head arrow), which allows calculation of the
diastolic transvalvular flow. Measurement of the transvalvular
velocity using continuous-wave Doppler (right) facilitates calculat-
ing the mitral valve area as the ratio of flow to velocity.
4 01
C(17) LV C(9) 0.5m/s LV
D(9) PCWP D(8)
50 50
LA
0 0
FIGURE 17.7. Pressure curve tracing obtained by catheterization
with simultaneous continuous-wave Doppler recording. The left
curves show a gradient measured simultaneously between the pul-
monary capillary wedge pressure (PCWP) and left ventricular (LV)
pressure. The gradient by catheterization (C), overestimates the
Doppler (D) gradient. The right curves show a gradient obtained
between the left atrial (LA) and LV pressures. The gradient by cath-
eterization and Doppler are identical.
which is degenerative without commissural fusion and
cannot be treated by balloon valvuloplasty.
Cardiac catheterization, which was the first method to
measure mitral valve area,46,47 is now rarely necessary for the
diagnosis or for severity assessment of MS.48 It is usually part
of pre–balloon-valvuloplasty assessment. It allows direct
verification of mitral gradient between LA and LV (Fig. 17.7)
of pulmonary pressures and resistance and of MR severity
by LV angiography. Coronary angiography may be performed
depending on the patient’s age and symptoms, particularly if
surgery is considered.
Management
Mitral stenosis is a mechanical obstruction to mitral inflow,
which should be relieved by a mechanical intervention
(balloon valvuloplasty, commissurotomy, or valve replace-
ment), indicated when the MS is severe and the patient pre-
sents with overt clinical consequences of the MS. As LV
dysfunction is not a major outcome issue in MS, interven-
tions in asymptomatic patients are rarely needed.
Medical management aims at avoiding symptoms and
complications. Appropriate rheumatic fever and infective
endocarditis prophylaxis are needed. Limitation of physical
activity and of salt intake, combined with low-dose diuretic
administration, allows maintenance in a minimally symp-
tomatic status sometimes for years. Patients with symptoms
associated with marked tachycardia10 with activity can
benefit from beta-blockade.49,50 The occurrence of atrial fibril-
lation (or flutter) requires administration of anticoagulation
initially by heparin followed by Coumadin51 and often of
treatment aiming at control of rapid ventricular response
using a combination of digoxin, beta-blockade, and calcium-
channel blockade. Cardioversion covered by anticoagulation
may be required urgently in patients with poor tolerance and
is otherwise considered in patients with recent (<3 months)
arrhythmia and without major atrial dilatation. Guidance
by TEE is useful to rule out atrial thrombus before car-
dioversion. As atrial arrhythmias are markers of disease
402
progression, recurrence should lead to the consideration of
mechanical intervention rather than repeated cardioversion.
Atrial fibrillation, even paroxysmal or a history of embolic
events, requires permanent anticoagulation.
Interventional treatment using percutaneous valvulo-
plasty with Inoue balloon (Fig. 17.8), or more rarely commis-
surotomy,52 opens the commissural fusion mostly unilaterally
and is the mainstay of mechanical obstruction relief cur-
rently. The most frequent approach is through transseptal
catheterization with preprocedural TEE to rule out the pres-
ence of atrial thrombus, and echo guidance to progressively
open the mitral orifice (Fig. 17.9) without inducing new
mitral regurgitation.53 Procedural mortality is <1% in high
volume centers, and good results (orifice area >1.5 cm2 with
MR <2+) are obtained in ≥85% of patients,54–56 and these
results are identical to those of surgical commissurotomy.57–
59
Postprocedural MR is often the result of valvular tears60
and may require urgent surgical intervention.54,61 The proce-
dure is indicated in patients with MS with a valve area
<1.5 cm2, with class III or IV symptoms, or transient heart
failure without atrial thrombus and with acceptable valvular
anatomy (valve score ≤8, no bicommissural calcification, and
MR <2+). Symptoms or severe exertional limitations may be
unveiled by exercise testing in patients with “asymptom-
atic” MS62 but with notable pulmonary hypertension. Patients
who complain of no dyspnea but who present with embolic
events and severe MS are also candidates for intervention
after anticoagulation. The quality of the immediate result is
mostly dependent on valvular anatomy,54,63,64 while that of
long-term result depends on age, heart failure at presenta-
tion, baseline anatomic characteristics, and the quality of
the immediate result.19,65 Patients with advanced valve score
may have short-term benefit but incur a high rate of second-
FIGURE 17.8. Percutaneous balloon valvuloplasty using the Inoue
balloon and the transseptal approach. The sequence is as follows:
upper left, the positioning of the balloon through the mitral orifice;
lower left: inflation and pull back of the distal component of the
balloon; upper right: partial inflation showing the marking of the
mitral orifice on the balloon; lower right: complete inflation for
commissural opening.
chapter 17
FIGURE 17.9. Echocardiographic examination post–balloon valvu-
loplasty in short axis view. RV, right ventricle: mv, mitral valve.
Note the large mitral orifice with the large commissural opening of
the medial commissure indicated by the arrow. The cross indicates
the orientation (A, anterior; P, posterior; L, left; R, right).
ary degradation.66 Long-term restenosis following surgical or
percutaneous commissurotomy may benefit from repeated
percutaneous intervention if the anatomic characteristics
remain adequate.55 Percutaneous valvuloplasty may be per-
formed during pregnancy with minimal irradiation and with
good maternal and fetal clinical results.67,68 At 10 years the
event-free survival after percutaneous valvuloplasty is 56%,
implying that after the procedure continued careful follow-
up is necessary.19
Surgical treatment, which has been lifesaving in the
initial phase of commissurotomy development,69–71 is rarely
indicated currently and is reserved for patients in whom
percutaneous intervention is considered contraindicated.
Open-heart commissurotomy may be performed in patients
with MS with severe subvalvular alterations requiring papil-
lary muscle splitting or with MR that may require associated
repair. However, most patients with advanced anatomic
alterations or MR ≥2+ require mitral valve replacement.
Because of the small but definite risk of interventional
or surgical treatment, patients with asymptomatic MS and
without embolic complications, even those with severe MS,
are rarely considered candidates for “preventive” interven-
tions. Asymptomatic patients with pulmonary hypertension
should be carefully evaluated, particularly with exercise
testing, to avoid underestimation of the functional limita-
tions. Therefore, indications for interventions are based on
comprehensive evaluation integrating clinical symptoms,
history of embolism, comorbidity, functional capacity, hemo-
dynamics, severity, and morphology of MS.
Mitral Valve Prolapse
The prolapse (fall below its normal position) or billowing
(bulge beyond its normal place) of the mitral valve is an
abnormal movement of the mitral valve during systole,
beyond its normal position and into the LA.72 Confusion has
 m i t r a l va lv e d i s e a s e s
surrounded mitral valve prolapse (MVP) because of terminol-
ogy (the use of the word prolapse to describe the movement
and its cause) and because of diagnostic criteria (the saddle
shape of the mitral annulus led to a false appearance of pro-
lapse and to excessive diagnoses of MVP in the 1980s). An
ensemble of etiologies causes this abnormal mitral move-
ment by a variety of mechanisms, with a variable extent and
variable consequences, so that MVP is a highly heteroge-
neous condition.73
Etiology and Mechanisms
A mitral prolapse movement requires, isolated or grouped,
any of the following mechanisms: excessive leaflet tissue,
chordal elongation or rupture, or papillary muscle elongation
or rupture.74 The etiology can be primary or secondary.
Primary MVPs have in common myxomatous degeneration,
which is diffuse or localized and is characterized by leaflet
redundancy and thickening due to an increase in spongiosa
thickness with increased hydric content,75 accumulation of
proteoglycans, and collagen alterations.74,76 The detailed
mechanisms of myxomatous degeneration are uncertain, but
alterations of matrix metalloproteinase expression in the
spongiosa suggest that the process of degradation-regenera-
tion of the matrix support tissue is dysfunctional.77 Primary
MVPs (also called floppy mitral valve) present in two forms:
(1) diffuse myxomatous degeneration (also called Barlow’s
disease), in addition to the prolapse present with extensive
valvular hooding, chordal elongation, and annular dilatation
(Fig. 17.10), and (2) localized myxomatous degeneration,
which is observed in older patients with chordal rupture
causing flail leaflets. Whether the myxomatous degeneration
causes the chordal rupture or is the consequence of the
tension on the flail leaflet is unknown, but the tissue in
patients with flail leaflets is characterized by chordae of
lower stiffness and failing at lower stress.78 However, chordal
rupture may also complicate the diffuse form of myxoma-
tous valve disease. Primary MVP has a prevalence between
0.6% and 3.5% in various echocardiographic population-
FIGURE 17.10. Anatomic posterior view of a heart showing the
mitral, tricuspid aortic and pulmonary valves, and extensive mitral
valve prolapse. Note the extensive billowing with hooding and
thickening involving both leaflets.
403
based studies,79–82 and is usually sporadic but may be famil-
ial; linkage analysis mapped loci on chromosome 11, 16, or
X associated with MVP.83–85
Secondary prolapse of mitral leaflets can be seen with
diseases, such as rheumatic disease, with the initial rheu-
matic insult or later after rupture of chordae; endocarditis
complicated by ruptured chordae; coronary disease compli-
cated by elongation or rupture of the papillary muscles;
hypertrophic cardiomyopathy, with ruptured mitral chordae;
posttraumatic chordal or papillary muscle rupture; and con-
nective tissue disorders (e.g., Marfan’s disease).
Pathophysiology
Mitral valve prolapse, although due to permanent valve
lesions, is a dynamic condition. Because the length of the
mitral apparatus is constant, the MVP often does not occur
in early systole while LV volume is close to the end-diastolic
volume. With ventricular emptying, the papillary muscles
move toward the heart’s base and center, and at a specific LV
volume the length of valve and chordae allows one or two
leaflets to billow into the LA.86 The occurrence of the pro-
lapse causes a sudden tension of chordae, producing a sound
(click) and may be followed by MR (end-systolic murmur).87,88
Even for MVPs with sufficient chordal elongation (or rupture)
to produce holosystolic regurgitation, LV emptying causes an
aggravation of the prolapse and the MR increases throughout
systole (Fig. 17.11) to culminate with the largest regurgitant
orifice at end-systole.89,90 Thus maneuvers that increase LV
volume (recumbent position, increased afterload) tend to
delay the occurrence of the prolapse, while maneuvers that
decrease LV volume (standing, vasodilators) lead to an earlier
prolapse in systole. Thus, the consequence of MVP, regarding
MR severity in individual patients, is variable during the
cardiac cycle and under the influence of changes in loading
conditions due to the magnitude of the loss of coaptation
owing to the prolapse. Similarly, MR complicating MVP is
widely different between patients due to differences in the
coaptation abnormality.73
Mitral valve prolapse is a progressive disease. The lesions
of simple MVP without flail leaflets are encountered mostly
in young patients,73 whereas flail leaflets and chordal rupture
are diagnosed mostly in older patients.91 The mechanism of
anatomic progression of MVP is unknown but it leads to
progressive MR, in particular because of the occurrence of
new ruptured chords and also because of progression of
annular dilatation.92 The overload due to MR induces LA and
LV overload and dysfunction.
Natural History
Mitral valve prolapse has been reported as carrying a high
risk of complications in hospital-based studies. More recently,
population and community studies provided a more balanced
view of the clinical outcome of MVP.73 The lifetime progres-
sion and complication rates of affected patients have not been
defined, but outcome according to initial presentation at
diagnosis is now better defined. Patients younger than 50
with MVP but no other complication display an excellent
outcome (no excess mortality and low morbidity), showing
that myxomatous degeneration of the mitral valve, in and of
404 chapter 17

FIGURE 17.11. Sequential measurement of

the regurgitant orifice throughout systole in a
patient with mitral valve prolapse showing the
progressively increasing mitral regurgitation.
The upper images show the flow convergence
diameter measurement while the lower images
show the corresponding continuous-wave
velocity, from early systole (left) to middle
systole, to mid-late systole, to late systole
(right). From early to late systole, the effective
regurgitant orifice increased from 0.52 to 0.58
to 0.78 to 1.27 cm2.

itself, is a generally benign condition.73,81,93 The major primary
risk factors and determinants of outcome are severe degree
of MR or of LV dysfunction. Risk factors of lesser severity
(secondary risk factors) are age ≥50, slight MR, LA enlarge-
ment >40 mm, atrial fibrillation, and the presence of a flail
leaflet (Fig. 17.12). Patients without major risk factors but
with two or more minor risk factors incur no excess risk of
mortality but a high risk of cardiovascular morbid events
(6.2% per year) and of MVP-related events (1.7% per year),
whereas those with major risk factors incur excess mortality
and high rates of morbidity (18.5% per year) and MVP-related
events (15% per year) even if they are asymptomatic at diag-
nosis (Fig. 17.13).73 Thus, MVP is a highly heterogeneous
condition spanning from a benign finding to a severe
disease.
The role of valve thickness in outcome is controversial.
Thickened valves have been considered as a marker of poor
outcome in the pre-Doppler era,94 probably related to the

Overall survival Cardiac survival Cardiovascular morbidity

100 p(exp) = .17 100
100 No or 1 secondary RF
95 ± 2 ≥2 secondary RF
90 80 Primary RF
84 ± 5
CV morbidity (%)

p(exp) = .20
Survival (%)

87 ± 4
80
60
70
70 ± 5 No or 1 secondary RF 40 ± 4
≥2 secondary RF 40
60 p(exp) = .01 Primary RF 66 ± 10
p(dif) < .001 55 ± 2 p(dif) < .001 20
50 6±2
0 62 8 4 10 2 4 6 8 10
Years after diagnosis 0
0 4 2 6 8 10
FIGURE 17.12. Survival after diagnosis of asymptomatic mitral
valve prolapse in the community according to the presence of Years after diagnosis
primary and secondary risk factors at baseline. The left graph rep- FIGURE 17.13. Cardiovascular morbid events after diagnosis of
resents the overall survival; the right graph represents survival free asymptomatic mitral valve prolapse in the community according to
of cardiovascular death; p(dif), p value for comparison of the three the presence of primary and secondary risk factors at baseline. Note
curves; p(exp), p value for comparison of overall survival to the the wide difference in morbidity according to this classification,
expected survival. Note the excess mortality in patients with with the group with no or one secondary risk factor incurring little
primary risk factors, essentially mitral regurgitation, moderate or morbid events, where those with two or more secondary risk factors
severe, and note the very low mortality of patients with no or one incur frequent morbidity and those with primary risk factors incur
secondary risk factor. almost inescapable morbidity.
 m i t r a l va lv e d i s e a s e s 405
Lifetime risk Medical management A risk of sudden death associated with MVP has been
30 suggested by autopsy studies99 and has been a concern because
Expected of arrhythmias associated with MVP. However, these arrhyth-
Observed mias are most prevalent with severe MR,100 and longitudinal
Stroke rate (%)

20 p < .001 p = .009
10
7±1
3 ± 0.7
2±1
0
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Years Years
FIGURE 17.14. Cerebral ischemic event rates after diagnosis of
mitral valve prolapse in sinus rhythm in the community. The left
graph represents the event-rate throughout follow-up including after
cardiac surgery. The right graph indicates the event rate under con-
servative management only. The solid line represents the expected
rate of ischemic stroke in patients in sinus rhythm of same age and
sex in the same community. The dashed line represents the observed
rate of events. Both graphs show the modest but significant excess
risk of ischemic stroke in patients with mitral valve prolapse.
severity of MR. More recently, it was shown that mitral
thickening (≥5 mm) is not independently linked to mortality
or cardiac morbid events.73 However, mitral thickening is
associated with a small but significant excess risk of cerebral
ischemic events.95
The contribution of MVP to the occurrence of stroke is
controversial. Case-control studies reported discordant find-
ings.96,97 However, in the community-dwelling population,
MVP is associated with a small but definite lifetime risk of
stroke or transient ischemic attack (Fig. 17.14).95 The major
determinants of strokes in patients with MVP are linked to
the MR complicating the MVP, that is, the need for cardiac
surgery and the occurrence of atrial fibrillation.95 The link
between the occurrence of stroke and mitral thickening,
irrespective of the need for surgery, is consistent with the
reported observation of clots on thickened myxomatous leaf-
lets.98 Other morphologic characteristics (location of MVP or
flail segment) do not appear to determine stroke incidence.
However, the risk of stroke is only notable in patients older
than 50, and thus MVP is not a significant contributor to
strokes in young patients.97
studies showed that young patients with no or minimal MR
exhibit no excess risk of mortality,73 whereas older patients
with severe MR display excess mortality and notable risk of
sudden death especially in patients with symptoms or LV
dysfunction.101
5±1
Bacterial endocarditis is rare but may complicate MVP
and it justifies prophylaxis, particularly in patients with
MR.
Clinical Evaluation
Presentation is rarely motivated by symptoms related to MR,
such as dyspnea, arrhythmia, or heart failure (Table 17.2).
Most often presentation is for nonspecific symptoms, fatigue,
atypical chest pain, or palpitation, or diagnosis is made after
discovery of auscultatory abnormalities during a general
medical examination. Abnormal autonomic function leading
to clinical presentation in patients with MVP has received
attention but is controversial.102 Increased catecholergic
activity and reduced vagal response have not been confirmed
consistently.103
Physical examination may find marfanoid characteristics
with arched palate, pectus excavatum, and rarely kyphosco-
liosis. Examination may reveal signs of mild or more severe
MR, and the radiation of the murmur suggests specific leaflet
involvement. Radiation from the apex to the base suggests a
prolapse predominant or isolated from the posterior leaflet,
whereas in patients with anterior or bileaflet prolapse, the
murmur tends to radiate to the axilla and sometimes the
back. The typical findings of MVP are the midsystolic click
and end-systolic murmur.87 The click is a high-pitched sound
occurring in midsystole, and is well separated from S1 and
S2. As a result, these clicks are classified as nonejectional and
are quite different from ejectional clicks, which mimic a
split S1. Mitral clicks are best heard between the apex and
left sternal border as superficial sounds. Not infrequently,
there are multiple systolic clicks. Maneuvers that increase
ventricular volume, such as squatting, phenylephrine admin-
istration, and leg raising, shift the click later in systole,
whereas maneuvers that decrease LV volume, such as stand-
ing, amyl nitrate inhalation, or Valsalva maneuver, shift the
click earlier in systole. These changes explain the day-to-day

TABLE 17.2. Clinical syndromes of mitral valve prolapse (MVP) presentation

Incidental MVP Barlow’s syndrome Flail leaflet

Symptoms None; incidental finding by echo Chest pain Sudden dyspnea

Physical examination Normal Midsystolic click Loud murmur with basal radiation
End-systolic murmur
Pectus excavatum
ECG Normal ST-T change LA enlargement LVH
Chest x-ray Normal Cardiomegaly Enlarged LA
Echo-Doppler MVP of 2-mm depth with no or Bileaflet MVP Flail posterior leaflet; large ERO
trivial MR Moderate late systolic MR
Follow-up In 5 years In 1–2 years Consider valve repair
ERO, effective regurgitant orifice; LA, left atrium; LVH, left ventricular hypertrophy; M, mitral regurgitation; MVP, mitral valve prolapse.
406 chapter
variability in the detection and timing of the click. The
murmur in late systolic, immediately follows the click, and
changes in duration with the maneuvers that change the
timing of the click. The intensity and character of the
murmur are variable, but it is usually soft, blowing, and best
heard at the apex. The murmur may be confused with that
of hypertrophic cardiomyopathy because both murmurs
increase with standing and decrease with squatting. However,
the murmur of hypertrophic cardiomyopathy becomes louder
after amyl nitrate inhalation, whereas that of MR does not.
Postextrasystolic potentiation in murmur intensity in hyper-
trophic cardiomyopathy contrasts with the lack of change in
MVP. Also, in patients with MVP and notable MR the
murmur will tend to predominate at end-systole, a recogniz-
able feature different from the “rectangular” shape of the
murmur in other forms of MR (e.g., rheumatic MR).
The electrocardiogram (ECG) is usually normal but may
show flattening or inversion of the T waves in leads II, III,
and aVF, which may mimic ischemia in the inferior territory.
Premature ventricular contractions are frequently observed,
are sometimes bigeminal, and have been attributed to the
traction of the chordae on the papillary muscle. Atrial fibril-
lation is rare and is more frequent in patients with larger
degrees of MR and atrial dilatation. Chest radiography shows
no specific feature of MVP.
Doppler echocardiography is the mainstay of diagnosis,
and of assessment of the MVP’s extent and of the severity of
MR and of LV and LA overload and function. The diagnosis
of MVP has been a source of confusion,88 as normal mitral
valves may appear to billow in certain views, particularly the
four-chamber apical view because of the saddle shape of the
mitral annulus.104–106 Therefore, the current criteria require a
systolic movement beyond the plane of the annulus of at least
2 mm of the body or the tips of one or both mitral leaflets
detected in long-axis views (Fig. 17.15).105 With this criterion,
the detected prevalence of MVP is considerably lower than
initially reported, and false-positive diagnoses were elimi-
nated. Thickening of mitral leaflets beyond 5 mm is noted to
FIGURE 17.15. Echocardiographic long axis parasternal imaging in
systole showing a posterior leaflet prolapse. A solid line marks the
annulus plane from which the depth of the prolapse is measured.
LV, left ventricle; LA, left atrium; Ao, ascending aorta.
17
LV
RV
RA
LA
FIGURE 17.16. Echocardiographic four-chamber view of a patient
with a flail posterior mitral leaflet. The arrow indicates the flail
segment with a ruptured chordae attached. LV, left ventricle; LA,
left atrium; RV, right ventricle; RA, right atrium.
define the “classic” MVP but is not indispensable to the
diagnosis.81 It is important to note the uni- or bileaflet nature
of the MVP and the leaflet’s segments affected (using the A1–
A3, P1–P3 classification). Timing of the prolapse (holosystolic
vs. midsystolic) may be noted on 2D or M-mode echocardiog-
raphy.88 The presence of a flail leaflet or ruptured chords can
be detected by transthoracic echocardiography (Fig. 17.16), but
sensitivity is higher by TEE, which is indicated in a minority
of cases depending on the therapeutic implications of these
findings.107 Mitral regurgitation severity is assessed using the
criterion of the American Society of Echocardiography.108 The
size of the LA and LV is measured using 2D-directed M-mode
diameters or better using LA and LV volumes measurements.
The associations of tricuspid valve or more rarely aortic valve
prolapse are also examined.
Cardiac catheterization is used only as a preoperative
test. It may contribute to the assessment of MR and hemo-
dynamics and to defining the coronary anatomy. Left ven-
tricle angiogram may also observe large mitral prolapse.
Management
Mitral valve prolapse is a heterogeneous condition and man-
agement should be guided by the individualized risk strati-
fication, in which the degree of MR plays a central role.
Although the risk is low, endocarditis prophylaxis is recom-
mended for all patients. There is no medical treatment that
affects the course of the mitral tissue myxomatous degenera-
tion, and treatment focuses on the consequences of the
MVP.
Low-risk patients do not require close follow-up and may
be reevaluated at 5-year intervals unless new symptoms or
 m i t r a l va lv e d i s e a s e s 4 07
100 AL-MVP 100 PL-MVP approaches. With improved understanding of the natural
87% ± 2% 85% ± 2% history of MR, and most importantly with major advances
80 80 in conservative surgery, the management of MR has become
63% ± 5% 70% ± 3%
far more proactive.
Survival (%)

60 74% ± 4% 60
65% ± 5% Etiology and Mechanism
40 40 Mitral regurgitation is an organic mechanism if there is an
49% ± 4% 49% ± 5%
p = .003 p = .0004 intrinsic valve disease or a functional mechanism if the
20 Repair 20 Repair valve is structurally normal but regurgitates due to an extra-
Replacement Replacement valvular abnormality. Mitral regurgitation of ischemic etiol-
0 0 ogy may be organic (ruptured papillary muscle) or functional
5 0 10 15 0 5 10 15 (LV dysfunction). Nonischemic MR may be organic (e.g.,
Years after surgery Years after surgery
rheumatic) or functional (e.g., cardiomyopathy). The Carpen-
FIGURE 17.17. Survival after surgical correction of mitral valve
tier classification of MR mechanisms is as follows: type I,
prolapse (MVP) with severe mitral regurgitation, and with exclusive
posterior leaflet (PL) prolapse (right graph, PL-MVP) or anterior normal valvular movement (such as that seen with annular
leaflet (AL) involvement (left graph, AL-MVP). Survival of patients dilatation); type II, excessive movement (such as that due to
who underwent valve repair is indicated with a dashed line, whereas MVP or flail leaflets); type III, restrictive motion; type IIIa,
that of patients who underwent valve replacement is indicated with diastolic restriction (such as in rheumatic diseases); and type
a solid line. Note that irrespective of the location of the mitral valve
prolapse, valve repair provides an improved survival as compared to IIIb, systolic restriction (such as ischemic functional MR).
valve replacement and should be the preferred mode of correction Rheumatic MR is rarely pure, and in most cases is associ-
of mitral valve prolapse with mitral regurgitation. ated with stenosis and fusion of the commissures. Severe
rheumatic MR requiring surgical correction is still frequent
in developing countries but is now rare in developed coun-
tries.116 The underlying lesion is retractile fibrosis of leaflets
and chordae causing loss of coaptation (Fig. 17.18). Secondary
events develop. Patients with palpitations may benefit from dilatation of the mitral annulus tends to further decrease the
beta-blockade for symptom’s relief. The role of aspirin in contact between leaflets. Elongated or ruptured chords are
preventing embolic complications in patients with thickened infrequent.
leaflets is not established.109 Medium-risk patients, in par- Degenerative MR is often associated with MVP and rep-
ticular with mild or moderate MR, require more frequent resent the most frequent cause leading to surgery for severe
follow-up as the degree of MR tends to progress. Vasodilators, MR.116 Degenerative MR can be categorized as follows:
particularly with angiotensin blockade, are not yet confirmed
• Primary MVP with diffuse myxomatous infiltration
in stabilizing the degree of MR but are justified in treating
• Degenerative primary ruptured chordae, which involve
hypertensive patients.110 Atrial fibrillation should lead to
more often the posterior than the anterior leaflet and
reevaluation of the degree of MR and requires anticoagula-
occur more often in men than in women (Fig. 17.19).
tion.111 A limited number of patients with atrial fibrillation
There is usually no excessive tissue, but enlargement of
with uncontrolled ventricular response and moderate MR
the annulus may occur as in any MR. The involved leaflet
benefit from surgical treatment combining a Maze procedure
and mitral repair.112,113 Patients with severe MR are at high
risk. These patients are immediate candidates for surgery if
they are symptomatic or have LV dysfunction. For asymp-
tomatic patients there is no agreement on the need for early
surgery, but in the hands of surgeons skilled in reparative
procedures these patients can benefit from valve repair in
85% to 90% of cases, which implies a low operative risk and
excellent long-term outcome (Fig. 17.17). Therefore, delaying
surgery until severe symptoms or congestive heart failure
occurs compromises survival and should be avoided, justify-
ing a trend for proceeding with valve repair without waiting
for the occurrence of these severe complications.114,115

Mitral Regurgitation
Mitral regurgitation is characterized by an abnormal, reversed
blood flow from the LV to the LA. The etiologic profile of MR
is now dominated by degenerative and ischemic causes in
FIGURE 17.18. Anatomic posterior view of the left atrium and
developed countries. The development of noninvasive assess- mitral valve in a case of rheumatic mitral regurgitation. Note the
ment with Doppler echocardiographic methods, particularly wide orifice despite the presence of limited commissural fusion and
for quantitation of MR, has transformed diagnostic note the tissue retraction leaving a wide-open orifice.
408 chapter
shows myxomatous infiltration,117 but the other leaflet
usually remains normal. Calcification of the mitral
annulus or systemic hypertension may precede the occur-
rence of the ruptured chordae. Isolated ruptured chord
may occasionally be due to blunt thoracic trauma and
endocarditis (secondary forms).
• Degenerative MR without prolapse, which is usually
mild and due to valve sclerosis or isolated annular calci-
fication, in which regurgitation is secondary to deforma-
tion of the valves or annulus.
Infective endocarditis accounts for about 5% of cases of
severe MR. Vegetations may produce mild MR by interposi-
tion between leaflets. Severe endocarditic MR is usually
related to ruptured chords and less frequently to destruction
of mitral tissue involving either the leaflet’s edges or a per-
foration (Fig. 17.20).
FIGURE 17.20. Anatomic ventricular view of the mitral valve in a
case of endocarditic mitral regurgitation with perforation of the
anterior leaflet. Note the large perforation with inflammatory
borders.
17
FIGURE 17.19. Anatomic long-axis view of
the heart (left panel) and mitral valve (right
panel) in a case of degenerative mitral regurgi-
tation with flail posterior leaflet and ruptured
chordae. Note the thickening of the flail
segment of the posterior leaflet, whereas the
anterior leaflet is of normal thickness.
Ischemic and functional MR, that is, due to LV wall
dysfunction secondary to ischemia, scarring, aneurysm,
cardiomyopathy, or myocarditis, have in common the same
mechanism. The coaptation of intrinsically normal leaflets
is incomplete (Fig. 17.21).118 Rupture of papillary muscle pro-
duces MR because of the flail leaflet and involves in 80% of
cases the posteromedial papillary muscle and is most often
associated with infarction of the adjacent ventricular wall.119
It is the rarest form of heart rupture and of ischemic MR.
Complete rupture is rapidly fatal without surgery, and partial
or single-head rupture of the papillary muscle more often
allows emergency surgery.119
There are numerous other causes of MR. It is observed
frequently with color flow imaging, even in patients without
FIGURE 17.21. Anatomic view of the heart and mitral valve in a
case of functional mitral regurgitation due to ischemic heart disease
(with septal and anterior wall thinning and scarring). The mitral
valve is structurally normal. Traction by the papillary muscle and
chordae tether the leaflets within the LV cavity. Note the enlarged
and spherical LV and LA.
 m i t r a l va lv e d i s e a s e s
cardiac disease. Clinically significant MR may be found
in (1) connective tissue disorder: Marfan syndrome, Ehlers-
Danlos syndrome, pseudoxanthoma elasticum, osteogenesis
imperfecta, Hurler’s disease, systemic lupus erythematosus,
and anticardiolipin syndrome; (2) penetrating or nonpenetrat-
ing cardiac trauma; (3) myocardial disease: hypertrophic
cardiomyopathy or sarcoidosis; (4) endocardial lesions due to
eosinophilic syndrome, endocardial fibroelastosis, carcinoid
tumors, ergot toxicity, radiation toxicity,120 and diet or drug
toxicity121; (5) congenital lesions, such as cleft mitral valve
isolated or associated with persistent atrioventricular canal;
corrected transposition with or without Ebstein abnormality
of the left atrioventricular valve may also cause MR; and (6)
cardiac tumors.
Pathophysiology
The abnormal coaptation of the mitral leaflets creates a
regurgitant orifice during systole and is measured as the
effective regurgitant orifice (ERO), which represents the
lesion severity. The systolic pressure gradient between
the LV and LA is the driving force of the regurgitant flow,
which accumulates into a regurgitant volume (RVol). The
RVol is responsible for the volume overload, by entering the
LA in systole and the LV in diastole, modifying LV loading
and function.
Chronology of Regurgitation
The pressure gradient between the LV and atrium begins
with mitral closure (simultaneous to S1) and persists after
closure of the aortic valve (S2) until the mitral valve opens.122
Thus, timing of regurgitant flow is determined by that of the
regurgitant orifice and is most often holosystolic. Various
dynamic changes in regurgitant orifice can be observed
depending on its cause.90 With small regurgitant orifices, the
regurgitant orifice declines, with the ventricular volume
tending to limit regurgitation to early systole.122 Conversely,
in valve prolapse the regurgitant orifice appears or increases
late in systole, and variations of regurgitant flow throughout
systole are the complex results of combined effects of changes
of regurgitant orifice and gradient.89,90
Degree and Consequences of Regurgitation
The degree of volume overload depends on three factors: the
area of the regurgitant orifice,123 the regurgitant gradient, and
the regurgitant duration. The volume overload is usually less
severe in mitral than in aortic regurgitation, despite the
usually larger regurgitant gradient and orifice.123 Such differ-
ences are related to a shorter duration of MR during the
cardiac cycle in mitral than in aortic regurgitation.123 The
degree of MR is not fixed and may vary with interventions.
Vasodilators improve the clinical status of patients with
acute regurgitation,124 and the mechanism of improvement
is a decline in ERO area rather than that of the ventricu-
loatrial gradient. In functional125 and organic MR,126 the ERO
increases with increased afterload or ventricular volume and
decreases with decreased afterload or improved contractility,
but is not influenced by changes in heart rate.126 The regur-
gitant energy is produced by the LV and is transformed in
two components: the kinetic energy (regurgitant volume) and
409
the potential energy (elevation of atrial pressure). The typical
LA pressure change is the V wave,127 which is also deter-
mined by LA compliance.127 In acute MR, the LA is smaller
and less compliant than in chronic MR, and a similar RVol
produces a higher V wave and LA pressure, which in turn
minimizes the LV-LA gradient. Thus, for any ERO,123 acute
MR translates into more potential energy (LA pressure) with
smaller RVol (and murmur) than chronic MR. When MR
becomes chronic, the LA dilates, and the V wave is less
prominent and does not limit the regurgitant volume, and
the LA pressure may be normal even with severe MR.128 At
that stage, usually the cardiac output is decreased but the
pulmonary pressures are often normal. Pulmonary hyper-
tension in MR is poorly understood, and observed mostly in
elderly patients.
Left Ventricle Function
With MR the LV is dilated but less so than in aortic regurgi-
tation of comparable degree.129 End-diastolic LV volume and
wall stress are increased,129 and its shape becomes spherical.
End systolic volume is increased in chronic MR, but end
systolic wall stress is usually normal.130 The myocardial
mass is increased proportionately to LV dilatation.131 Left
ventricle function is difficult to characterize because of the
changes in preload and afterload. It has been suggested that
normalization of ejection fraction to the preload would
provide an appropriate assessment of LV function. Afterload
is more difficult to assess because the MR may decrease the
instantaneous impedance to ejection, but the measure of
afterload provided by end systolic wall stress is within the
normal range.130 However, the usual inverse correlation
between end systolic wall stress and ejection fraction is also
observed in MR.132 Complex indices using the afterload such
as the end systolic wall stress,133 or maximum elastance,130
normalized to the LV volume, have been proposed and may
be sensitive to subtle changes in function. Left ventricle
dysfunction is a frequent and dismal complication of MR.134,135
The mechanism of LV hypertrophy is a reduction in protein
degradation, but the mechanisms leading to interstitial fibro-
sis and LV dysfunction remain mysterious. Experimentally,
LV dysfunction is not due to changes in coronary blood flow.
The changes in myofiber contractility parallel those in LV
function136 and are associated with reduced myofiber
content,137 but the cause of the myofiber dysfunction and the
explanation of its high incidence have not been clarified.
During diastole LV relaxation is prolonged, but chamber
stiffness is reduced.138 Age and decreased systolic function138
are associated with increased chamber stiffness. The signifi-
cance of the diastolic abnormalities is unclear.
Ischemic and Functional Mitral Regurgitation
The pathophysiology of ruptured papillary muscles is poorly
known but it represents the most typical form of acute MR
with large ERO, low RVol, and often inaudible murmur but
severe clinical consequences due to the LA pressure eleva-
tion. In chronic ischemic MR (IMR) or functional MR (FMR),
the primary disease involves the LV, which is often poorly
contracting while the mitral valve is intrinsically normal.
The classically invoked mechanisms of MR, that is, papillary
muscle dysfunction and annular dilatation, have been shown
410 chapter
Ao
LV
T
LA
FIGURE 17.22. Echocardiographic long-axis view of the mitral
valve in a patient with ischemic mitral regurgitation (MR). The LV
is enlarged and demonstrates thinning of the inferolateral wall
consistent with an inferior myocardial infarction. The mitral valve
is protruding forward and the tenting area (T) under the mitral valve
up to the annulus (solid line) is large, preventing coaptation of the
mitral leaflet although they are structurally normal. The LA is
enlarged.
to contribute little to functional MR. The occurrence of MR
is due mostly to mitral valve tenting.139 Tenting is a systolic
deformation of the leaflets, which protrude forward in the LV
and thus cannot appose their rough zone on each other (Fig.
17.22). Other valvular contributors to the lack of coaptation
are the loss of annular contraction and the low ventricular
pressure pressing on mitral leaflets.139 Tenting as the main
determinant of IMR and FMR is in turn the consequence of
tethering by excessive traction on the secondary chordae due
to localized LV deformation (Fig. 17.23) with apical and infe-
rior displacement of papillary muscles,139–141 which explains
17
the predominance of IMR after inferior myocardial infarc-
tion.142 Therefore, similar degrees of LV enlargement or dys-
function may be associated with quite variable degrees of
IMR due to the variability in the local remodeling. The
importance of chordal tethering in generating tenting and
FMR or IMR has been demonstrated experimentally, by
inducing papillary muscle repositioning143 or by secondary
chordae cutting,144,145 which resulted in disappearance of the
MR. Cardiomyopathic versus ischemic LV dysfunction shows
slight differences in the distribution of chordal tethering and
tenting that are often predominant on the medial commis-
sure in IMR due to the frequent association with inferior
myocardial infarction. In functional versus organic MR,
RVol is usually smaller,146 and LV and LA dilatation are in
excess to the degree of MR.123 Nevertheless, MR is associated
with elevated LA pressure,123 poor outcome,147 and is a marker
of sensitivity to vasodilators.
Hormonal Activation in Organic
Mitral Regurgitation
Natriuretic peptides are activated in experimental148 and
clinical149 studies. The main determinant of elevation of
A-type natriuretic peptide is the elevation of atrial pres-
sures,149 but also atrial arrhythmias, which result in dispro-
portionate elevation of this natriuretic peptide. Thus, B-type
natriuretic peptide (BNP) has been the focus of increasing
interest. Pilot studies suggested that BNP reflected the sever-
ity of symptoms. Its activation is weakly linked to the degree
of MR and is more notably determined by the consequences
of MR, LA enlargement, LV dysfunction, and the degree of
heart failure associated with the MR in particular. In that,
it appears as a promising marker of outcome. The catechol-
amine activity is increased in MR with norepinephrine
release rates increased compared to controls, even in asymp-
tomatic patients150 and similar to those measured in cardio-
myopathy.151 Alterations in adrenergic activity and receptor
density are strongly correlated to the degree of LV over-
load152,153 and dysfunction154,155 and to hormonal activation.156
Importantly, in long-term experiments with MR due to rup-
tured chords, similar to the most frequent human form of
FIGURE 17.23. Echocardiographic apical long-
axis view with two-dimensional imaging of
papillary muscles (left) and with color flow
imaging of the left atrium (right). Left, the ver-
tical arrows show the tips of the papillary
muscles tensing the secondary chordae inserted
on the body of the leaflet (horizontal arrows)
and pulling the leaflets apically, away from the
annulus (arrowheads), resulting in tenting.
Right, the tenting results in a large jet of mitral
regurgitation.
 m i t r a l va lv e d i s e a s e s 411
MR, bradycardia induced by beta-blockers provides recovery 100
of LV function.157 Activation of the renin-angiotensin system
is also noted. In dogs with organic MR, systemic activation Class I-II
80
of the renin-angiotensin system is rare,158 but tissue levels of

Survival (%)
angiotensin II are markedly elevated.159,160 The role of tissue 60 67% ± 7%
angiotensin activation in the development of hypertrophy
and fibrosis is not fully clarified. Beta-1-blockade prevents 40
angiotensin-II–mediated tissue catecholamine release,161 but
the therapeutic role of hormonal modulation in human MR Class III-IV
20
is not yet defined. 21% ± 11% p < .0001

Natural History
Because organic and functional MR occur in very different
contexts, it is important to analyze their natural history
separately.
Organic
From the presurgical era to the 1980s, assessment of the
degree of MR has remained qualitative and imprecise, so that
the natural history of MR was ill-defined. Patients with mild
rheumatic MR appeared to have a good prognosis,162 whereas
in those with more severe MR higher mortality has been
noted.91,163 In patients with unoperated and clinically signifi-
cant MR, long-term survival was reported as high as 60% at
10 years164 or as low as 46%165 or even 27%166 at 5 years. In
our experience with flail mitral leaflets, at 10 years, survival
was 57%, which represents an excess mortality as compared
to the expected survival (Fig. 17.24).91 A notable component
of sudden death has been noted. Such a devastating complica-
tion occurs more often if the ventricular function is
decreased167 but may also occur in patients with normal ejec-
tion fraction who are asymptomatic.163 In our experience,
sudden death in patients with MR due to flail leaflets occurs
at a rate of 1.8% per year.101 The rates are higher in patients
with symptoms (Fig. 17.25) or reduced ejection fraction
(<60%; Fig. 17.26), but even in the absence of these risk
factors sudden death rate is 0.8% per year,101 or approximately
the double of the expected rate of sudden death in the general
0
0 1 2 5 3 6 4 7 8 9 10
Years
FIGURE 17.25. Natural history of mitral regurgitation due to flail
leaflets: survival after diagnosis under medical management accord-
ing to symptomatic status at baseline. The patients presenting in
New York Heart Association class III or IV incur considerable mor-
tality under medical management (solid line). Those presenting in
New York Heart Association class I or II display a better survival,
but note that one third die within 10 years under medical manage-
ment (dotted line).
population. These combined data suggested that survival
under medical management is determined by the degree of
MR. This hypothesis was supported by the study of MVP in
the community, which showed that the degree of MR due to
MVP was the strongest determinant of survival after diag-
nosis, even in asymptomatic patients.73 This hypothesis was
confirmed in a prospective study of organic MR with degree
of MR quantified using modern Doppler echocardiographic
methods and stratified according to guidelines of the Ameri-
can Society of Echocardiography.168 The ERO area proved to
be the strongest predictor of survival after diagnosis (Fig.
17.27) and patients with ERO ≥40 mm2 incurred excess mor-
tality as compared to expected mortality. Importantly, the

100

80 EF ≥ 60%
100
Survival (%)

60 61% ± 8%

80 40
Survival (%)

65% EF < 60% 40% ± 12%

20 p = .001
60 Expected
Observed 0
57% 0 1 2 5 3 6 4 7 8 9 10
p = .016
Years
40 FIGURE 17.26. Natural history of mitral regurgitation due to flail
0 2 4 6 8 10 leaflets: survival after diagnosis under medical management accord-
Years ing to echocardiographic ejection fraction at baseline. The patients
FIGURE 17.24. Natural history of mitral regurgitation due to flail presenting with ejection fraction (EF) <60% incur considerable mor-
leaflets: survival after diagnosis under medical management. The tality under medical management (solid line). Those presenting
expected survival for age and sex is indicated by a dashed line. The with EF ≥60% display a better survival but note that almost 40%
observed survival indicated by a solid line is significantly lower. die within 10 years under medical management (dotted line).
412 chapter
patients with moderate MR (ERO 20–39 mm2) displayed
mortality that was initially low but increased markedly after
3 years.
Morbidity in patients with severe MR is also high. In
patients who were initially asymptomatic, approximately
10% per year develop symptoms,169 which may be hastened
by atrial fibrillation. In patients with flail leaflets, heart
failure occurred in 63% within 10 years of diagnosis.91 Atrial
fibrillation occurred at a rate of 5% per year in patients
diagnosed in sinus rhythm and was associated after its
occurrence with increased mortality under conservative
management.111 Left atrium enlargement is a strong predictor
of occurrence of atrial fibrillation.111 Quantitation of MR
provides important predictors of outcome, and cardiac events
(cardiac death, heart failure, new atrial fibrillation) occur at
a rate almost six times higher in patients with ERO ≥40 mm2
than in those with ERO <20 mm2 (Fig. 17.28).168 Finally,
surgery is almost unavoidable in patients with severe MR.
Indeed, 10 years after diagnosis of MR due to flail leaflets,
90% of patients underwent surgery or died before surgery
could be performed,91 whereas in patients with any etiology
of MR and ERO ≥40 mm2 the rate of death or surgery is 86%
at 5 years.168
The predictors of poor outcome in patients medically
treated are (1) severe symptoms [New York Heart Association
(NYHA) class III–IV],165 even if the symptoms are transient91;
(2) pulmonary hypertension; (3) markedly increased LV end-
diastolic volume or arteriovenous difference in O2170; (4)
reduced ejection fraction91; (5) marked LA enlargement; and
(6) ERO area ≥40 mm2.168 Comparison of prognosis in medi-
cally and surgically treated patients shows a trend in favor
of the surgical treatment,163 especially early surgery,91 with
definite improvement of outcome of patients with decreased
systolic LV function.170 Asymptomatic patients who undergo
100
91% ± 3%
90
Survival (%)
80 66% ± 6%
ERO <20 mm2
70
ERO 20–39 mm2
ERO ≥40 mm2
60
p < .01
58% ± 9%
50
0 1 2 3 4 5
Years
FIGURE 17.27. Natural history of mitral regurgitation quantita-
tively defined: survival after diagnosis under medical management
according to Doppler-echocardiographic effective regurgitant orifice
(ERO) at baseline. The patients presenting with ERO <20 mm2 incur
minimal mortality, not different from the expected mortality (solid
line). Those presenting with ERO ≥40 mm2 display a considerable
mortality, higher than the expected mortality (dashed line). The
patients with ERO ≥20 mm2 and <40 mm2, or the moderate MR as
per the American Society of Echocardiography classification (dotted
line) show initially little mortality but after 3 years mortality mark-
edly increases.
17
62% ± 8%
60
ERO 1–19 mm2
Cardiac events rate (%)
50 ERO 20–39 mm2
ERO ≥40 mm2
40% ± 7%
40
p < .01
30
20
15% ± 4%
10
0
0 1 3 2 4
5
Years
FIGURE 17.28. Natural history of mitral regurgitation quanti-
tatively defined: cardiac events (cardiac death, heart failure, or
new atrial fibrillation) after diagnosis under medical management
according to Doppler-echocardiographic effective regurgitant orifice
(ERO) at baseline. The patients presenting with ERO <20 mm2 incur
minimal morbidity (solid line). Those presenting with ERO ≥40 mm2
display a considerable mortality, higher than the expected mortality
(dashed line). The patients with ERO ≥20 mm2 and <40 mm2, or the
moderate MR as per the American Society of Echocardiography
classification (dotted line) show initially little morbidity but after 3
years the event rate markedly increases.
valve repair display a considerable reduction of mortality
with restoration of life expectancy.168
The progression of LV dysfunction in patients with
organic MR medically treated is not well defined. Progres-
sion of the degree of MR is usually slow, with progression of
regurgitant volume of 7 to 8 mL per year, but it reaches 20 mL
per year in patients with new flail leaflets.92 The mechanism
of progression of MR is an increase in ERO without change
in gradient. The major determinant of regression of MR is a
reduction in afterload, whereas increase in annular size and
new flail are major determinant of progression of MR.92 The
progression of the degree of MR is the probable mechanism
by which patients with moderate MR (ERO 20–39 mm2) expe-
rience a marked increase in risk within a few years after
diagnosis.
Functional
Data on the natural history of functional MR are limited.
Functional MR complicating cardiomyopathy appears to
contribute to the poor outcome of this disease.171,172 Recently,
more compelling information has been gathered on IMR,
which is noted in approximately one patient in five post–
myocardial infarction,147,173 irrespective of the presence of ST
elevation.173 The presence of IMR is associated with more
severe clinical presentation167,173,174 and severity of LV remod-
eling.175 During follow-up, IMR (Fig. 17.29) is associated with
increased mortality (approximately doubling of the mortality
risk) even after adjustment or matching for the associated
LV alterations,147,173,174 and revascularization by surgery176 or
interventional procedures.177 Furthermore, IMR is linked to
subsequent occurrence of heart failure,173 even in patients
 m i t r a l va lv e d i s e a s e s 413
100

0.8 p < .0001

61% ± 6% 80
68% ± 12%

Incidence of CHF (%)

0.6 Controls
Survival

ERO, mm2
60 ≥20
0.4 38% ± 5% 46% ± 9%
MR 1–19
0
40
0.2
p < .0001 18% ± 5%
0.0 20
0 1 2 4 3 5 6 7
Years
FIGURE 17.29. Natural history of ischemic mitral regurgitation: 0
survival after diagnosis in patients with Q-wave myocardial infarc- 0 1 2 3 4 5 6
tion matched for age, sex, and EF with (solid line) and without FIGURE 17.31. Natural history of ischemic mitral regurgitation:
(dashed line) ischemic mitral regurgitation. Note that patients with occurrence of congestive heart failure after diagnosis in initially
ischemic MR incur a considerably higher mortality despite similar asymptomatic patients with Q-wave myocardial infarction and
ejection fraction. quantified MR, matched for age, sex, and EF between those without
MR (dashed line) and with MR and effective regurgitant orifice
(ERO) 1 to 19 mm2 (dotted line) or ≥20 mm2 (solid line). Note that
patients with larger ERO due to ischemic MR incur a considerably
higher rate of congestive heart failure despite asymptomatic status
and similar ejection fraction at baseline.

who were asymptomatic at baseline.178 Importantly, it appears

that even a degree of IMR that would be labeled as mild or
moderate is associated with adverse outcomes. Indeed, in the
SAVE study in which severe MR was an exclusion criterion,
IMR severely affected the outcome.147 This concept of lower
thresholds for “severe” IMR has been confirmed in quantita-
tive studies, which showed that patients with ERO ≥20 mm2
incur a considerable risk of mortality (Fig. 17.30),174,179 and
heart failure (Fig. 17.31).178 Thus, it is essential to evaluate
IMR with specific criteria of severity. Ischemic MR is more
dynamic than organic MR, and an exercise-induced increase
in IMR degree180 may portend a high risk of subsequent mor-
tality179 and heart failure.181 Therefore, current information
suggests that IMR has a poor outcome.
100
80
61% ± 6%
Survival (%)
Clinical Evaluation
Sex distribution of disease has changed in parallel to the
changes in etiology of MR. With the decrease in rheumatic
heart disease, severe MR is now predominantly seen in males
(65–75%). Prevalence of MR increases with older age,182 and
therefore, patients with severe MR most often present in the
sixth decade of life.91 Clinical presentation is determined by
the degree, rapidity of development, and cause of MR.
Patients with mild MR usually have no symptoms. Severe
MR is diagnosed most often because of the murmur when
no or minimal symptoms are present.91 Fatigue and mild
dyspnea on exertion are the most usual symptoms and are
rapidly improved by rest. The administration of diuretics and
progressive self-limitation of physical activity may prevent
the occurrence of more severe symptoms. Severe dyspnea on
exertion or, more rarely, paroxysmal nocturnal dyspnea,
frank pulmonary edema, or even hemoptysis, may be
observed later in the course of the disease. Such severe symp-
toms may be triggered by new onset of atrial fibrillation, an

increase in the degree of MR, the occurrence of endocarditis

60
or ruptured chord, or a change in ventricular compliance or
function.
40 ERO 47% ± 8%
0 With severe MR of acute onset, symptoms are usually
1–19 29% ± 9%
more dramatic, such as pulmonary edema and congestive
20
heart failure, which may subside with administration of
≥20 p < .0001
diuretic and increased LA compliance, an improvement that
0
should not falsely reassure, as such patients remain at high
0 1 2 3 4 5
Years risk even after symptoms have improved.91 A syndrome of
FIGURE 17.30. Natural history of ischemic mitral regurgitation: sudden onset of atypical chest pain and dyspnea may occur
survival after diagnosis in patients with Q-wave myocardial infarc- with abrupt chordal rupture. Rupture of papillary muscle
tion and quantified MR, matched for age, sex, and EF between those usually has a dramatic presentation with cardiogenic shock
without MR (dashed line) and with MR and effective regurgitant
orifice (ERO) 1 to 19 mm2 (dotted line) or ≥20 mm2 (solid line).
or a severe pulmonary edema. Pulmonary edema may be also
Note that patients with larger ERO due to ischemic MR incur a observed in transient severe papillary muscle dysfunction.
considerably higher mortality despite similar ejection fraction. Sudden death as the initial presentation of MR is rare.167
414 chapter 17

Physical examination usually finds a normal blood pres-

sure and brisk carotid upstroke. Cardiac palpation may show
laterally displaced, diffuse, and brief apical impulse. An
apical systolic thrill is characteristic of severe MR. A right
ventricular heave (left sternal border lift) is observed with
right ventricular dilatation and may be difficult to distin-
guish from a LA lift due to the dilated, expansive LA, which
is usually lower.
S1 is included in the murmur and usually normal but may
be increased in rheumatic disease. S2 is usually normal but
may be paradoxically split if the LV ejection time is markedly
shortened. The presence of a third heart sound is directly
related to the volume of the regurgitation in patients with
organic MR.183 It is often associated with an early diastolic
rumble due to the increased mitral flow in diastole even
without mitral stenosis. The S3 and diastolic rumble are
low-pitched sounds and may be difficult to detect without
careful auscultation in the left lateral decubitus position.
The S3 increases with expiration. In ischemic-functional
MR, S3 corresponds more often to restrictive LV filling. An
atrial gallop is heard mainly in MR of recent onset and in
ischemic/functional MR in sinus rhythm. Midsystolic clicks
are markers of valve prolapse.
The hallmark of MR is the systolic murmur, most often
holosystolic and including first and second heart sounds. If
an opening snap or S3 are mistakenly interpreted as S2, the FIGURE 17.33. Chest radiography in a patient with mitral regurgi-
murmur may appear midsystolic. A careful examination tation. There is mild cardiomegaly with LA enlargement.
beginning at the base of the heart to identify S2 and progress-
ing toward the apex will facilitate recognizing the origin of
the murmur. The murmur is blowing but may be harsh, lels the degree of MR.185 Murmurs of shorter duration usually
especially in valve prolapse. Maximum intensity is usually correspond to mild MR; they may be mid-late systolic in
apical with radiation to the axilla in rheumatic or anterior MVP or early systolic in FMR.
leaflet prolapse MR. In posterior leaflet prolapse, the jet is However, with myocardial infarction and in general in
usually superiorly and medially directed and the murmur functional MR, severe MR may be totally silent.186 Indeed,
radiates toward the base of the heart.184 The murmur may be the intensity of murmur is usually low and does not parallel
heard in the back, in the neck, and sometimes on the skull. MR severity,185 so that the presence and intensity of murmur
When the murmur radiates to the base, it may be difficult to is a poor detector of FMR or IMR.147,173
distinguish from that of aortic stenosis or obstructive cardio- The ECG’s most frequent feature is atrial fibrillation,
myopathy, and pharmacologic maneuvers showing that the found in approximately 60% to 75% of earlier series and
murmur decreases with amyl nitrite and increases with now present in approximately 30% to 50% of surgically
methoxamine, strongly suggest MR. Murmur intensity does corrected MR.187 Patients in sinus rhythm may present
not increase with postextrasystolic beats and usually paral- with signs of left atrial enlargement (Fig. 17.32). Left
ventricle hypertrophy is more rarely seen and may be associ-
ated with secondary ST-T abnormalities.188 Right ventricular
hypertrophy is uncommon. The ECG, especially in acute
MR, may be entirely normal. In ischemic MR, Q waves in
the inferior leads or left bundle branch block are often
noted.
Chest roentgenogram often shows cardiomegaly in
chronic organic MR or in ischemic/functional MR. Left
atrium body and appendage dilatation is frequent, but giant
LA is rare and usually seen in severe mixed valve disease
(Fig. 17.33). Although valvular calcifications are rare, annular
calcification is seen as a C-shaped density below the posterior
leaflet and is frequent. Because LA pressure is frequently
normal, even with severe MR, signs of pulmonary hyperten-
sion or pulmonary edema are rarely observed.
The clinical, ECG, and radiographic signs are often
FIGURE 17.32. Electrocardiogram in a patient with mitral regurgi-
tation and sinus rhythm. The prolonged duration and morphology
grouped into specific clinical syndromes suggestive of the
of the P wave is consistent with LA enlargement. The deep S wave diagnosis and are schematically separated in four syndromes
in V2 is consistent with borderline left ventricular hypertrophy. summarized in Table 17.3.
 m i t r a l va lv e d i s e a s e s 415
TABLE 17.3. Clinical syndromes of mitral regurgitation (MR) presentation
Sclerotic MR Chronic MR Acute MR Ischemic/functional MR

Symptoms None; incidental diagnosis Fatigue Pulmonary edema CHF

Physical examination Early systolic murmur Loud murmur S3 Loud murmur S4 Soft Murmur S4, S3
ECG Normal Atrial fibrillation Normal Q waves, LBBB
Chest x-ray Normal Cardiomegaly Normal heart size Cardiomegaly, pulmonary
Pulmonary edema edema
Echo-Doppler Jet may be large but is Enlarged LA Jet eccentric and thin Severe LV dysfunction
purely early systolic Incipient LV “Normal” mitral structure
dysfunction
Clinical pitfall Overestimate MR on the Ignore the LV Underestimate MR Ignore the silent but
jet basis alterations clinically important MR
CHF, congestive heart failure; LA, left atrium; LBBB, left bundle branch block; LV, left ventricle; MR, mitral regurgitation.

Doppler echocardiography is the mainstay of the diagno- The assessment of severity of MR is based on the criteria
sis of MR, of the morphologic assessment to determine the defined by the American Society of Echocardiography. The
etiology and mechanism of MR, and of the quantitation of guiding concepts are that the entire Doppler echocardio-
MR and of its consequences. graphic information is gathered (lesion, color-flow, pulsed
The morphologic features of the most common causes are and continuous wave Doppler) but that specific signs for each
discussed below. grade of MR are preferred, and that in the analysis of color-
Rheumatic MR is characterized by thickening of the leaf- flow imaging vena contracta measurements are preferred to
lets and chordae. The posterior leaflet has reduced mobility, jet analysis, and that overall, as often as possible, quantita-
whereas the anterior leaflet may be doming if commissural tive methods should be preferred.108 The methods facilitating
fusion is associated. A valvular prolapse is usually not present collecting these specific signs and the gradation scheme for
unless a ruptured chordae or active rheumatic carditis is MR are delineated below.
present. Similar lesions are observed in lupus or anticardio- Color-flow imaging defines the origin and direction of the
lipin syndrome in which transesophageal echocardiography jet, related to etiology (Figs. 17.35 and 17.36). Jet length, jet to
may also show small vegetations. left atrial area ratio, or more simply jet area193 shows rough
In degenerative MR, prolapse is observed with the passage correlations to MR severity. Small jets consistently corre-
of valvular tissue beyond the annulus plane in long-axis view spond to mild MR.146 However, color-flow imaging has sig-
(as indicated in the MVP section). Localization of the leaflet nificant limitations intrinsically related to the nature of
involved (most often the posterior) is confirmed by the initial regurgitant jets. The extent of a jet is determined by its
direction of the jet. A large mitral annular calcification may momentum, and thus as much by regurgitant velocity as by
represent a limitation for conservative surgery if extensive regurgitant flow. Also jets are constrained by the LA and
and severe. Flail segments appear as a complete eversion of expand more in a large LA.146 The eccentric jets of valve
the segment with or without the small floating echo of prolapse194 impinge on the LA wall and tend to underesti-
ruptured chordae (Fig. 17.34).107 mate MR.146 Central jets of functional MR expand markedly
The mechanism of MR due to bacterial endocarditis is in the enlarged LA and tends to overestimate MR.146
most often flail leaflets (due to the ruptured infected chordae),
which are relatively easy to diagnose.107 Perforations are more
difficult to diagnose. Mitral annular abscesses are rare and
are best detected by transesophageal echocardiography. Veg-
etations can be seen on leaflets or on ruptured chords with
superior sensitivity by transesophageal echocardiography.189
To diagnose IMR or FMR, a dilated annulus,118,190 is non-
specific,146 but annular contraction is reduced. The features
of ischemic heart disease may be observed as regional wall
motion abnormalities (Fig. 17.22).118 The leaflet tissue is
normal. The mitral tenting is due to the abnormal traction
by the secondary chordae on the leaflets,139 which deforms
the leaflets with a typical mid-leaflet tethering and the jet of
MR is central (Fig. 17.23).118,190 Rarely, the tethering predomi-
nates on one leaflet and the other leaflet overshoots in systole
beyond the tethered leaflet (but without prolapse) and the jet
is eccentric. Short axis views may reveal the origin of MR
on the medial commissure in IMR due to inferior myocardial
infarction.191 With papillary muscle rupture,119 MR is due to
the flail leaflet. The diagnosis is based on visualization (if FIGURE 17.34. Transesophageal echocardiography showing a flail
necessary by TEE) of a small mass of muscle attached to posterior leaflet (arrowheads) with ruptured chord (long arrow). Note
chordae and floating freely during the cardiac cycle.192 the normal thickness of the anterior leaflet and the enlarged LA.
416 chapter
Transesophageal echocardiography usually shows larger jets
but does not suppress these limitations of color-flow imaging.
The vena contracta is the region of the regurgitant flow
immediately below the flow convergence through the regur-
gitant orifice.195 Therefore, direct measurement of the vena
contracta width provides a surrogate of the regurgitant orifice
area. The vena contracta width is simple, appears superior to
jet measurements, and can be obtained either through trans-
esophageal195 or transthoracic echocardiography.196
Pulsed-wave Doppler assessment of pulmonary venous
velocity profile is useful to assess the degree of MR.197 Sys-
tolic reversal in pulmonary veins is a specific sign of severe
MR (Fig. 17.37) and is related not only to MR severity but
also to jet direction and LA pressure.198 Consequently,
FIGURE 17.36. Central jet of mitral regurgitation (apical long-axis
view) in a patient with functional mitral regurgitation. Despite a
small regurgitant volume the jet is large and fills most of the LA.
17
FIGURE 17.35. Eccentric jet of mitral regurgi-
tation associated with a flail posterior leaflet.
(Left) An echocardiographic four-chamber view
of the flail leaflet (arrow). (Right) A jet directed
superiorly in the left atrium, remaining thin
and wall-attached (Coanda effect) to the bottom
of the LA.
pulmonary venous reversal may be absent or asymmetric
in severe MR.198
The goal of the quantitative methods is to measure the
volume overload expressed as the regurgitant volume (differ-
ence between the total and forward stroke volume) or frac-
tion (proportion of LV ejection volume regurgitated in the
LA). The lesion severity is expressed as the effective regurgi-
tant orifice (ERO) area and calculated as follows123,199:
ERO = regurgitant flow/regurgitant velocity, or
ERO = regurgitant volume/regurgitant TVI
where regurgitant TVI is the time velocity integral of the
regurgitant jet.
Quantitation of MR can be performed using various
methods:
• Quantitative Doppler is based on the calculation of the
mitral and aortic stroke volumes (Fig. 17.38) using pulsed
wave Doppler.200 The principle is simple and applicable
D
.50
n/s
.50
FIGURE 17.37. Pulsed-wave Doppler recording of pulmonary
venous flow in a patient with severe mitral regurgitation. The early
forward systolic flow is blunted and followed by a late systolic flow
reversal (S). The diastolic flow (D) is normal.
 m i t r a l va lv e d i s e a s e s 417

FIGURE 17.38. Quantitative Doppler

measurement of the mitral regurgitant
volume. The lower images show the
measurement of annular diameters and
the upper tracings the measurement of
pulsed-Doppler velocity at the annular
levels. On the left the mitral stroke
volume is measured, and on the right the
aortic stroke volume. The difference
between these volumes is the regurgi-
tant volume, 81 mL in this example.

in most cases, but the measurement of the mitral stroke
volume is technically demanding with a significant
learning phase.200
• Quantitative two-dimensional echocardiography is of
similar principle, but is based on measurement of LV
volumes for total stroke volume calculation.201
• The proximal isovelocity surface area (PISA) method,
conversely directly measures regurgitant flow by analyz-
ing the flow convergence proximal to the regurgitant
orifice and is based on the principle of conservation of
mass. Because color flow mapping allows precise deter-
mination of velocity in the flow convergence region, the
regurgitant flow can be calculated. Using regurgitant
flow and velocity, regurgitant orifice (Fig. 17.39) and
volume can be calculated.199 This method is simple and
accurate if the assumptions are respected.

FIGURE 17.39. Proximal flow conver-

gence (PISA) measurement of the mitral
effective regurgitant orifice. (Left) The
color flow imaging of the flow conver-
gence with down shifting of the color
baseline so that the blue-yellow aliasing
velocity reaches 53 cm/s. The flow con-
vergence radius of 0.94 cm allows calcu-
lation of regurgitant flow at 294 mL/s.
(Right) The continuous-wave Doppler Flow = 294 mL/sec. MR velocity = 557 cm/s
measurement of the peak regurgitant
velocity at 557 cm/s. The ratio of flow to
velocity calculates the effective regurgi-
ERO = flow/velocity = 0.53 cm2 or 53 mm2
tant orifice at 0.53 cm2.
418 chapter 17

TABLE 17.4. Signs used for MR severity assessment by Doppler-echocardiography

Mild Moderate Severe

Specific signs • Small central jet <4 cm or <20%

2
Signs of MR > mild present, • Vena contracta width ≥0.7 cm with
of LA area but no criteria for severe MR large central MR jet (area >40% of
• Vena contracta width <0.3 cm LA) or with wall-impinging jet of any
• No or minimal flow convergence size, swirling in LA
• Large flow convergence
• Systolic reversal in pulmonary veins
• Prominent flail MV leaflet or
ruptured papillary muscle
• Dense, triangular CW Doppler MR jet
Supportive signs • Systolic dominant flow in Intermediate signs, findings • E-wave dominant mitral inflow
pulmonary veins (E >1.2 m/sec)
• A-wave dominant mitral inflow • Enlarged LV and LA size (particularly
• Soft density, parabolic CW when normal LV function is present)
Doppler MR signal
• Normal LV size

Quantitative parameters
RVol (mL/beat) <30 30–44 45–59 ≥60
RF (%) <30 30–39 40–49 ≥50
ERO (cm2) <0.20 0.20–0.29 0.30–0.39 ≥0.4

The gradation schemes in mild, moderate, or severe MR

for specific and supportive signs are presented in Table 17.4.
Importantly, RVol ≥60 mL and ERO area ≥40 mm2 (or 0.40 cm2)
are thresholds representing severe organic MR,202 and are
associated with excess risk under medical management.168 It
is also important to note that smaller RVol and ERO are
markers of IMR with severe clinical consequences,174,178 and
therefore that differential grading for organic and FMR
should be used.
Assessment of left ventricular and atrial function is most
often based on guided M-mode diameters, with assessment
of LV size, mass, and wall stress.187,203,204 The LV volumes can
be reliably measured by two-dimensional echocardiogra-
phy.205,206 The ejection fraction can be calculated 207 or esti-
mated.208 M-mode diameter or volume can assess the LA size
by two-dimensional echocardiography.209

Cardiac Catheterization
Cardiac catheterization is rarely performed for the diagnosis
of MR but may assess the hemodynamics, MR severity, and
LV function if Doppler echocardiographic imaging is poor or
ambiguous, and allows assessment of coronary anatomy
preoperatively.
The major hemodynamic consequences of MR are reduc-
tion of cardiac output and elevation of pulmonary artery
wedge pressure. Marked pulmonary hypertension is rarely
present. The large V wave of the LA or pulmonary wedge
pressure (Fig. 17.40) is more frequent in acute than in chronic
MR,210 but can be observed in either disease with reduced
left atrial compliance without MR.211
The assessment of MR degree can be obtained by LV
selective angiography and can be qualitatively graded in
three or four grades on the basis of the degree and persistence FIGURE 17.40. Cardiac catheterization with simultaneous record-
of opacification of the LA.212 Although time honored, this ing of the LA and LV pressure and of the transmitral continuous-
wave Doppler. Note the large V wave on the LA pressure tracing
method has limitations similar to all qualitative methods.213 reflected on the Doppler tracing by the triangular shape of the sys-
Quantitation of MR can be obtained by comparing the tolic jet signal revealing the ventriculoatrial equalization of pres-
angiographic stroke volume to the forward stroke volume sure at end-systole.
 m i t r a l va lv e d i s e a s e s
calculated by the Fick or thermodilution methods214 to cal-
culate RVol. The angiographic stroke volume usually overes-
timates the true stroke volume, and corrections have been
used to minimize the overestimation of RVol. Subtraction of
two stroke volumes introduces a potentially high range of
error, which cannot be verified by combined methods or by
repeating the measurements, and therefore this method is
rarely utilized.
The assessment of LV function can be performed using
quantitative angiography. Left ventricle volumes correlate
strongly with the regurgitant volume, duration, and etiology
of MR and LV function. The most frequently utilized indices
of LV function are end-systolic volume and ejection fraction,
which are useful prognostic indices.135,215 High-fidelity pres-
sure recording with LV angiography allows calculation of
more complex indices of LV distensibility in diastole,138 and
of wall stress, maximum LV elastance, and LV systolic stiff-
ness. The additional value of these complex measurements
has been investigated in small groups of patients and remains
to be defined in larger populations.
Selective coronary angiography allows definition of coro-
nary anatomy. Obstructive coronary atherosclerosis contin-
ues to be frequent even in the absence of angina,216 and
coronary angiography is performed ordinarily in patients
older than 40 to 50 years before surgery.217
Management
Medical Treatment
Prevention of infective endocarditis using the appropriate
prophylaxis is necessary in patients with MR.218 Young
patients with rheumatic MR should receive rheumatic fever
prophylaxis. In patients with atrial fibrillation, rate control
is achieved using Digoxin or beta-blockers. Long-term main-
tenance of sinus rhythm after cardioversion in patients with
severe MR or enlarged LA is usually not possible in patients
medically managed. However, return to sinus rhythm after
surgery is possible in patients with atrial fibrillation of short
duration.219 Oral anticoagulation should be used in patients
with atrial fibrillation. Diuretic treatment is useful for the
control of heart failure and for the chronic control of symp-
toms, especially dyspnea. However, these efforts should not
delay consideration of surgical repair in patients who are
otherwise candidates for surgical therapy.
Acute afterload reduction may decrease the degree and
consequences of MR.124 This effect is achieved by reducing
the LV systolic pressure but also by decreasing the effective
regurgitant orifice area.125 Acute utilization of sodium nitro-
prusside in unstable patients with severe MR, especially in
the context of myocardial infarction, may be lifesaving in
preparation for surgery.124
Chronic afterload reduction is more controversial.
Hydralazine has positive acute effects,220 but this drug is
often poorly tolerated chronically. The effects of angiotensin-
converting enzyme inhibitors have been analyzed in small
series,221–223 and their long-term efficacy is not defined. Fur-
thermore, discrepancies between series are noted regarding
the effect on the degree of MR 224 and on LV remodeling.225
In a nonrandomized open series, we observed positive results
on MR severity, LV volumes, and LA enlargement of treat-
419
ment with angiotensin-receptor blockade.226 Because there
are no results of long-term randomized studies, vasoactive
therapy is not yet recommended for chronic treatment of
MR.110,217 Despite interesting animal data,157,227,228 beta-block-
ade in chronic organic MR remains unproven in human
subjects.
Conversely in IMR and FMR there is a strong body of
evidence suggesting that medical treatment improves the
degree and consequences of MR. Angiotensin-converting
enzyme inhibitors or angiotensin receptor blockers decrease
afterload and remodeling and improve MR.229 Furthermore,
beta-blockade also improves LV remodeling and decreases
the degree of FMR with subsequent improvement in
survival.230–233 Therefore, these drug therapies are considered
standard in patients with ischemic and functional MR.
Interventional treatment remains currently experimen-
tal. Devices that allow percutaneous suture between the
mitral leaflets,234,235 similar to the surgical Alfieri suture236
or annular cinching,237,238 mimicking annuloplasty, are under
initial evaluation. Great hopes of new therapeutic avenues
are yet to be confirmed.239
Surgical Treatment
The approach to surgery can be the traditional median ster-
notomy or the more recently used “minimally invasive”
approaches, which range from port-access surgery to small
sternotomy to thoracotomy.240 These new techniques appear
interesting but their long-term outcome remains uncertain.
There are two main valvular surgical options: mitral valve
repair and valve replacement.
Mitral valve repair is possible in >85% of patients with
MR, when the intervention is performed in advanced repair
centers by surgeons with considerable experience with mitral
surgery.168 Nationally, valve repair is performed in approxi-
mately 50% of patients operated for mitral valve diseases.
The frequency with which valve repair can be used varies
with the experience of the operating team and the spectrum
of the underlying valve disease; repair is more often feasible
with degenerative than with rheumatic or endocarditic valve
disease.107
Valvular procedures involve plication or more often exci-
sion of a valve segment with prolapse (Fig. 17.41).241 However,
the resulting reduction in area of the leaflet could reduce
coaptation and induce residual MR; therefore, annuloplasty
is usually a routine part of the repair.242 This type of repair
is most successful with posterior leaflet prolapse. However,
postoperative systolic anterior motion of the mitral valve and
LV outflow tract obstruction may be observed.243 This com-
plication is due mainly to hypovolemia and excessive use of
inotropes.244 However, extensive myxomatous disease of the
posterior leaflet with excessive leaflet length may lead to
persistent systolic anterior motion, which can be prevented
by sliding repair, which reduces the leaflet length.245 With
anterior leaflet prolapse, because of the limited width of the
leaflet, the risk of residual MR is higher with plication or
resection.114,244,246 Other highly repairable leaflet abnormali-
ties include congenital clefts and acquired perforation, which
may be closed by using a patch. New procedures extended
the armamentarium of valvular procedures used to correct
lesions traditionally not considered repairable. In patients
420 chapter
FIGURE 17.41. Schematic representation of the mitral valve repair
technique in a patient with flail posterior leaflet (upper left) with
triangular resection of the flail segment (upper right), reapproxima-
tion of the leaflets segments left in place and restoration of an
appropriate coaptation line.
with leaflets retraction, mitral leaflet augmentation with a
pericardial patch may be helpful.247,248 Similar approaches
have been proposed in ischemic MR.249
Subvalvular procedures are often necessary. In patients
with elongated chordae, chordal shortening was intended to
ensure appropriate coaptation of leaflets, but the durability
of this procedure is limited.114 Major recent improvements
were the use of transposition of chordae or of artificial
chordae,250–252 which have made anterior leaflet prolapse
repair almost as feasible and as durable as posterior leaflet
prolapse repair.246
Annular dilatation, almost constantly associated with
MR, is treated by reduction of mitral circumference, i.e.,
annuloplasty.253 A rigid ring was originally developed by Car-
pentier, but flexible annuloplasty rings have been developed
to preserve the normal systolic contraction of the mitral
annulus,254 and even simple bands have been proposed to
support the repaired leaflet. No definitive differences have
been demonstrated between the various rings. In ischemic
and functional MR, restrictive annuloplasty has been advo-
cated,255 because standard annuloplasty leads to frequent
recurrence.256 Although early experience with this approach
appears interesting,257 the effect on survival is uncertain.258
Intraoperative assessment of valve repair259 is essential to
assess the adequacy of mitral valve reconstruction before
completion of the operation,260 and is a significant compo-
nent of improved results of mitral repair. When satisfactory
17
repair cannot be achieved, it is preferable to replace the
valve immediately. To assess the adequacy of mitral repair
(residual stenosis, regurgitation, or systolic anterior motion),
TEE, which does not interfere with the surgical procedure,
is performed routinely.244
Valve replacement must be performed when mitral repair
is impossible or is unsuccessful. The choice is between a
mechanical valve of potentially excellent durability but with
a hazard of thromboembolism and a biologic valve with
undefined long-term durability261 but less tendency to cause
thromboembolism. With atrial fibrillation, chronic antico-
agulant therapy is necessary even with a bioprosthesis, so
that avoiding anticoagulation is not relevant in choosing a
prosthesis. An important component in maintaining LV
function postoperatively is chordal preservation during valve
replacement.262,263
Postoperative outcome after surgery for organic MR is
essential to determine the appropriate indications. Valve
repair, by preserving the normal valvular tissue, is preferable
to valve replacement. Compared to prosthetic replacement,
valve repair has a lower operative mortality.264,265 Direct com-
parison of the results of valve repair and replacement is dif-
ficult265 because patients undergoing valve repair are usually
at a less advanced stage of the disease than patients undergo-
ing valve replacement.264 However, survival and LV function
after valve repair are better than after insertion of a pros-
thetic valve,264,266,267 even in patients with anterior leaflet
prolapse (Fig. 17.17).246 Better ventricular function with val-
vuloplasty may be due to preservation of chordae and papil-
lary muscles.268 Durability of valve repair for degenerative
disease is excellent if no more than mild residual MR
is accepted intraoperatively,114,246 even very long term after
surgery.269 Some centers noted, despite superior survival,
higher rates of recurrent MR and lesser durability after valve
repair,270 suggesting that the results of each individual center
should be analyzed in indicating mitral repair. However,
valve repair has the same low rate of reoperation than valve
replacement.246,264 Mitral regurgitation postrepair is attrib-
uted in two thirds of the cases to new lesions and in one
third to an inadequate primary correction.271 Therefore, valve
repair is the preferred procedure for surgical correction of
organic MR.
Operative mortality has been reported between 5% and
12%261 in earlier series, but most patients had prosthetic
valve replacement rather than reconstruction. The operative
risk is lower in the current era, around 1% in patients younger
than 75 years with organic MR whether they had valve repair
or replacement,187 and around 2% to 3% above that age. Left
ventricle function is not a predictor of operative mortality,
and patients with organic MR even with markedly depressed
function have a reasonable chance of surviving surgery.187
Age, symptoms, and coronary disease are the most impor-
tant predictors of operative mortality.187 The operative mor-
tality is notably higher in ischemic MR even after valve
repair.272,273
Long-term postoperative survival has considerably
improved, and survival after valve repair is close to expected
survival, whereas it is reduced compared to expected sur-
vival after valve replacement.114,246,264,269 Another important
determinant of long-term postoperative outcome is the
preoperative symptomatic status. Patients with severe
 m i t r a l va lv e d i s e a s e s
100
p < .0001 p = .18
80
Survival (%)
60
Observed
40 Expected
20 NYHA III–IV NYHA I–II
0
40 26 8 10 0 2 4 6 8
Years Years
FIGURE 17.42. Long-term postoperative outcome according to pre-
operative symptoms in patients with isolated mitral regurgitation.
The left graph shows that observed postoperative survival (dotted
line) in patients presenting with New York Heart Association class
III or IV is significantly lower than the expected survival (solid line).
The right graph shows that observed survival in patients operated
with no or minimal symptoms (class I or II) is identical to the
expected survival consistent with restoration of life expectancy by
mitral surgery in patients operated at that stage.
preoperative symptoms, NYHA class III or IV, incur indepen-
dently of all baseline characteristics, in particular age, ejec-
tion fraction, and the type of surgery performed, an excess
operative and long-term mortality despite their postoperative
symptomatic improvement.274 Importantly, patients preop-
eratively in class I or II incur a very low operative risk 274,275
and an excellent long-term survival, identical to the expected
survival (Fig. 17.42).274 These results have been confirmed by
comparing outcome after diagnosis of organic MR between
patients operated early and conservatively managed, showing
that the early surgical approach not only provides a survival
advantage,276 but also results in restoration of life expectancy
in patients asymptomatic at diagnosis.168 These data suggest
that in centers and patients at low operative risk, early repair
of organic mitral regurgitation in asymptomatic patients
suppresses the ominous consequences of severe MR and
restores life expectancy.
After mitral surgery for symptoms, most patients improve
symptomatically by at least one functional class and some
become asymptomatic. However, with time postoperative
heart failure and symptomatic deterioration tend to occur at
a progressively increasing rate (38% at 10 years in operative
survivors) and is most often (two thirds of the cases) due to
residual LV dysfunction.277 Valvular or prosthetic dysfunc-
tions explain heart failure in approximately one third of
cases.277
The most frequent cause of mortality after surgical
correction of MR is LV dysfunction187 due to chronic irrever-
sible myocardial damage.131,134,135 Left ventricle dysfunction
occurred in our experience in approximately one third of
patients with organic MR.134 The majority of patients dem-
onstrate a decrease in ejection fraction after successful valve
replacement.131,134 This decline may be the result of several
factors: cumulative permanent myocardial damage, occa-
sional myocardial insult sustained at the time of operation,
diminished preload, and probably an increase in impedance
to ejection after elimination of the MR. However, the
4 21
relationships between pre- and postoperative LV func-
tion,130,131,134,135,215 and between preoperative LV function and
postoperative survival,133,187,203 underline the fact that LV dys-
function is most often already present preoperatively. Because
of the modified loading conditions, multiple and complex
indices of LV function have been proposed.130,132,133 Despite
these altered loading conditions, preoperative ejection frac-
tion is an acceptable independent predictor of postoperative
ejection fraction131,134,135 and survival.187 In general, one can
estimate that the postoperative ejection fraction likely will
decrease by approximately 10% early after valve replace-
10
ment.131,134,135 However, there is a significant individual varia-
tion, and more decline is observed with markedly increased
end-systolic diameter,134,203 volume,135,215 or wall stress134 or
in patients with severe symptoms, prolonged duration of MR,
or coronary disease.134 A markedly reduced preoperative ejec-
tion fraction (<50%) is associated with a high late mortality
(Fig. 17.43),187 but nevertheless surgery provides a better
outcome than medical treatment.170 Even a “borderline”
ejection fraction (50% to 60%) is associated with an excess
late mortality.187 Therefore, signs of overt LV dysfunction in
MR are LV diameter ≥45 mm or ejection fraction <60%.217
Nevertheless, the end-systolic diameter rarely and belatedly
reaches 45 mm,278 and the best outcome of surgery is obtained
in patients with both end-systolic diameter <45 mm and
ejection fraction ≥60%.134,187,278
Atrial fibrillation when chronic preoperatively usually
persists postoperatively, unless it is of brief duration.219 The
association of a Maze procedure with mitral valve repair can
be accomplished with minimal risk; it maintains sinus
rhythm279 and may reduce the embolic risk. Even patients
operated in sinus rhythm incur a notable risk of postopera-
tive atrial fibrillation, determined in particular by LA
enlargement.280 Postoperative atrial fibrillation increases the
risk of postoperative heart failure or stroke, suggesting that
surgery before excessive LA enlargement should be consid-
ered. Differences in thromboembolic risk after valve repair
100
80 73%
Survival (%)
60 53%
EF ≥60%
40
EF 50–60%
32%
20 EF <50%
p = .0001
0
0 2 4 6 8 10
Years
FIGURE 17.43. Postoperative survival (after mitral regurgitation
surgery) according to preoperative ejection fraction (EF). Consider-
able mortality is observed when EF is <50% preoperatively, whereas
excess mortality is lesser but significant with pseudo-normal EF
(50–60%) and the best survival is obtained in patients with EF
≥60%.
422 chapter
and valve replacement have been variably estimated 264,265 but
appear to favor valve repair. In addition, because following
valve repair anticoagulation is recommended permanently
only if atrial fibrillation persists, the occurrence of bleeding
is less common than following prosthetic replacement.264
Postoperative outcome after surgery for functional MR
(or IMR) is less well known. Patients present with a more
advanced clinical situation, with more heart failure, more
reduction of LV function, and comorbid conditions such as
reduced renal function. The operative mortality is higher
than in patients with organic MR, and long-term survival is
reduced.281 Valve repair superiority to valve replacement is
uncertain and may be limited to patients with the least
severe condition.272 Furthermore, valve repair is complicated
by more frequent recurrence of MR than in organic
MR.256,282,283 Therefore, the indications of surgery in IMR and
FMR remain uncertain but recent improvements145,249,257,284,285
suggest that more aggressive indications for repair may be a
future consideration.
Indications for Surgery
For ischemic MR, recognized rescue indications of surgery
address patients with severe symptoms and severe IMR or
FMR. However, the recognition that moderate ischemic MR
is a condition that may result in poor outcome of patients
undergoing coronary bypass surgery,286 there is an ongoing
debate regarding extending indications of valve repair to
these patients to obtain the best possible result.257 The treat-
ment of FMR due to cardiomyopathy provides an uncertain
survival benefit,258 but the current low risk of surgery opens
consideration of valve repair before the occurrence of intrac-
table heart failure.285
For organic MR, based on the most recent data regarding
the natural history of MR with and without surgery, the
indications for surgery in patients with severe MR have
evolved 217 and can be outlined as follows:
R ESCUE INDICATIONS
Patients with severe symptoms (functional class NYHA III
or IV): Patients with transient severe symptoms even if they
markedly improve with medical treatment should be consid-
ered within this category. Patients with overt LV dysfunc-
tion, even if asymptomatic, should also be offered prompt
surgical repair. However, these indications, which represent
most of the class I indications in the current guidelines,217
imply an excess postoperative risk without restoration of life
expectancy.187,274
E ARLY INDICATIONS
Patients with no or minimal symptoms, severe MR based on
ERO ≥40 mm2 and no sign of LV dysfunction (ejection frac-
tion ≥60%) are candidates for this type of indication. In
centers where the operative risk is low and the percentage of
valve repair high, such patients can expect the best results
of surgery and a survival identical to the expected sur-
vival,187,274 with restoration of life expectancy.168 Therefore,
surgery is a reasonable option in patients with low comorbid-
ity. However, because surgery in these patients is justified
neither by symptoms nor by LV dysfunction certain condi-
tions should be fulfilled:
17
• Low operative risk: Both the operative mortality in the
institution where such an indication is contemplated and
the operative risk for the individual patient involved
should be minimal (1% to 2%).
• Reparability: The valvular lesions as determined by
echocardiography should be in all probability repairable
and the surgeon performing the intervention should
have a high degree of experience with all forms of valve
repair.
• Intraoperative TEE should be performed by experienced
physicians, to monitor the repair procedure and help with
decisions warranted by an imperfect result.287
• Quantitation of MR should be performed systematically
in these patients preoperatively using multiple noninva-
sive techniques to determine objectively the degree of
MR and affirm that surgery is warranted.
Therefore, despite the considerable progress recently accom-
plished, currently not all patients and not all institutions
are candidates for these early indications of surgical correc-
tion of organic MR, but surgery should be considered early
in the course of MR when severe MR has been thoroughly
documented.
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17
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 1 Rheumatic Fever
8 Y.S. Chandrashekhar and Jagat Narula
The Global Burden of Rheumatic Fever . . . . . . . . . . . . .
Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Mechanisms of Damage . . . . . . . . . . . . . . . . . . . . . . . . . .
Pathology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Key Points
• Streptococcal group A β-hemolytic pharyngitis mediates
acute rheumatic fever (ARF).
• Cardiac involvement in ARF involves pericardium, myo-
cardium, and endocardium.
• The “pathognomonic” histopathologic finding in the
myocardium is the Aschoff nodule.
• Arthritis is often the earliest manifestation of ARF and
brings the patient to clinical attention.
• Carditis is the only manifestation of ARF that results in
permanent deformity. Clinically detectable cardiac invol-
vement occurs in a significant proportion of patients with
ARF.
Rheumatic fever (RF) is a delayed, noninfectious consequence
of pharyngitis caused by group A β-hemolytic streptococci
(GABHS). While it is rare in the developed world, RF remains
a major problem worldwide.1 However, RF still continues to
show up unexpectedly even in the First World as evidenced
by occasional outbreaks in the United States.2 Furthermore,
given the magnitude of international travel and immigration,
clinicians everywhere are likely to encounter RF or its dev-
astating cardiac sequelae. Finally, the cause of the rise and
fall of RF in the developed world has not been fully explained
at a time when GABHS carrier rates have not been signifi-
cantly diminished.3 This raises the possibility of a sudden,
unexpected resurgence, and RF thus remains an important
disease to understand. Acute rheumatic fever affects multiple
organ systems, which makes it a difficult diagnosis in regular
practice; most commonly it presents as a combination of
arthritis, carditis, chorea, erythema marginatum, and/or
subcutaneous nodules, and valvular heart disease remains
a major long-term sequela. It has thus been aptly said that
“rheumatic fever licks the joints, but bites the heart.” This
chapter briefly discusses the pathogenesis, recognition, treat-
ment, and prevention of acute RF. The reader is referred
elsewhere4 for more in-depth treatment of this topic.
431 Clinical Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
432 Laboratory Investigations . . . . . . . . . . . . . . . . . . . . . . . . . 436
432 Natural History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
432 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
434 Streptococcal Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
The Global Burden of Rheumatic Fever
Acute RF (ARF) was a major problem in the U.S. until
the 1960s, and in fact was a common cause of disqualifica-
tion among young men and women being considered for
the military. Since then, RF has largely disappeared as
a major cause of illness in the U.S.5 Improved socioeco-
nomic status, reduced crowding, the advent of antibiotics,
and the widespread treatment of streptococcal throat
infections have contributed to this decline. Unfortunately,
ARF continues to be rampant in the developing world.
The World Health Organization (WHO)6 reported an inci-
dence of ARF of fewer than 1 case per 100,000 population
per year in the industrialized world, compared to 100 to
150 cases per 100,000 population in some areas of the
eastern Mediterranean, the western Pacific and China.
Acute RF remains a cause of much morbidity in the young.
Rheumatic heart disease (RHD), a long-term sequela of
RF, continues to be the most common cause of cardio-
vascular complication and death in young persons in
the developing countries. Surveys in school-age children
show an RHD prevalence as high as 78 per 1000 in some
developing countries.7 It accounts for more than one third
of cardiovascular admissions to hospitals in developing
countries and constitutes a major indication for cardiac
surgery.8 Thus, RF and RHD impose a significant economic
burden on the total health budget in developing countries.
Having said that, RF continues to show up all over the
world, and several outbreaks have occurred in the U.S. in
portions of Utah and Ohio and at U.S. Naval Training
Centers.9 Many of these outbreaks have involved middle-
class suburbs, less crowded communities, and people
with access to excellent health care—a situation entirely
unlike the developing world, where socioeconomic
issues are thought to be responsible for RF outbreaks.
This once again emphasizes our limited understanding
of RF.
4 31
432 chapter
Etiopathogenesis
The pathogenesis of rheumatic fever and RF-induced cardiac
damage is not well understood. The lack of a good clinical
model for RF is an important limitation. However, there is
a significant body of data to suggest an autoimmune process.
The salient features involved in the pathogenesis include (1)
a human host who harbors “RF susceptibility factors,” which
are thought to increase the proclivity to developing ARF; (2)
pharyngitis (and interestingly, not other sites of streptococ-
cal infection) with certain strains of GABHS with rheumato-
genic potential; (3) the presence of an immune response
against specific streptococcal antigens; the magnitude of
this response correlates with the occurrence of subsequent
ARF; and (4) an interval of 1 to 5 weeks between GABHS
pharyngitis and the development of ARF that presumably
allows time for mounting an immune-mediated injury.
Host Factors
Only a few individuals with group A streptococcal infection
develop RF,10 and the genetic makeup of the host may convey
differing susceptibility to ARF. The putative “susceptibility
factor” remains unclear so far, and indeed there may be many
such factors. Identifying these factors is likely to help us
target preventive measures and is the focus of intense study.
Certain racial characteristics (e.g., Samoans in Hawaii and
Maori in New Zealand) and a history of previous episodes of
RF increased the susceptibility to RF after GABHS pharyn-
gitis. Another factor may be the differing ability to mount a
vigorous antibody response since this correlates with the
occurrence of ARF. Familial or genetic susceptibility to
RF has been postulated.11,12 Acute RF risk correlates with
the increased prevalence of human leukocyte antigen (HLA)
DR4 in the U.S.12 and Saudi Arabia13 and with the increased
prevalence of DR3 and DQw2 in India.14 However, these
associations were obtained with older serologic methods
and have to be confirmed with newer methods of typing.
Some other markers, such as B-cell alloantigen D8/17, have
shown a strong association with susceptibility to RF15 in U.S.
populations, but these perform less efficiently in North
Indian populations where other markers seem to perform
better. Finally, target organ sensitivity may also be geneti-
cally determined in rheumatic fever, and this kind of sensi-
tivity may determine which tissues get deposited with
antibodies.16
Factors Within Streptococci
Among the various serotypes of group A streptococci, only
some appear more likely to initiate acute RF (M-types 1, 3,
5, 6, 14, 18, 19, 24, 27, and 29), whereas some other strains
are not commonly associated with ARF (M2, 4, and 28).
Furthermore, only throat and not skin infections mediate
ARF. The exact mechanism by which GABHS initiates RF
is unclear, and it is also not known why throat infections
and not other streptococcal infections lead to RF. In general,
the RF strains tend to be rich in M protein, provoke an
intense M-type–specific immune response, and probably
share epitopes with human tissue. However, the concept of
18
rheumatogenic streptococci and the concept that only throat
infection can cause ARF is not universally accepted17 and
awaits further study.
Mechanisms of Damage
Despite some claims of direct injury by streptococci, viruses,
or toxins, most data suggest that RF is an autoimmune injury.
Antibodies (cross-reactive and polyspecific) that react to
shared antigens between streptococci and human tissue
(molecular mimicry) are thought to underlie this process.
Rheumatogenic streptococci contain multiple antigenic
determinants that partially mimic normal human tissue
antigens.10 Thus the hyaluronate capsule, the streptococcal
membrane, and the M-proteins share similarity with valve
glycoproteins, myocardial sarcolemma, and cardiac contrac-
tile proteins, respectively. Following streptococcal pharyngi-
tis, these antigens, which are recognized as foreign by the
susceptible host, induce a hyperactive humoral and cellular
immune response that damages native tissues bearing similar
antigen. The type of damage is then partly the result of which
tissue shows what kinds of mimicry. For example, antibodies
to the N-acetylglucosamine moiety of group A polysaccha-
ride cross-react with the heart valve tissue,18 and this is
thought to mediate valve damage; indeed such antibodies are
increased in patients with rheumatic heart valve disease.19
Breakdown of tolerance is an important component in
the pathogenesis of ARF. The M-protein epitopes not only
can trigger heart cross-reactive antibodies and T-cell
responses20 but also can act as superantigens.21 This might
explain the widespread immune response overriding the his-
tocompatibility barrier. In fact, both humoral and cellular
immune responses are more vigorous in patients with ARF
than in normal subjects and might be related to superanti-
genic property of streptococcal M protein. A significant T-
cell infiltration is also observed in the valvular tissue, and
T cells isolated from valvular tissue of patients with rheu-
matic heart disease respond to streptococcal M5 protein and
also cross-react with cardiac myosin.22 This homology with
cardiac myosin can be expected to decrease tolerance and
may enhance T-cell–mediated inflammatory damage.23
Pathology
The cardiac and noncardiac tissues differ in how they react to
ARF. The inflammatory process in the skin, joints, and brain
tends to regress spontaneously without any significant resid-
ual effects. There is swelling with serous effusion in the
joints. Inflammatory infiltration and edema are evident in
the synovial membranes. A fibrinoid exudates frequently
lines the membranes. The blood vessels in the articular and
periarticular areas are often inflamed and show infiltration
with lymphocytes and polymorphonuclear leukocytes. On
the other hand, the subcutaneous nodules have a center of
fibrinoid necrosis with peripheral inflammatory reaction of
lymphocytes and occasional polymorphonuclear leukocytes.
Cardiac involvement in RF affects all three layers: peri-
cardium, myocardium, and endocardium. The pericarditis is
 r h eum at ic fev er 433

A
A

B B
FIGURE 18.1. (A,B) Pericarditis. Gross pathologic specimens
obtained from a patient who died of rheumatic fever. The outer, or
parietal, layer of the pericardium has been partially reflected away,
revealing the epicardium, which is covered with shaggy fibrinous
exudates as if a buttered sandwich had been pulled apart—hence the
term bread-and-butter pericarditis.

typically fibrinous (Fig. 18.1). The histopathologic findings in

myocardium include the “pathognomonic” Aschoff nodule
(Fig. 18.2).24 The Aschoff granuloma consists of a central area
of fibrinoid necrosis surrounded by cells of histiocytic-
macrophage origin (Anitschkow cells), which show a typical
owl’s eye–shaped nucleus. These cells are usually found in
the subendocardial or perivascular regions in the myocar-
dium. There is surprisingly little histopathologic damage to C
the myocardium, even in patients with florid clinical carditis FIGURE 18.2. (A) Low-power microscopic intramyocardial view
and heart failure.25,26 Myocyte necrosis is uncommon, and shows Aschoff bodies. Note the nodular aggregate of Aschoff cells
immediately adjacent to a coronary arteriole (Hematoxylin and
the cellular infiltrate is confined to the interstitium. This eosin, ×120). (B,C) High-power microscopic view of an Aschoff body
correlates with the lack of troponin leaks even in patients illustrates the characteristic “owl-and-caterpillar” nuclei (H&E,
with frank rheumatic myocarditis.27 The conduction system ×250).
shows little pathology even in the presence of clinical
conduction defects.
The valves bear the brunt of the disease. The valves are
inflamed and thickened during the acute stage of the rheu- of the leaflets (Fig. 18.3), that are not associated with throm-
matic activity. The surface of the valves develops small, boembolic sequelae. A mild degree of inflammation leads to
sterile vegetations or verrucae, particularly along the edges fusion of the cusps while more severe inflammatory reaction
 434 chapter
A monly involved, occasional involvement of smaller joints in
B Although other manifestations of RF are not associated with
C
FIGURE 18.3. Valvulitis. (A) Gross appearance of the mitral valve
shows characteristic tiny, wartlike verrucae or vegetations on its
inflow side (atrial surface). (B) Similar verrucae on the ventricular
surface of the aortic valve. The verrucae are sterile and small and
only rarely result in embolization (unlike vegetations of bacterial
endocarditis). (C) Microscopic appearance.
extends into the subvalvular apparatus as well. This can
result in early mitral or tricuspid regurgitation, caused partly
by leaflet prolapse as well as annular dilatation. Aortic
incompetence also occurs as a consequence of thickening
and distortion of the valve leaflets. The scarring process may
18
be gradual, and patients with acute RF may be seen without
evidence of aortic valve affliction only to develop aortic
regurgitation at a later date. Mitral and rarely aortic stenosis
are late sequelae that result from scarring and inflammatory
fusion of leaflet cusps.
Clinical Features
Joint Symptoms
Arthritis is the earliest manifestation of RF and frequently
brings the patient to clinical attention.28 Arthritis occurs in
at least two thirds of patients, and is more common in older
patients. Although larger joints of the extremities are com-
the hand and feet may be seen; hips, spine, or axial joints are
rarely affected. The joints are swollen, hot, red, and tender.
The joints are inflamed at different times and for various
intervals to impart a migratory character to joint pains.
Monoarticular arthritis is not common. Arthritis usually
resolves in 3 to 4 weeks even without treatment but responds
instantly to aspirin therapy, and does not lead to permanent
damage. Arthralgia without objective signs of inflammation
is common in younger patients, in the presence of carditis,
particularly in rheumatic recurrences and in RHD patients
in the developing countries.29 Some forms of polyarthritis
after streptococcal pharyngitis may represent a reactive phe-
nomenon. Poststreptococcal arthropathy is characterized by
recurrent, severe, prolonged polyarthritis in adults that is not
very responsive to nonsteroidal antiinflammatory agents.
arthropathy, some patients end up with residual heart
disease.30 Prophylaxis in reactive arthropathy remains
similar to that for patients with RF, but very little data are
available to provide definite recommendations.
Cardiac Involvement
Carditis is the only manifestation of RF that results in per-
manent deformity.31 The cardiac involvement in RF has been
reported to occur in nearly one third of almost all cases in
various studies and in up to one half of cases in a prospective
series. Clinical carditis was seen in 72% of patients in a
resurgence of RF in Salt Lake City,2 which is similar to the
prevalence in the early part of the 20th century in the United
States.32 Subclinical carditis is being increasingly detected
with modern imaging methods; evidence of valvular regur-
gitation was seen in 19% of additional cases with the use of
echocardiography. Active rheumatic carditis can present in
a number of ways, including subclinical cardiac involve-
ment, acute or even fulminant congestive heart failure, and,
occasionally, chronic ongoing carditis. Younger patients
often present with carditis, whereas joint involvement is
more common in older patients.28 Although episodes of car-
ditis occur less frequently in older patients, they present
more often with unexplained worsening of congestive heart
failure. The clinical findings may be suggestive of pericar-
ditis, myocarditis, and valvulitis, and the guidelines for
the diagnosis of rheumatic carditis are summarized in
Table 18.1.
 r h eum at ic fev er
TABLE 18.1. Simplified schema for the diagnosis of acute rheumatic carditis*
Criteria First attacks
Valvulitis New onset apical systolic murmur or aortic regurgitation murmur
Carey-Coombs murmur
Myocarditis Unexplained cardiomegaly
Unexplained congestive heart failure/gallop sounds
Pericarditis Pericardial rub
Pericardial effusion
Miscellaneous Conduction disturbances or unexplained tachycardia†
Echocardiographic imaging‡
Nuclear imaging‡
Morphology evidence at surgery
Histologic evidence at biopsy or pathology
* Supportive evidence is required for the presence of acute rheumatic fever according to the Jones criteria. In patients with known rheumatic heart disease,
acute rheumatic fever can be diagnosed with minor criteria along with evidence of antecedent streptococcal infection.
† These would be considered soft criteria.
‡ The significance of these methods is controversial.
Endocarditis
Endocardial inflammation most commonly affects the mitral
and aortic valves, and the clinical diagnosis of rheumatic
endocarditis is based on the demonstration of mitral or aortic
regurgitation murmurs, or both. Mitral valve disease is seen
in approximately 70% of patients, mitral and aortic valve
disease occurs in an additional 25%, and isolated aortic valve
disease occurs in 5% to 8%. Clinical tricuspid or pulmonary
valve involvement is rare in the first attack of RF. The use
of echocardiography has clarified the mechanism of valve
regurgitation in RF.33 Although mild-to-moderate mitral
regurgitation is due to left ventricular dilatation with mild
or no annular dilatation, more severe degrees of mitral regur-
gitation are associated with marked annular dilatation,
chordal elongation, and anterior mitral leaflet prolapse.34
Rarely chordae may rupture, to result in flail leaflets and
severe regurgitation. Because mitral regurgitation frequently
disappears on follow-up,28,35,36 it is likely that a functional
mechanism rather than a permanent structural alteration in
the valve or annulus underlies the development of mitral
regurgitation. Inflammatory changes in the aortic valves and
the aortic ring result in aortic regurgitation; aortic valve
prolapse may contribute occasionally.
Myocarditis
Myocardial involvement is generally associated with new-
onset cardiomegaly, an interval increase in cardiac size, or
the development of congestive heart failure.26,31,37 The left
ventricular systolic function and myocardial contractility
indexes are normal in patients with rheumatic carditis, and
only minimal myocyte damage is pathologically seen in
rheumatic carditis. It is has been thought that hemodynami-
cally significant valvular lesions lead to the development of
congestive heart failure.37
Pericarditis
Clinical rheumatic pericarditis occurs in up to 15% of
patients during the acute stage of RF, and the presence of an
evanescent pericardial friction rub in this setting is evidence
435
Recurrences
Change in murmur
New-onset murmur
Worsening cardiomegaly
Worsening congestive heart failure
Pericardial rub
Pericardial effusion
of rheumatic carditis. The presence of pericarditis usually
indicates severe carditis.31
Rheumatic pericarditis is almost always associated with
findings of valvular involvement. A pericardial rub can
sometimes mask the underlying valvular murmurs. However,
other causes need to be considered if no valvulitis-related
murmur is audible after the resolution of pericarditis.31
Rheumatic pericarditis is often associated with a mild-to-
moderate serosanguineous effusion, and the development of
pericardial tamponade is rare.
Sydenham’s Chorea
Chorea is a late manifestation of RF that is characterized by
a series of involuntary movements that commonly involve
the face and extremities associated with emotional lability.28
It commonly affects children between the ages of 7 and 14
years, and occurs more frequently in girls; it is rarely seen
in adults. Chorea is often associated with carditis and sub-
cutaneous nodules, but it appears several weeks after an
acute attack of RF and when the acute manifestations have
disappeared. The patients thus do not fulfill the Jones criteria
at this time. The course of chorea is rather gradual as the
patient appears increasingly nervous, becomes dysarthric,
makes grimacing gestures, develops difficulty in writing,
and shows characteristic purposeless movements of the arms
and legs, which may be associated with muscular weakness.
The chronic movements are exaggerated in effort or excite-
ment but subside during sleep. Chorea is usually a self-
limited condition and resolves without residual damage but
the associated carditis can leave behind valvular damage.
Skin Manifestations
Subcutaneous nodules and erythema marginatum are two
important skin manifestations of RF. Subcutaneous nodules
occur late in the course of rheumatic fever. They are observed
in up to 20% of patients, and their presence is usually associ-
ated with carditis. Subcutaneous nodules occur on bony
prominences, vertebral spinous processes, or extensor
tendons, and are painless. They usually appear in crops,
are variable in size, and disappear within 2 to 3 months.
436 chapter
Erythema marginatum can be an early or a late manifesta-
tion. It occurs in fewer than 15% of patients and is present
on the trunk and proximal extremities as a serpiginous,
macular, nonpruritic, and evanescent rash.
Clinical Diagnosis
There is no single diagnostic test or pathognomonic sign that
allows an absolute diagnosis of RF, and the condition is rec-
ognized through a constellation of signs and symptoms in
the setting of recent GABHS pharyngitis. In 1944, Jones38
described the clinical manifestations of RF and categorized
them as major and minor. Since that time, the Jones criteria
have been modified several times under the auspices of the
American Heart Association. More recently, modifications
have been suggested by the WHO1 (Table 18.2). Various com-
binations of major and minor criteria are used for diagnosing
ARF. The major manifestations include the presence of
carditis, chorea, subcutaneous nodules, migratory arthritis
involving large joints, and the skin rash known as erythema
marginatum. The minor manifestations include fever, pro-
longed joint pains, prolonged electrocardiographic PR inter-
val, laboratory indicators of inflammation, and acute phase
reactants. An elevated antistreptolysin O (ASO) titer or other
evidence of preceding streptococcal infection is considered a
prerequisite.
Although the Jones criteria remain the cornerstone of
diagnosing ARF, they are continually changing to balance
sensitivity/specificity, address different forms of presenta-
tion, accommodate a variable diagnostic armamentarium in
different regions of the world, and reflect new information.
The most current WHO iteration has many clinically impor-
tant distinctions: (1) First attacks of RF and recurrent attacks
in patients with no evidence of previous established RHD
still need to adhere to the Jones criteria. (2) To diagnose recur-
rence in patients with established RHD requires only two
convincing minor manifestations plus evidence of a recent
streptococcal infection. (3) Evidence for recent streptococcal
infection is not required in rheumatic chorea and insidious
onset of clear rheumatic carditis. It should be remembered
that these guidelines are general expert opinion and have not
been prospectively tested for operating characteristics.
Although Jones criteria provide an excellent set of guide-
lines for the diagnosis of RF, it is also important to remember
that similar manifestations may be present in varying
TABLE 18.2. Jones criteria for diagnosis of acute fever*
Major criteria Minor criteria
Carditis Arthralgia
Polyarthritis Fever
Chorea Elevated erythrocyte sedimentation rate
Subcutaneous nodules Positive C-reactive protein
Erythema marginatum Leukocytosis
Prolonged PR interval
* Two major criteria or one major plus two minor criteria are required for the
diagnosis of rheumatic fever. Supportive evidence of recent streptococcal
infection is also required for all diagnoses. Chorea, indolent carditis, and
poststreptococcal arthritis may not fulfill Jones criteria at the time of
diagnosis.59
18
degrees in other systemic illnesses, leading to the potential
for misdiagnosis. For example, streptococcal infection is
relatively common, and an elevated ASO titer indicates only
previous infection. Similarly, arthralgia is prevalent in asso-
ciation with several viral syndromes, and carditis may occur
as a consequence of Coxsackie B virus, Lyme disease, or
Kawasaki’s infection. The early manifestations of other col-
lagen diseases, such as systemic lupus erythematosus, may
also lead to confusion in diagnosis when they are associated
with inflammatory abnormalities of the heart valves, par-
ticularly the mitral valve. Rheumatoid arthritis may produce
aortic regurgitation, and inflammatory reaction within the
pericardium or conduction system may result in pericarditis
or heart block. There may be an erythema multiforme type
of rash and laboratory evidence of an elevated erythrocyte
sedimentation rate (ESR), anemia, and marked leukocytosis.
For these reasons, rheumatoid arthritis is easily confused
with RF. In a patient who has streptococcal infection and
carditis, particularly with evidence of migratory polyarthri-
tis, the diagnosis of RF should be assumed until proved
otherwise.
Laboratory Investigations
Evidence of preceding streptococcal infection is a prerequi-
site for the diagnosis of RF. Because RF is a postinfectious
immunologic complication, microbiologic evidence is
limited, and the evidence for recent streptococcal infection
is usually obtained with the antistreptococcal antibody tests.
The most commonly used antibody assays include ASO and
antideoxyribonuclease B (anti-DNase B), and other antibody
tests such as hyaluronidase, streptokinase, and nicotinamide
adenine dinucleotidase are occasionally used.39 The antibody
response to various streptococcal antigens develops within
the first month and remains detectable up to 3 to 6 months
after the infection. ASO titers are determined by an aggluti-
nation test or a hemolytic inhibition test, and in healthy
adults the titers are usually less than 85 Todd units/mL,
whereas school-age children can have ASO titers up to 170 U.
Generally, an ASO level of more than 240 U in adults or more
than 330 U in children is used for diagnosis, but a better
diagnostic specificity is obtained by the demonstration of an
interval increase in ASO in two serial samples. Because ASO
titers rise and fall more rapidly, the anti-DNase B test can be
performed if ASO is nondiagnostic. A rapid slide agglutina-
tion test that looks at antibodies against several (five) strep-
tococcal antigens, the streptozyme test, has been proposed
to improve the detection of streptococcal infection.
The electrocardiogram may be normal in a patient with
ARF. In patients who have cardiac involvement, ST-segment
change may signal pericarditis, and repolarization abnor-
malities, including QT prolongation and T inversion, may
occur in myocarditis. In addition, there may be associated
arrhythmias with extrasystoles, supraventricular tachycar-
dia, and atrioventricular blocks. First-degree atrioventricular
block is commonly seen in patients with RF but is equally
common in patients with or without carditis. The chest
radiograph has been traditionally used to evaluate cardio-
megaly and is an inexpensive way to study the evolution of
the patient under treatment.
 r h eum at ic fev er
Echocardiography has become the tool of choice in diag-
nosis and monitoring cardiac structure and function. Current
echocardiographic techniques were not available during
many of the major RF epidemics, and thus its role has
remained unclear. However, with newer data that are avail-
able, it might be time to selectively include this modality in
the Jones criteria. An echocardiogram will quickly resolve
whether a clinically undetectable murmur is truly absent
and will protect patients with clinical carditis from being
grouped with noncarditic patients, who have a more benign
prognosis and require shorter secondary prophylaxis regimen.
Indeed there are emerging data indicating that echocardiog-
raphy can detect valve regurgitation more often than clinical
exam alone40; this advantage is greater with aortic valve
involvement. More importantly, these kinds of data also
suggest that echo detectable valve regurgitation can persist
in a significant number of patients despite adequate prophy-
laxis, suggesting that echo detectable cardiac involvement
might represent clinically important cardiac damage. A
strategy to incorporate echocardiography into the Jones
criteria is undoubtedly very appealing.41
However, the Jones criteria are meant to have widespread
applicability, and this transition to incorporating echocar-
diography should be achieved with multiple caveats. There
is a concern that echocardiography may lead to the over-
diagnosis of rheumatic carditis, and some investigators feel
that the application of echocardiography should be some-
what dependent on the regional practice environment. Echo-
cardiography should be routinely used to detect carditis in
the developed world. It is widely available, first attacks are
common, and the detection of carditis may be easy through
echo. Subclinical cardiac involvement is quite common.
Overdiagnosis, while possible, is avoided if strict criteria are
applied for the exclusion of physiologic valvular regurgita-
tion.42 Even if echocardiography inappropriately detected
subclinical carditis, serial echocardiographic studies will
resolve the significance of such valve dysfunction. There-
fore, the detection of subclinical carditis and even mis-
labeling a minority of patients with RF as having carditis
for a short period of time until their clinical situation is
resolved should not adversely affect the overall management
strategy.
On the other hand, the clinical situation is quite different
in the developing world,43 where the incidence of recurrent
RF and the prevalence of RHD are very high and access to
medical care is limited. First attacks are rarely witnessed,
and patients present with recurrences and usually with
established heart disease. Physical examination is the most
commonly used method to detect patients with and without
cardiac involvement. Moreover, there is some evidence,
albeit controversial, that echocardiography in advanced
disease does not demonstrate any incremental diagnostic
benefit in endemic areas; this is probably due to a cumulative
effect of multiple, clinical and subclinical recurrences. 33 In
another study, most of the echo detectable carditis was also
clinically detectable within a short period of follow-up.44
Recurrences are common and medical records are sparse;
thus one cannot be sure if trivial regurgitation is new carditis
or residua of previous episodes in patients with streptococcal
pharyngitis. Echocardiographic facilities are not widely
available, and the cost and additional workload imposed with
4 37
the universal use of echocardiography in RF episodes are
likely to be enormous. Therefore, the detection of subclinical
carditis in this population not only is very costly but also
probably will not change the management strategy very
much; none of the RF therapies available to date modify the
natural history of carditis, and the initial period of prophy-
laxis is no different in patients without and with mild car-
ditis.43 In this population, the presence of RHD is a reason
for lifelong prophylaxis, and echocardiography could be per-
formed at the time of discontinuation of prophylaxis. The
absence of heart disease at this time should allow the with-
drawal of prophylaxis, whereas the presence of valvular
disease should prompt lifelong prophylaxis. It is interesting
to note that adding echocardiography to the initial workup,
did not seem to make prophylaxis more rigorous in the devel-
oped world; only a small proportion of patients were taking
prophylaxis on long-term follow-up. Finally, the natural
history of echo detectable carditis is just being evaluated, and
there may be merit in exercising caution45 about making
echocardiography the cornerstone of diagnosing carditis.
Until there is a convincing body of data that demonstrates
the need to detect subclinical carditis and the possibility of
actually modifying its natural history, echo detectable car-
ditis may divert scarce and valuable prophylaxis resources
from more proven entities that need these urgently. There-
fore, echocardiography should be selectively recommended
for the investigation of RF in developing countries.43 Of
course, the role of echocardiography in the detection and
management of established RHD is unquestioned in any
population.
Computed tomography or magnetic resonance imaging
may also be useful in myocarditis but their role in RF remains
unclear.46 Endomyocardial biopsies have been performed in
persons with acute rheumatic carditis. Aschoff nodules,
which are pathognomonic features of rheumatic carditis, are
observed in 40% of subjects, thereby offering a test of limited
sensitivity.25 However, because the biopsy results are mostly
normal in patients with chronic RHD or noncarditic mani-
festations of RF, the specificity of the test is very high. In
addition, various radionuclide imaging approaches have been
evaluated in rheumatic carditis with variable success47; these
include imaging with indium 111 (111In)-labeled antimyosin
antibodies, radiolabeled leukocytes, and gallium 67 (67Ga)
scintigraphy. However, there needs to be more study about
the role of such procedures, and they should be considered
research at this time.
Natural History
A major problem with understanding the natural history of
RF is that most data are old and have not been reevaluated in
the current diagnostic and therapeutic milieu. It appears that
the natural history of RF has changed significantly with the
advent of prophylaxis, better recognition of antecedent strep-
tococcal infections, social changes, and evolution in strepto-
coccal virulence. Rheumatic fever appears to behave
differently in the developing versus the developed world.
Patients in the latter regions, probably due to conducive socio-
economic factors, demonstrate multiple recurrences and a
particularly aggressive course.48 However, it is heartening
438 chapter
that even in this situation, regular prophylaxis favorably
modifies this bleak natural history.
First attacks of RF in children characteristically occur
between the ages of 5 and 15 years. Rheumatic fever rarely
occurs in children younger than 2 years, and first attacks
after the age of 40 years are also less common. Individuals
who have RF are susceptible to recurrences of the disease,
but this again diminishes with time. Rheumatic fever can
recur with various manifestations at intervals of weeks,
months, or years, with apparent inactivity between these
episodes. The presence of congestive heart failure (CHF) is a
seriously adverse prognostic indicator; failure of cardiomeg-
aly and congestive cardiac failure to improve with treatment
are associated with the worst prognosis. Patients with the
initial syndrome of Sydenham’s chorea have a lower mortal-
ity and morbidity rate.
In patients who have no major valvular damage, the pre-
vention of recurrent attacks leads to a significantly better
prognosis with regard to overall survival and freedom from
heart disease. If there is valvular involvement, the scarring
process may lead to long-term impairment of valve function
that progresses over 10 to 30 years, with various combina-
tions of stenosis and regurgitation. Perhaps the most insidi-
ous of these is mitral stenosis, which may develop very
late—as long as 20 years after the onset of the acute infec-
tion—often with no symptoms until the onset of atrial fibril-
lation. The onset of arrhythmias can be the beginning of
rather rapid deterioration or thrombotic complications.
Patients with valve dysfunction remain at risk for subacute
bacterial endocarditis and should receive prophylactic
antibiotics prior to procedures as indicated by consensus
guidelines.
Treatment
The primary objective in the treatment of the patient with
acute RF is the elimination of offending streptococci with
appropriate antibiotic therapy; penicillin remains the agent
of choice. There is a long list of choices for this purpose but
it is important to remember that some of the more com-
monly used ones may not be as effective as others in prevent-
ing recurrent ARF.49 The second objective of treatment of
acute RF is to eliminate the inflammatory state, particularly
that involving vital organs such as the heart. Salicylates,
predominantly aspirin, have been used for many years as
antiinflammatory agents in RF. They are very effective and
the diagnosis of RF is suspect if high-dose salicylates do not
significantly resolve joint pain and inflammation within 48
hours. Relatively high doses are needed: up to 8 to 10 g/day
(100 mg/kg/day) for a period of 3 to 4 weeks. A gradual taper
is recommended to avoid rebound worsening. Salicylates do
not alter the natural history of the disease. Corticosteroids
are used in patients with severe carditis and heart failure.
Steroids rapidly suppress the toxic state, subside inflamma-
tion, help prevent the appearance of new murmurs, help
murmurs disappear faster, allow faster resolution of pericar-
dial effusions, and may be lifesaving in critical illness.50
Similar to other therapies in RF, they do not alter the long-
term natural history.50 However, most of the studies are old,
have serious methodologic problems, and have not studied
18
combinations of current immunosuppressive therapies. A
short course of steroids is commonly used in patients with
severe carditis. Prednisone at 1 to 2 mg/kg/day is given for a
period of 3 weeks with a tapering schedule once the acute
symptoms resolve. There are no definitive end points for
discontinuing antiinflammatory therapy in RF. General
indicators include the absence of clinical symptoms and
signs of rheumatic activity, in addition to normalization of
acute-phase reactants, usually ESR. Too rapid reduction can
be accompanied by a symptomatic rebound. The steroid taper
is occasionally covered with salicylates to prevent a relapse.
If heart failure continues to persist despite steroid therapy,
surgical repair of mechanical lesions should be considered
instead of prolonged trials with high-dose steroids. There is
little data on newer forms of immunosuppressive therapy.
It was long believed that surgery should not be under-
taken during an acute inflammatory state, because earlier
studies had showed increased surgical mortality rates in
patients with acute RF. However, this is changing. Essop and
associates37 reported no deaths among patients with mitral
or mitral and aortic valve replacement during active carditis,
and surgery was associated with rapid and remarkable
improvement, including a reduction in left ventricular
dimensions. A subsequent series with a much longer follow-
up period has shown that surgery during acute rheumatic
carditis may be associated with a somewhat less favorable
outcome of mitral valve repair, and surgical option during
the acute episode should be reserved for subjects who are
refractory in medical therapy.51 In this study of Skoularigis
and colleagues,51 there was a relatively higher incidence of
valve failure (27%), and the presence of acute carditis was
the strongest predictor of reoperation. Cardiac surgery has
been used with greater success in chronic RHD. It appears
that there may be a significant degree of repairable valves,52,53
and valve repair can be undertaken, albeit with some risk of
reoperation.
The third important objective in the treatment of RF
is to prevent recurrences of rheumatic activity.54 This is
achieved by long-term antibiotic prophylaxis to prevent
GABHS pharyngitis. A secondary prophylaxis program
should begin during the acute episode of RF and is essentially
based on the ability to prevent streptococcal pharyngitis.
Rheumatic fever is a recurrent disease, and patients with
carditis in previous attacks have a higher recurrence rate per
streptococcal infection than those without previous cardi-
tis.55–57 The likelihood of risk of recurrence per streptococcal
infection may range up to 40% to 60% in young patients
with established RHD, and every recurrence further damages
the heart. Rheumatic fever recurrences can be prevented by
chemoprophylaxis of streptococcal infections, which results
in an eventual reduction in the prevalence of residual heart
disease,36,54–57 reduced need for operations, and a possible
subsequent reduction in mortality rates due to RHD. The
duration of prophylaxis is dependent on the anticipated risk
of a recurrence of RF with each throat infection with Strep-
tococcus, and is determined by the presence of carditis in the
index RF episodes and the likelihood of acquiring streptococ-
cal infection. The recurrence of RF is likely to be higher in
patients with carditis or residual heart disease, multiple pre-
vious attacks, and younger age, whereas the risk decreases
with the interval after the last attack. Streptococcal
 r h eum at ic fev er 439
TABLE 18.3. Secondary prevention of rheumatic fever
Agent Dose Mode Duration

Benzathine penicillin G* 1.2 million U IM Every 4 weeks†

Penicillin V‡ 250 mg b.i.d. PO Daily
Sulfadiazine§ PO Daily
<27 kg (60 lb) 500 mg
≥27 kg (60 lb) 1000 mg
With penicillin and sulfa allergy
Erythromycin 250 mg b.i.d. PO Daily
* Use drug at room temperature and with procaine penicillin to reduce pain.
† Consider three times weekly in high-risk situations, including in Third World countries.
‡ May interfere with oral contraception.
§ Avoid use in pregnancy. More effective than oral penicillin.

infections are more common in schoolchildren, their parents,
teachers or health personnel in contact with children, and
persons living in closed quarters or in crowded housing. The
recommendations for the choice of antibiotics and duration
of prophylaxis are listed in Tables 18.3 and 18.4.1,54 The need
for prophylaxis should be reassessed periodically. In all situ-
ations, the decision to discontinue prophylaxis should be
made after discussing the potential risks and benefits with
the patients. While it is obvious that this program has the
potential to significantly reduce morbidity with ARF, the
success rates of optimally adhering to these guidelines has
remained dismal.58 This illustrates the immense number of
challenges in controlling rheumatic fever.
Streptococcal Vaccine
The most effective way to reduce the global burden of RHD
would be the development of an antistreptococcal vaccine.59
The main target has been the streptococcal M protein, the
principal virulence factor in group A streptococci since anti-
bodies to M protein are long lasting and protective.60 These
approaches have been centered on either the type-specific
N-terminal region (which protects against specific serotype)
or the highly conserved carboxy-terminal region (which pro-
tects against multiple serotypes and also reduces coloniza-
tion). In general vaccine strategies need to address the risk of
cross-reactive epitopes (cross-reactivity against human heart
and synovium), diverse M-type streptococci in a population,
and the cyclical nature of prevalent organisms.61 The N-ter-
minal sequence (which is devoid of possible homology with
human myocardial tissue) from all putative strains that
could cause RF in a community can be used in a multivalent
streptococcal vaccine. One of the current vaccines includes
an octavalent antigenic peptide,62 and the other contains
recombinant M-protein fragments linked to Escherichia
coli–labile toxin.63 The advantage of antibodies against the
C-terminal region is that it is useful against multiple strep-
tococcal strains. Non–M-protein moieties have also been a
focus of vaccine development. Intranasal immunization of
mice with a defective form of the streptococcal C5a pepti-
dase (which demonstrates excellent structural similarity in
most streptococci) reduced the colonizing potential of several
different streptococcal M serotypes.64 C5 peptidase antibod-
ies presumably help clearance of streptococci with the added
advantage of a less likelihood of cross-reactive antibody for-
mation. A similar benefit might accrue from including a
streptococcal extracellular protease in a vaccine form. Mice
passively or actively immunized with the streptococcal pyro-
genic exotoxin B (SpeB) lived longer than nonimmunized
animals after infection with group A streptococci.65 There is
a major push toward finding an effective vaccine; some vac-
cines are undergoing clinical testing, and an effective strep-
tococcal vaccine is likely to be available soon. A successful
vaccine could change the face of RF worldwide.

TABLE 18.4. Duration of secondary rheumatic fever prophylaxis*

Risk of streptococcal infections†

Not high

Category High <40 yrs of age ≥40 yrs of age‡

RHD Lifelong Until 40 yr‡ None‡

History of carditis Until 40 yr of age‡ Until 21 yr of age‡ or 10 yr since last attack¶ None||
and no RHD§
RF and no carditis Until 21 yr of age‡ or 10 yr from last attack¶ Until 21 yr of age|| or 5 yr since last attack¶ None||
RF, rheumatic fever; RHD, residual rheumatic heart disease of any severity.
Patients from developing countries, with large RF burden, should be considered at high risk for recurrent infections.
* Each case is judged individually after considering the clinical situation and patient wishes.
† Modify prophylaxis in epidemic situations, especially if virulent streptococci reemerge.
‡ Should be at least 10 years since last attack and should not have history of multiple attacks.
§ Use echocardiography if possible to prove or disprove RHD.
|| Should be at least 10 years since last attack and should not have history of multiple attacks.
¶ Whichever is longer in duration.
440 chapter
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 1 Infective Endocarditis
9 Walter R. Wilson and Eddy Barasch (Second Edition),
revised for The Third Edition by
Layne O. Gentry and Temple W. Williams, Jr.
Incidence, Anatomic Considerations,
and Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . 443
Clinical Recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444
Microbiologic Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
Key Points
• Patients with acute fulminant bacterial infective endo-
carditis (IE) caused by Staphylococcus aureus, Strepto-
coccus pneumoniae, or Neisseria gonorrhoeae, often
present with fever, metastatic abscesses, rapid valvular
destruction, and the sudden onset of congestive heart
failure.
• Patients with subacute or chronic IE often have viridans
streptococci, enterococci, or gram-negative bacilli of the
HACEK group (Haemophilus species, Actinobacillus
actinomycetemcomitans, Cardiobacterium hominis,
Eikenella species, and Kingella kingae) as etiologies.
• Vegetations of >2 mm in size are readily detected by
transesophageal echocardiography (TEE), which may
detect vegetations of smaller size, prosthetic valve vege-
tations, and perivalvular extension of infection.
• A history of a preceding dental procedure, genitourinary
manipulation, or urinary tract infection is present in
20% to 30% of patients with viridans streptococcal or
enterococcal endocarditis.
• The frequency of negative blood cultures in patients
with suspected IE ranges from 5% to 25%. The adminis-
tration of antimicrobial agents before blood cultures are
obtained increases the likelihood of negative blood cul-
tures and is the most common cause of culture-negative
endocarditis.
• Although virtually any microorganism is capable of
causing IE, at least 75% of non–addiction-associated
cases are caused by streptococci or staphylococci.
Addiction-associated IE is most often caused by S.
aureus, S. epidermidis, gram-negative bacilli, or Candida
species.
• Prosthetic valve endocarditis can be divided into early
onset (within 2 to 6 months postoperatively) and late
onset (>6 months postoperatively). Coagulase-negative
staphylococci or gram-negative bacilli most often cause
early-onset PVE, whereas late-onset PVE cases are caused
Evidence-Based Scoring System . . . . . . . . . . . . . . . . . . . . 447
Medical Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
Treatment of Complications . . . . . . . . . . . . . . . . . . . . . . . 452
Prosthetic Valve Endocarditis . . . . . . . . . . . . . . . . . . . . . . 457
by the same spectrum of microorganisms responsible for
native valve non–addiction-associated endocarditis.
The term infective endocarditis (IE) describes infection of
the endocardium caused by a microorganism. Endocarditis
most often involves the heart valves but may involve septal
defects, mural endocardium, arteriovenous shunts, or a
patent ductus arteriosus. The terms acute and subacute were
used previously to classify patients with IE. These terms
were based on the progression of untreated patients and are
primarily of historic interest. Most authorities now use the
term infective endocarditis rather than subacute or acute
bacterial endocarditis to describe endocardial infection.
In the preantibiotic era, the fact that patients recovered
from serious bacterial infections is testimony to the major
role played by host defense mechanisms in controlling or
eradicating bacterial infection. This is not the case with IE;
host defense mechanisms play little role in the control of IE,
and the mortality rate among untreated patients is virtually
100%. In no other infectious diseases is cure so dependent
on the administration of appropriate bactericidal antimicro-
bial agents. The successful management of patients with IE
is based on (1) recognition of the syndrome consistent with
IE, (2) recovery of microorganisms from blood or cardiac
valve vegetation cultures, (3) administration of appropriate
antimicrobial agents, (4) management of complications, and
(5) adequate prophylactic measures.
Incidence, Anatomic Considerations,
and Pathophysiology
A population-based study in Olmsted County, Minnesota,
showed the estimated age- and sex-adjusted incidence of IE
to be 4.9 per 100,000 person years.1 Males (rate ratio 2.51) and
advanced age (rate ratio 8.81 for age ≥65 years compared with
<65 years) were associated with higher rates of endocarditis.
In another study, endocarditis accounted for approximately
4 43
444 chapter
1 case per 1000 hospital admissions.2 The cardiac valve
involved with endocarditis varies among reported series. The
rate of infection of the mitral valve alone ranged from 24%
to 45%; for the aortic valve alone, the rate was 5% to 36%;
and for the aortic and mitral valves combined, the rate was
0% to 35%.3–6
The aortic valve is more commonly involved among male
patients, and mitral valve infections dominate in female
patients. Tricuspid valve involvement ranged from 0% to 6%,
and pulmonary valve involvement was less than 1%. Tricus-
pid valve endocarditis has increased in incidence since about
1980 because of the large number of addicts who abuse intra-
venous drugs. In the United States, mitral valve prolapse
(MVP) with regurgitation is the most common underlying
cardiac defect predisposing to IE; previously, rheumatic val-
vular heart disease was the most common predisposing con-
dition. Underlying congenital heart disease has been reported
in 6% to 24% of patients with IE. However, as many as 40%
of patients develop IE with no demonstrable underlying val-
vular heart disease.5 Presumably, these patients are at risk
because of calcified mitral or aortic valves or other degenera-
tive cardiac diseases or because of infection with virulent
microorganisms that infect previously normal cardiac
valves.7
Pathophysiologic events that result in IE involving a
normal cardiac valve differ from those affecting a previously
abnormal valve. Endocarditis affecting a previously abnor-
mal cardiac valve results from a series of factors or events.
Valvular insufficiency, congenital cardiac lesions such as
septal defects, or other valvular abnormalities produce tur-
bulent blood flow and a jet effect that traumatizes the endo-
thelial surface and results in deposition of a fibrin-platelet
matrix called nonbacterial thrombotic endocarditis. 8 Tran-
sient bacteremias occur frequently, often in association with
procedures such as dental extraction, tooth brushing, or
chewing or as a result of manipulations of the urogenital
system, gastrointestinal tract, or oral respiratory tract. Colo-
nization of nonbacterial thrombotic lesions during transient
bacteremia results in IE. Once colonization occurs, vegeta-
tions enlarge through further deposition of fibrin, platelets,
and bacteria. The dense fibrin-platelet matrix provides a
sanctuary for bacteria against host defenses and impairs pen-
etration of antibiotics into the vegetation. Certain micro-
organisms, such as viridans streptococci, enterococci,
staphylococci, and Pseudomonas aeruginosa, are more adher-
ent to cardiac valve endothelium than other microorganisms
not commonly associated with IE.9 The adherence of strep-
tococci may be, in part, related to the extracellular produc-
tion of a polysaccharide called dextran.10 Platelets may also
play a role in the pathophysiology of IE. Staphylococci and
streptococci stimulate platelet aggregation, and these aggre-
gates may have an increased affinity for nonbacterial throm-
botic lesions.11
Nonbacterial thrombotic endocarditis probably does not
play a major role, if any, in the pathophysiology of IE involv-
ing normal cardiac valves. The organisms responsible for IE
involving previously normal cardiac valves, such as Staphy-
lococcus aureus, Streptococcus pneumoniae, Neisseria gon-
orrhoeae, and Streptococcus pyogenes, differ from those that
usually infect an abnormal cardiac valve. Infective endocar-
ditis in the former patients is usually caused by bacteremia
19
originating from the focus of infection, such as the skin,
musculoskeletal system, or genitourinary tract. Although
the pathophysiology of IE in these patients is poorly under-
stood, it may be related to the high magnitude of bacteremia,
virulence of the microorganisms, and possibly binding to
specific receptors on the surface of endothelial cells.
Clinical Recognition
Physical Examination
The clinical manifestations of IE may involve any organ
system and are largely dependent on the infecting microor-
ganism. Patients with acute fulminant IE caused by S. aureus,
S. pneumoniae, or N. gonorrhoeae usually present with fever,
metastatic abscesses, rapid valvular destruction, and the
sudden onset of severe congestive heart failure (CHF) and
have a high mortality rate. More commonly, patients present
with a subacute or chronic form of IE that is usually caused
by viridans streptococci, enterococci, or fastidious gram-
negative bacilli of the HACEK group (Haemophilus species,
Actinobacillus actinomycetemcomitans, Cardiobacterium
hominis, Eikenella species, and Kingella kingae). The history
of a preceding dental procedure, genitourinary tract manipu-
lation, or urinary tract infection is present in 20% to 30%
of patients with viridans streptococcal or enterococcal endo-
carditis.5 Initial symptoms are nonspecific and include
anorexia, weight loss, fatigue, fever, headaches, myalgias,
and arthralgias. This condition may be confused with a
number of other chronic febrile illnesses, such as lymphoma,
other malignancies, other chronic infectious diseases, and
collagen vascular disorders. The duration of symptoms in the
subacute or chronic form ranges from 1 to 2 weeks to more
than 1 year.
Although fever is present in virtually all patients with
IE, it may be absent in patients who have received antimi-
crobial therapy. A cardiac murmur is present in at least 85%
of patients but may be absent in patients with right-sided
endocarditis. A change in a preexisting murmur or the devel-
opment of a new regurgitant murmur is an important finding.
Peripheral embolic or hypersensitivity phenomena occur in
at least 60% of patients with the subacute or chronic form
of IE.5 Osler nodes occur in 10% to 25% of patients and are
characterized by small, tender, slightly nodular lesions
usually located on the palms of the hands and soles of the
feet. Osler nodes are thought to occur as a result of the depo-
sition of circulating immune complexes or, possibly, micro-
emboli of vegetations that contain bacteria. Roth spots occur
in about 10% of patients with IE and are characteristically
present in the retina. Approximately 10% of patients develop
macular, nontender, erythematous lesions on the palms and
soles, known as Janeway lesions. Splenomegaly occurs in
25% to 60% of patients with IE, and myalgias and arthralgias
occur in at least 40%. Large systemic emboli have been
observed in 10% to 30% of patients and are more often asso-
ciated with infection caused by nutritionally variant viri-
dans streptococci, members of the HACEK group, group B
streptococci, and fungal endocarditis. Headaches have been
reported in up to 60% to 80% of patients with IE.12,13 Approx-
imately 20% to 40% of patients develop neurologic manifes-
 in fectiv e en doca r ditis 445
tations, including ataxia, aphasia, alterations in mental TABLE 19.1. Proposed new criteria for the diagnosis of infective
status, or other changes resulting from cerebral emboli or endocarditis
hypersensitivity phenomena.13 Intracranial mycotic aneu- Definite infective endocarditis
rysms are documented in approximately 1% of patients with Pathologic criteria
IE; they may be asymptomatic or present with catastrophic Microorganisms: demonstrated by culture or histology in a
vegetation, or in a vegetation that has embolized, or in an
complications resulting from rupture and hemorrhage.12 intracardiac abscess, or
Pathologic lesions: vegetation or intracardiac abscess present,
confirmed by histology showing active endocarditis
Laboratory Examination Clinical criteria, using specific definitions listed in Table 19.2
Two major criteria, or
Because patients with IE may present with a chronic, non-
One major and three minor criteria, or
specific febrile illness that may mimic a wide variety of other Five minor criteria
diseases, clinicians must be alert to the possibility of IE. This Possible infective endocarditis
is especially true for patients who have received partial treat- Findings consistent with infective endocarditis that fall short of
ment with antibiotics that has rendered blood cultures nega- “definite” but not “rejected”
tive and temporarily eliminated the fever. It therefore may Rejected
be necessary in these patients to observe them after the Firm alternate diagnosis for manifestations of endocarditis, or
withdrawal of antibiotic therapy and to periodically obtain Resolution of manifestations of endocarditis, with antibiotic
therapy for 4 days or less, or
blood cultures. No pathologic evidence of infective endocarditis at surgery or
The diagnosis of IE depends on recognition of the clinical autopsy, after antibiotic therapy for 4 days or less
syndrome and the recovery of bacteria or fungi from two or
more cultures of blood obtained at intervals during a 48-hour
period. In most cases, bacteremia associated with IE is con-
tinuous, and if any blood culture is positive, most of the other
specimens cultured will also be positive. Therefore, it is
community acquired or without an apparent primary focus.
usually unnecessary to obtain more than three sets of blood
These bacteremias have the highest risk of being associated
cultures within a 24-hour period on 2 consecutive days. Col-
with IE. A second major criterion includes evidence of endo-
lection of blood for culture during temperature elevations
cardial involvement demonstrable by echocardiography or by
does not increase the likelihood of a positive blood culture.
the development of a new valvular regurgitation. Echocardio-
However, cases of IE caused by nutritionally variant viridans
graphic findings associated with IE are clearly defined by the
streptococci or members of the HACEK group may have
Duke criteria (Table 19.2).
intermittently positive blood cultures. The recovery of these
Six common but less specific findings of IE are catego-
microorganisms from more than one blood culture has such
rized as minor criteria according to the Duke strategy (Table
a high association with IE that this diagnosis must be con-
19.2). The validity of the Duke criteria in establishing the
sidered even in the absence of physical findings suggestive
diagnosis of IE has been confirmed in at least 11 published
of IE.
studies that include approximately 1700 patients.15 Based on
Durack and colleagues14 from Duke University (Duke
these studies, patients suspected of having IE should be eval-
criteria) proposed a new diagnostic strategy to define cases
uated clinically using the Duke criteria as the primary diag-
of IE. The Duke criteria combine important traditional diag-
nostic schema.
nostic parameters, such as persistent bacteremia, newly
Most other laboratory findings for patients with IE are
developed valvular insufficiency, and peripheral manifesta-
nonspecific. Anemia is often present and is that of chronic
tions, with echocardiographic findings. According to the
disease, with normochromic, normocytic indices. In the sub-
Duke criteria, patients suspected of having IE may be classi-
acute form, the leukocyte count is usually normal. Rheuma-
fied into one of three categories: definite, possible, or rejected.
toid factor is present in 40% to 50% of cases.5 Circulating
Definite cases of IE are defined by clinical criteria (Table 19.1)
immune complexes may be detected in the majority of
or by pathologic diagnosis at surgery or autopsy. Possible
patients with IE, but they are also present in patients with
cases of IE are those not meeting the criteria for definite IE,
bacteremia without endocarditis.5 The erythrocyte sedimen-
and rejected cases are those with no pathologic evidence of
tation rate (ESR) is usually elevated. Urinary sediment abnor-
IE or a rapid resolution of signs and symptoms with either
malities are common, reflecting renal involvement caused
no treatment or short-termed antimicrobial therapy or the
by deposition of circulating immune complexes. Microscopic
determination of an alternative diagnosis.
hematuria and erythrocyte casts are frequently present. Elec-
According to the Duke criteria, cases of definite IE may
trocardiographic abnormalities are nonspecific in patients
be diagnosed by the presence of two major criteria or one
with IE; heart block may occur in association with infections
major and three minor criteria or five minor criteria (Table
involving the cardiac conduction system, and atrial or ven-
19.2). Among the major criteria, the presence of certain
tricular ectopy is often noted in patients with intramyocar-
microorganisms in blood culture, such as viridans strepto-
dial abscesses.
cocci or members of the HACEK group, is rarely seen in
patients without IE. In contrast, bacteremia in patients
Role of Echocardiography in Diagnosis
caused by S. aureus or enterococci may be associated with
IE or non-IE infections. According to the Duke criteria, bac- Echocardiography is useful to detect valvular vegetations,
teremia with staphylococci or enterococci is considered myocardial abscess, valvular dysfunction, or prosthetic valve
likely to be associated with IE only when such bacteria are dehiscence in patients with IE. However, either transthoracic
446 chapter 19

TABLE 19.2. Specific definitions of major and minor criteria

Major criteria
Positive blood culture for infective endocarditis
Typical microorganism for infective endocarditis from two separate blood cultures
Viridans streptococci,* Streptococcus bovis, HACEK group, or
Community-acquired Staphylococcus aureus or enterococci, in the absence of primary focus, or
Persistently positive blood culture, defined as a recovery of a microorganism consistent with infective endocarditis from:
1. Blood cultures drawn more than 12 hours apart, or
2. All of three or a majority of four or more separate blood cultures, with first and last drawn at least 1 hour apart
Evidence of endocardial involvement
Positive echocardiogram for infective endocarditis
1. Oscillating intracardiac mass, on valve or supporting structures, or in the path of regurgitant jets, or on implanted material, in the
absence of an alternative anatomic explanation, or
2. Abscess, or
3. New partial dehiscence of prosthetic valve, or
4. New valvular regurgitation (increase or change in preexisting murmur not sufficient)
Minor criteria
Predisposition: predisposing heart condition or intravenous drug use
Fever: ≥38.0°C (100.4°F)
Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival
hemorrhages, Janeway lesions
Immunologic phenomena: glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor
Microbiologic evidence: positive blood culture but not meeting major criterion as noted previously† or serologic evidence of active
infection with organism consistent with infective endocarditis
Echocardiogram: consistent with infective endocarditis but not meeting major criterion as noted previously
HACEK, Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella species, and Kingella kingae.
* Including nutritional variant stains.
† Excluding single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis.

(TTE) or transesophageal (TEE) echocardiography should be who have a relatively low risk for IE such as those with bac-
performed in all patients suspected of having IE as shown in teremia due to enterococci or other organisms with an
Figure 19.1.15 TTE has a high specificity for valvular vegeta- obvious portal of entry. However, in patients with obesity,
tions (98%), but the sensitivity is less than 60%. Vegetations chest wall deformities, chronic obstructive lung disease, or
of more than 2 mm are readily detected with TEE. Transtho- a prosthetic cardiac valve, TTE may be inadequate to accu-
racic echocardiography is adequate to exclude IE in patients rately detect valvular vegetations or other abnormalities
associated with IE. In these patients, TEE has a higher sen-
sitivity for the detection of vegetations and cardiac complica-
tions of IE. Compared with TTE, TEE has a higher sensitivity
Infective endocarditis suspected
High initial patient risk,+
(80% to 100%) and specificity (94%) for the detection of
Low initial patient risk†
and low clinical suspicion moderate to high clinical perivalvular extension of infection. The use of TEE is prefer-
suspicion or difficult imaging
candidate able to the use of TTE in patients with a high risk for the
Initial TTE Initial TEE complications of IE (Table 19.3).15
– + – +
The role of TEE in patients with bacteremia caused by S.
Increased
aureus is somewhat controversial. Patients with S. aureus
Low Rx High Look for
suspicion suspicion suspicion other source
Rx bacteremia are at risk of IE. Transthoracic echocardiography
persists during High-risk echo No high-risk persists of symptoms
clinical
course
features* echo features* may not be adequate to detect small valvular vegetations or
– + other cardiac complications of S. aureus bacteremia, whereas
Repeat
TEE
TEE TEE for No TEE unless Alternative
detection of clinical status + – diagnosis
complications deteriorates established
– + Look for
Rx other
source
Look for Rx TABLE 19.3. Clinical situations constituting high risk for
other Follow-up TEE or TTE to
source reassess vegetations, complications for infective endocarditis
complications or Rx response
as clinically indicated Prosthetic cardiac valves
FIGURE 19.1. An approach to the diagnostic use of echocardiogra- Left-sided infective endocarditis
phy. *High-risk echocardiographic features include large or mobile
Staphylococcus aureus infective endocarditis
vegetations, valvular insufficiency, the suggestion of perivalvular
extension, or secondary ventricular dysfunction (see the text). †For Fungal infective endocarditis
example, a patient with fever and a previously known heart murmur Previous infective endocarditis
and no other stigmata of infective endocarditis. +High initial patient
Prolonged clinical symptoms (≥3 months)
risks include prosthetic heart valves, many congenital heart dis-
eases, previous endocarditis, new murmur, heart failure, or other Cyanotic congenital heart disease
stigmata of endocarditis. Rx, antibiotic treatment for endocarditis; Patients with systemic to pulmonary shunts
TEE, transesophageal echocardiography; TTE, transthoracic
Poor clinical response to antimicrobial therapy
echocardiography.
 in fectiv e en doca r ditis
TEE has a higher sensitivity and specificity in these patients.16
Not all patients with S. aureus bacteremia should undergo
TTE or TEE. However, those with signs of persistent infec-
tion or persistent bacteremia or who develop other signs of
IE should undergo TEE.
Negative results on TTE or TEE do not definitively
exclude the diagnosis of IE. Among patients in whom the
clinical diagnosis of IE persists after an initial negative echo-
cardiographic study, repeat TTE or TEE may be justified. The
timing of the repeat study depends on the clinical status of
the patient and should be individualized for each patient.
Patients with Suspected Endocarditis and
Negative Blood Cultures
The frequency of negative blood cultures in patients with
suspected IE ranges from 5% to 25%. The administration of
antimicrobial agents before blood cultures are obtained
increases the likelihood of negative blood cultures and is the
most common cause of culture-negative endocarditis. The
duration and type of prior antimicrobial therapy and the
susceptibility of the microorganism determine the duration
and time that blood cultures will be negative. In these
patients, after the discontinuation of antimicrobial agents,
blood cultures may remain negative for a few days or for
weeks. Among patients with suspected IE who are stable
hemodynamically and who do not appear toxic, it is prefera-
ble to delay the onset of empiric antimicrobial therapy until
a specific microbiologic diagnosis is made. Many of these
patients have been ill for weeks to months, and in these
stable patients it is preferable to delay the onset of empiric
therapy for a few days in an attempt to establish a specific
microbiologic diagnosis.
Patients with suspected IE who have not received prior
antimicrobial therapy and in whom blood cultures remain
negative after 48 to 72 hours of incubation should be
suspected of having infection caused by fastidious micro-
organisms that are not readily recovered from standard
blood-culturing systems. For example, HACEK microorgan-
isms and nutritionally variant viridans streptococci (Abio-
trophia species) account for 5% to 10% of cases of endocarditis.
These microorganisms may require prolonged incubation
and specialized subculture techniques for identification.
Other causes of endocarditis, such as Brucella species or
Legionella species, require special blood-culturing tech-
niques, and communication with the microbiology labora-
tory is essential in these cases. Aspergillus is an uncommon
cause of endocarditis or prosthetic valve endocarditis and is
rarely, if ever, recovered from blood cultures. The identifica-
tion of Aspergillus may result from an examination of patho-
logic specimens, such as a large peripheral embolus.
Other microbiologic causes of endocarditis, such as Coxi-
ella burnetii or Bartonella species, may be diagnosed by
serologic techniques or from tissue culture-based techniques.
Polymerase chain reaction performed on blood may be useful
for the diagnosis of IE caused by Tropheryma whippelii,
Bartonella species, or other unusual causes of IE. In all cases
of suspected IE with negative blood cultures, the microbiol-
ogy laboratory should be consulted for advice regarding spe-
cialized techniques to recover fastidious or uncommon
microbiologic causes of IE.
4 47
TABLE 19.4. Microbiologic cause of native valve, non-addict-
associated infective endocarditis
Microorganism Patients (%)
Viridans streptococci 48
Enterococci 15
Staphylococcus aureus 18
Coagulase-negative staphylococci 6
HACEK 9
Other microorganism 1
Negative blood cultures 3
Total 100
HACEK, Haemophilus species, Actinobacillus actinomycetemcomitans,
Cardiobacterium hominis, Eikenella species, and Kingella kingae.
Microbiologic Etiology
Although virtually any microorganism is capable of causing
IE, at least 75% of non–addiction-associated cases are caused
by streptococci or staphylococci (Table 19.4).17,18 Addict-asso-
ciated IE is most often caused by S. aureus, S. epidermidis,
gram-negative bacilli, or Candida species. Prosthetic valve
endocarditis (PVE) can be divided into early onset (within 2
to 6 months postoperatively) and late onset (>6 months post-
operatively). Early-onset PVE is most often caused by coagu-
lase-negative staphylococci S. aureus or gram-negative bacilli,
whereas late-onset PVE cases are caused by the same spec-
trum of microorganisms responsible for native valve non–
addiction-associated endocarditis.
Evidence-Based Scoring System
The American College of Cardiology/American Heart Asso-
ciation evidence-based scoring system was first introduced
into the American Heart Association’s Guidelines for Endo-
carditis in June 2005 (http://circ.ahajournals.org/manual_
IIsteps6.shtml). The system is based on a classification of
recommendations and the level of evidence. Such a system
assists clinicians in the interpretation of these recommenda-
tions and aids in treatment decisions. Use of this system is
meant to support clinicians’ decision making in the treat-
ment and management of endocarditis.
Classification of Recommendations
Class I: Conditions for which there is evidence, general
agreement, or both, that a given procedure or treatment
is useful and effective.
Class II: Conditions for which there is conflicting evidence,
a divergence of opinion, or both, about the usefulness/
efficacy of a procedure or treatment.
Class IIa: Weight of evidence/opinion is in favor of
usefulness/efficiency.
Class IIb: Usefulness/efficacy is less well established by
evidence/opinion.
Class III: Conditions for which there is evidence, general
agreement, or both, that the procedure/treatment is not
useful/effective and in some cases, may be harmful.
448 chapter 19

Level of Evidence
Level of evidence A: Data derived from multiple randomized
clinical trials.
Level of evidence B: Data derived from a single randomized
trial or nonrandomized studies.
Level of evidence C: Consensus of opinion of experts.
Medical Treatment
It is important to establish the microbiologic diagnosis, if
possible, before the initiation of antimicrobial therapy. Most
patients with IE have been ill for weeks and in some cases
for as long as 1 year. There is usually no urgent need to
initiate antimicrobial therapy in these patients. Failure to
identify the microbiologic cause may lead to prolonged hos-
pitalization and increased costs, multiple iatrogenic compli-
cations related to inappropriate therapy, progressive cardiac
valvular damage with the development of CHF, and possible
relapse of infection. Conversely, patients with the acute
septic form of IE or those in whom the microbiologic diag-
nosis has been established should receive antimicrobial
therapy promptly. Antimicrobial therapy should not be
delayed pending the results of in vitro susceptibility tests or
additional diagnostic studies. Antimicrobial regimens that
have been established as effective therapy for IE are given in
the following sections and tables.17
Penicillin-Susceptible Streptococci
The majority of patients with penicillin-susceptible viridans
streptococcal or Streptococcus bovis IE can be treated suc-
cessfully for 2 weeks with aqueous penicillin G or ceftriax-
one together with gentamicin (Table 19.5).17 It is not necessary
to use the same dosages of gentamicin required for the treat-
ment of patients with gram-negative bacillary infections.
The concentrations of gentamicin necessary to act synergis-
tically with penicillin against streptococci or staphylococci
are relatively low (3 μg/mL). Therefore, patients with penicil-
lin-susceptible streptococcal endocarditis who have normal
renal function should receive low-dose gentamicin therapy
(1 mg/kg body weight every 8 hours or 3 mg/kg body weight
in a single daily dose). Subsequent dosages of gentamicin can
be readjusted to achieve a 1-hour concentration in serum of
3 μg/mL and a trough concentration of 1 μg/mL of gentami-
cin. The use of low-dose gentamicin therapy in these patients
significantly reduces the risk of gentamicin-associated neph-
rotoxicity or cranial nerve VIII toxicity.18 Patients with an
extracardiac focus of infection, a myocardial abscess, a
mycotic aneurysm, or preexisting nephrotoxicity or cranial
nerve VIII abnormality should not be treated with the 2-week
regimen; they should receive therapy with penicillin G or a
cephalosporin administered alone for 4 weeks.17
Ceftriaxone administered in a single daily dose of 2 g for
4 weeks is effective therapy for patients with penicillin-sus-
ceptible streptococcal endocarditis.19 The advantage of cef-
triaxone therapy is that patients who are hemodynamically
stable can be discharged from the hospital to complete anti-
microbial therapy on an outpatient basis. Another advantage
is that ceftriaxone can be administered intramuscularly,
which further facilitates outpatient therapy. Patients unable
to tolerate penicillin or ceftriaxone should be treated with
vancomycin for 4 weeks.17
The antimicrobial therapy for patients with IE caused by
viridans streptococci with a minimum inhibitory concentra-
tion of more than 0.1 pg/μL of penicillin but less than 0.5 pg/
mL of penicillin is shown in Table 19.6.17 When IE is caused
by viridans streptococci with a minimum inhibitory concen-

TABLE 19.5. Suggested regimens for therapy of native valve endocarditis due to penicillin-susceptible viridans: streptococci and
Streptococcus bovis (minimum inhibitory concentration £0.1 m g/mL)*
Antibiotic Dosage and route Duration (weeks) Comments

Aqueous crystalline penicillin G 12–18 million U/24 h IV either 4 Preferred in most patients older than 65 yr and
sodium continuously or in six equally in those with impairment of the eighth nerve
or divided doses or renal function
Ceftriaxone sodium 2 g once daily IV or IM† 4
Aqueous crystalline penicillin G 12–18 million U/24 h IV either 2 When obtained 1 h after a 20–30 min IV infusion
sodium continuously or in six equally or IM injection, serum concentration of
divided doses gentamicin of approximately 3 μg/ml is
With gentamicin sulfate‡ 1 mg/kg IM or IV every 8 h 2 desirable; trough concentration should be
<1 μg/ml
Vancomycin hydrochloride§ 30 mg/kg per 24 h IV in two 4 Vancomycin therapy is recommended for patients
equally divided doses, not to allergic to β-lactams (see text); peak serum
exceed 2 g/24 h unless serum concentrations of vancomycin should be
levels are monitored obtained 1 h after completion of the infusion
and should be in the range of 30–45 μg/mL for
twice-daily dosing
* Dosages recommended are for patients with normal renal function.
† Patients should be informed that IM injection of ceftriaxone is painful.
‡ Dosing of gentamicin on a mg/kg basis will produce higher serum concentrations in obese patients than in lean patients. Therefore, in obese patients, dosing
should be based on ideal body weight. Ideal body weight for men is 50 kg + 2.3 kg per inch over 5 feet, and ideal body weight for women is 45.5 kg + 2.3 kg per
inch over 5 feet. Relative contraindications to the use of gentamicin are age >65 years, renal impairment, or impairment of the eighth nerve. Other potentially
nephrotoxic agents (e.g., nonsteroidal antiinflammatory drugs) should be used cautiously in patients receiving gentamicin.
§ Vancomycin dosage should be reduced in patients with impaired renal function. Vancomycin given on a mg/kg basis will produce higher serum concentra-
tions in obese patients than in lean patients. Therefore, in obese patients, dosing should be based on ideal body weight. Each dose of vancomycin should be
infused over at least 1 h to reduce the risk of the histamine-release “red man” syndrome.
 in fectiv e en doca r ditis 449
TABLE 19.6. Therapy for native valve endocarditis due to strains of viridans streptococci and Streptococcus bovis relatively resistant to
penicillin G (minimum inhibitory concentration >0.1 mg/mL and <0.5 mg/mL)*
Antibiotic Dosage and route Durationt (weeks) Comments

Aqueous crystalline 18 million U/24 h IV either continuously 4 Cefazolin or other first-generation

penicillin G or in six equally divided doses cephalosporins may be substituted
sodium for penicillin in patients whose
With gentamicin 1 mg/kg IM or IV every 8 h 2 penicillin hypersensitivity is not of
sulfate† the immediate type
Vancomycin 30 mg/kg per 24 h IV in two equally 4 Vancomycin therapy is recommended
hydrochloride‡ divided doses, not to exceed 2 g/24 h for patients allergic to β-lactams
unless serum levels are monitored
* Dosages recommended are for patients with normal renal function.
† For specific dosing adjustment and issues concerning gentamicin (obese patients, relative contraindications), see Table 19.5 footnotes.
‡ For specific dosing adjustment and issues concerning vancomycin (obese patients, length of infusion), see Table 19.5 footnotes.

tration of at least 0.5 pg/μL of penicillin or PVE caused by Enterococci

viridans streptococci or S. bovis, appropriate antimicrobial
therapy is as shown in Table 19.7.17 Approximately 5% to 7%
of cases of viridans streptococcal IE are caused by nutrition-
ally variant viridans streptococci (Abiotrophia species).
These organisms require pyridoxal-supplemented media for
growth. Infective endocarditis caused by these microorgan-
isms has a higher relapse rate after 2 weeks of therapy with
penicillin and gentamicin or 4 weeks of single-drug therapy.
Therefore, patients with IE caused by nutritionally variant
viridans streptococci should be treated for 4 weeks with
a combination of penicillin and low-dose gentamicin
(Table 19.7).17
Patients with pneumococcal IE often present with an
acute fulminant course. These patients should receive
therapy with penicillin G, a cephalosporin, or vancomycin
administered for 4 weeks. Few data are available concerning
the optimal therapy for IE caused by group B streptococci.
Most authorities recommend 4-week therapy with penicil-
lin, a cephalosporin, or vancomycin, combined with low-
dose gentamicin for the first 2 weeks of treatment.
Enterococci (Streptococcus faecalis, Streptococcus faecium,
Streptococcus durans) are inhibited but not killed in vitro
by penicillin or vancomycin alone. Successful therapy of
enterococcal endocarditis requires the administration of
penicillin, ampicillin, or vancomycin together with an ami-
noglycoside, usually gentamicin. The most important factor
in the outcome of patients with enterococcal endocarditis is
the duration of symptoms before the initiation of effective
antimicrobial therapy. Patients with symptoms of infection
for more than 3 months have significantly higher relapse and
mortality rates than do those with a shorter duration of
illness.18 Patients with symptoms for less than 3 months can
be treated successfully for 4 weeks with penicillin or ampi-
cillin, together with gentamicin (Table 19.7).17 Patients ill for
more than 3 months and those with PVE should receive 6
weeks of therapy. Concentrations of gentamicin in serum
should be monitored closely to ensure that the 1-hour con-
centration is 3 μg/mL and the trough concentration is 1 μg/
mL. The administration of higher dosages of gentamicin does

TABLE 19.7. Standard therapy for endocarditis due to enterococci*

Antibiotic Dosage and route Duration (weeks) Comments

Aqueous crystalline 18–30 million U/24 h IV either 4–6 4-wk therapy recommended for patients with
penicillin G sodium continuously or in six equally symptoms <3 mo in duration; 6-wk therapy
divided doses recommended for patients with symptoms
With gentamicin sulfate† 1 mg/kg IM or IV every 8 h 4–6 >3 mo in duration
Ampicillin sodium 12 g/24 h IV either continuously 4–6
or in six equally divided doses
With gentamicin sulfate† 1 mg/kg IM or IV every 8 h 4–6
Vancomycin hydrochloride†‡ 30 mg/kg per 24 h IV in two 4–6 Vancomycin therapy is recommended for
equally divided doses, not to patients allergic to β–lactams; cephalosporins
exceed 2 g/24 h unless serum are not acceptable alternatives for patients
levels are monitored allergic to penicillin
With gentamicin sulfate† 1 mg/kg IM or IV every 8 h 4–6
* All enterococci causing endocarditis must be tested for antimicrobial susceptibility to select optimal therapy (see text). This table is for endocarditis due to
gentamicin- or vancomycin-susceptible enterococci, viridans streptococci with a minimum inhibitory concentration of >0.5 μg/mL, nutritionally variant viri-
dans streptococci, or prosthetic valve endocarditis caused by viridans streptococci or Streptococcus bovis. Antibiotic dosages are for patients with normal
renal function.
† For specific dosing adjustment and issues concerning gentamicin (obese patients, relative contraindications), see Table 19.5 footnotes.
‡ For specific dosing adjustment and issues concerning vancomycin (obese patients, length of infusion), see Table 19.5 footnotes.
450 chapter 19

not improve efficacy or enhance synergy with penicillin. Staphylococci

However, it does significantly increase the risk for
nephrotoxicity.
The treatment of enterococcal endocarditis is becoming
increasingly complicated because of the development of
resistance of enterococci to multiple antimicrobial agents.
Enterococci are uniformly resistant to the cephalosporins.
Since the late 1980s, strains of enterococci have been re-
covered with high-level resistance in vitro to gentamicin,
streptomycin, and other aminoglycosides; penicillin and
ampicillin; and vancomycin. Enterococci that are highly
resistant to an aminoglycoside are not killed synergistically
by combinations of either penicillin or vancomycin together
with that aminoglycoside. Moreover, vancomycin-resistant
strains of enterococci frequently exhibit high-level resistance
to aminoglycosides and often to penicillins. Currently, no
bactericidal regimen is available for the treatment of patients
with enterococcal IE caused by these multiply resistant
microorganisms. A small number of patients with multiply
resistant enterococcal IE have been treated successfully with
a combination of imipenem and ampicillin. Quinupristin-
dalfopristin (Synercid) and linezolid (Zyvox) have been effec-
tive treatment in some patients with IE caused by
vancomycin-resistant strains of S. faecium. The treatment of
patients with infections caused by strains of multiply resis-
tant enterococci should be performed in collaboration with
an infectious disease specialist and a cardiothoracic surgeon.17
Cardiac valve replacement may offer these patients the only
hope of survival.
S. aureus (Methicillin Susceptible)
Patients with S. aureus native valve left-sided endocarditis
or PVE should receive 6 weeks of therapy with nafcillin,
oxacillin, a first-generation cephalosporin (e.g., cefazolin), or
vancomycin (Table 19.8).17 In in vitro and in animal model
studies of experimental endocarditis, the combination of naf-
cillin and gentamicin was more effective than either drug
alone.20,21 The administration of nafcillin for 6 weeks com-
bined with gentamicin for the first 2 weeks of therapy did
not improve survival rates or reduce complications compared
with patients treated with nafcillin alone.22 However, the
combination of nafcillin and gentamicin did significantly
shorten the duration of S. aureus bacteremia compared with
patients who received therapy with nafcillin alone. If clini-
cians prefer to use the combination of nafcillin and genta-
micin, the dosage of gentamicin could be the same as that
for patients with viridans streptococcal endocarditis, and the
duration of gentamicin therapy should not exceed the initial
3 to 5 days of treatment. Antimicrobial therapy for S. aureus
is shown in Table 19.9.17 Intravenous drug abusers with right-
sided methicillin-susceptible S. aureus IE who do not have
extrapulmonary or extracardiac foci of infection can be
treated successfully with a combination of nafcillin and low-
dose tobramycin or gentamicin for 2 weeks.23 Addicts who
do not qualify for the 2-week regimen should receive therapy
for 4 to 6 weeks.

TABLE 19.8. Therapy for endocarditis due to staphylococcus in the absence of prosthetic material*
Antibiotic Dosage and route Duration Comments

Methicillin-susceptible staphylococci
Regimens for non-β-lactam-allergic patients
Nafcillin sodium or oxacillin sodium 2 g IV every 4 h 4–6 weeks Benefit of additional
aminoglycosides has not
been established
With optional addition of gentamicin sulfate† 1 mg/kg IM or IV every 8 h 3–5 days
Regimens for β-lactam-allergic patients
Cefazolin (or other first-generation 2 g IV every 8 h 4–6 weeks Cephalosporins should be
cephalosporins in equivalent dosages) avoided in patients with
immediate-type
hypersensitivity to
penicillin
With optional addition of gentamicin† 1 mg/kg IM or IV every 8 h 3–5 days
Vancomycin hydrochloride‡ 30 mg/kg per 24 h IV in two 4–6 weeks Recommended for patients
equally divided doses, not allergic to penicillin
to exceed 2 g/24 h unless
serum levels are monitored
Methicillin-resistant staphylococci
Vancomycin hydrochloride‡ 30 mg/kg per 24 h IV in two 4–6 weeks
equally divided doses, not
to exceed 2 g/24 h unless
serum levels are monitored
* For treatment of endocarditis due to penicillin-susceptible staphylococci (minimum inhibitory concentration ≤0.1 μg/mL), aqueous crystalline penicillin G
sodium (Table 19.5, first regimen) can be used for 4 to 6 weeks instead of nafcillin or oxacillin. Shorter antibiotic courses have been effective in some drug
addicts with right-sided endocarditis due to Staphylococcus (see text). See text for comments on use of rifampin.
† For specific dosing adjustment and issues concerning gentamicin (obese patients, relative contraindications), see Table 19.5 footnotes.
‡ For specific dosing adjustment and issues concerning vancomycin (obese patients, length of infusion), see Table 19.5 footnotes.
 in fectiv e en doca r ditis 4 51
TABLE 19.9. Treatment of staphylococcal endocarditis in the presence of a prosthetic valve or other prosthetic material*
Antibiotic Dosage and route Duration (weeks) Comments

Regimen for methicillin-resistant staphylococci

Vancomycin hydrochloride†
With rifampin‡
And with gentamicin sulfate∫ ||
30 mg/kg per 24 h IV in 2 or 4 ≥6
equally divided doses, not
to exceed 2 g/24 h unless
serum levels are monitored
300 mg PO every 8 h ≥6 Rifampin increases the amount of warfarin
1.0 mg/kg IM or IV every 8 h 2 sodium required for antithrombotic therapy

Regimen for methicillin-sensitive staphylococci

Nafcillin sodium or oxacillin 2 g IV every 4 h ≥6 First-generation cephalosporins or vancomycin
sodium should be used in patients allergic to
With rifampin‡ 300 mg PO every 8 h ≥6 β-lactam; cephalosporins should be avoided
And with gentamicin sulfate∫ || 1.0 mg/kg IM or IV every 8 h 2 in patients with immediate-type
hypersensitivity to penicillin or with
methicillin-resistant staphylococci
* Dosages recommended are for patients with normal renal function.
† For specific dosing adjustment and issues concerning vancomycin (obese patients, length of infusion), see Table 19.5 footnotes.
‡ Rifampin plays a unique role in the eradication of staphylococcal infection involving prosthetic material (see text); combination therapy is essential to prevent
emergence of rifampin resistance.
∫ For specific dosing adjustment and issues concerning gentamicin (obese patients, relative contraindications), see Table 19.5 footnotes.
|| Use during initial 2 weeks.

S. aureus (Methicillin Resistant) HACEK Group

Patients with methicillin-resistant IE should be treated for 6
weeks with vancomycin (Table 19.8).17 The only effective
alternative is cotrimoxazole therapy (trimethoprim/
sulfamethoxazole).
Coagulase-Negative Staphylococci (S. epidermidis)
Native valve IE caused by coagulase-negative staphylococci
is relatively uncommon, and most strains are susceptible to
nafcillin. These patients should be treated with the same
therapy used to treat methicillin-susceptible left-sided S.
aureus endocarditis. Patients with infective endocarditis
caused by methicillin-resistant strains should receive vanco-
mycin therapy for 6 weeks. Coagulase-negative staphylococci
are the most common cause of early-onset PVE.24,25 Most of
these strains are resistant to nafcillin or cefazolin. The most
effective therapy for patients with coagulase-negative staphy-
lococcal PVE is a combination of vancomycin and rifampin
administered for 6 weeks with low-dose gentamicin therapy
for the first 2 weeks of treatment (see Table 19.9).17
Endocarditis caused by the HACEK group of microorganisms
accounts for about 5% of non–addiction-associated cases.
Previous studies have shown that these patients can be
treated successfully with 3 weeks of intravenous ampicillin
therapy.26 However, occasional strains of Haemophilus para-
influenzae produce β-lactamase. Susceptibility tests are dif-
ficult to perform on the HACEK group of microorganisms.
Therefore, they should be considered to be β-lactamase pro-
ducers until shown otherwise. Ceftriaxone administered in
a single dose of 2 g/d for 3 weeks is effective treatment for IE
caused by this group of microorganisms (Table 19.10).17
Other Gram-Negative Bacillary Microorganisms
Non–addiction-associated native valve IE caused by gram-
negative bacilli other than the HACEK group is rare. Most
cases of native valve gram-negative bacillary endocarditis
occur in addicts and are most often caused by P. aeruginosa,
Serratia, and Klebsiella. The choice of effective antimicro-
bial therapy should be based on in vitro susceptibility tests,

TABLE 19.10. Therapy for endocarditis due to HACEK microorganisms*

Antibiotic Dosage and route Duration (weeks) Comments

Ceftriaxone sodium† 2 g once daily IV or IM† 4 Cefotaxime sodium or other third-generation

cephalosporins may be substituted
Ampicillin sodium‡ 12 g/24 h IV either continuously or 4
in six equally divided doses
With gentamicin sulfate§ 1 mg/kg IM or IV every 8 h 4
HACEK, Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella species, and Kingella kingae.
* Antibiotic dosages are for patients with normal renal function.
† Patients should be informed that IM injection of ceftriaxone is painful. For patients unable to tolerate β-lactam therapy, consult text.
‡ Ampicillin should not be used if laboratory tests show β-lactamase production.
§ For specific dosing adjustment and issues concerning gentamicin (obese patients, relative contraindications), see Table 19.5 footnotes.
452 chapter
and the selection of a specific antimicrobial agent should be
the least toxic, most active agent in vitro. In general, therapy
should be administered for 4 to 6 weeks.
Gram-negative bacilli are the second most common cause
of early-onset PVE. The same principles of therapy for the
selection of an antimicrobial agent or a combination of agents
used for addiction-associated IE should be applied to patients
with gram-negative bacillary PVE. The duration of therapy
should be 4 to 6 weeks.
Fungal Endocarditis
Endocarditis caused by Candida should be treated with
amphotericin B or, if susceptible, with fluconazole. After 7
to 10 days of therapy, the infected cardiac valve should be
excised. There are few documented cases of cure of fungal
endocarditis with medical therapy alone. Aspergillus endo-
carditis most often occurs in association with cardiac valve
replacement surgery. Aspergilli are relatively resistant to
amphotericin B and other antifungal agents. Therapy should
be initiated with amphotericin B, followed by early surgical
intervention. Fungal endocarditis is associated with the for-
mation of large cardiac valve vegetations, and embolization
to systemic vessels is common. The mortality rate associated
with fungal endocarditis, especially that with prosthetic
valve infection, is high.
Culture-Negative Endocarditis
Culture-negative endocarditis most often occurs in patients
who have received recent antimicrobial therapy. Unless the
need for antimicrobial therapy is urgent, it is preferable to
withhold therapy for a few days until positive blood cultures
establish the microbiologic diagnosis. For patients with acute
fulminating IE or those in whom blood cultures remain
negative, therapy should be started with a combination of
vancomycin and low-dose gentamicin. As described earlier,
patients with culture-negative endocarditis should be
evaluated for Q fever, chlamydia, mycoplasma, or fungal
endocarditis. Patients with nutritionally variant viridans
streptococcal IE and those with HACEK endocarditis may
have intermittently positive blood cultures, and prolonged
incubation may be required before results are positive.
Treatment of Complications
The complications of IE that are considered here are those
that involve the heart and adjacent structures or those that
are extracardiac, and those that occur most commonly and
are accessible to diagnosis and treatment.
Cardiac Complications
Heart Failure
Heart failure caused by valvular insufficiency is the most
common serious complication of IE and is the leading cause
of death. Patients with moderate to severe CHF caused by IE
who are unresponsive to medical therapy alone have a higher
mortality than do patients with CHF who are treated with a
medical regimen and cardiac valve replacement.27–31 Aortic
19
Functional class Sudden onset Functional
III or IV of severe aortic class ≤II
heart failure insufficiency heart failure
Treat medically Treat medically
Responsive Unresponsive Urgent cardiac Deterioration Stable
after 24–48 valve to class
hours replacement III or IV
Complete course
of antimicrobials
Complete course
of antimicrobials
Cardiac valve
replacement
if necessary
FIGURE 19.2. Diagram of our approach to the management of
patients with infective endocarditis and heart failure. Class II, III,
and IV are the New York Heart Association functional
classification.
valve IE is associated with a higher mortality rate than is
mitral valve infection.28 Our approach to the management of
patients with CHF caused by IE is shown in Figure 19.2.30
The most important factor in the decision to proceed with
cardiac valve replacement and the timing of surgical inter-
vention is the hemodynamic status of the patient. Among
patients with severe CHF who fail to respond to medical
therapy after 24 to 48 hours, consideration should be given
to prompt surgical intervention regardless of the duration of
preoperative antimicrobial therapy. In these patients, pro-
crastination in cardiac valve replacement in an attempt to
complete the course of antimicrobial therapy preoperatively
usually results in death from CHF. The operative mortality
rate of patients who undergo cardiac valve replacement owing
to CHF caused by IE is directly related to the degree of CHF
present at the time of surgery. In a 13-year study done at the
Mayo Clinic, the operative mortality rate was highest in
patients with class IV disability preoperatively, and the oper-
ative mortality rate in patients with or without IE was
remarkably similar when the degree of heart failure was the
same as that at the time of operation.31
Echocardiography is useful in the management of patients
with IE and heart failure. Assessment of valvular dysfunc-
tion and hemodynamic status by echocardiography is impor-
tant in decision making concerning the necessity and timing
of surgical intervention.5,32–35
Echocardiography is used to define ventricular function,
size, and wall motion, and valvular insufficiency may be
quantified. Progressive increase in ventricular size, elevation
of pulmonary artery pressure, and wall motion abnormalities
on serial echocardiography suggest the onset or worsening of
heart failure and suggest the need for surgical intervention
(Table 19.11).15 Reportedly, there is a higher frequency of com-
plications, including CHF and need for cardiac valve replace-
ment, myocardial abscess, and death, among patients with
IE in whom vegetations were detected on echocardiography
compared with patients without echocardiographic evidence
of vegetation. Patients with larger vegetations (Fig. 19.3) were
also reportedly at high risk for complication in some
studies,33,36,37 but not in others.32,38 On the basis of these
observations, some authorities have recommended early sur-
gical intervention if valvular vegetations are detected by
echocardiography.39–42
 in fectiv e en doca r ditis 453
TABLE 19.11. Echocardiographic features suggesting potential
need for surgical intervention*
Vegetation
Persistent vegetation after systemic embolization
Anterior mitral leaflet vegetation, particularly with size
>10 mm†
One or more embolic events during first 2 weeks of
antimicrobial therapy†‡
Two or more embolic events during or after antimicrobial
therapy
Increase in vegetation size after 4 weeks of antimicrobial
therapy

Valvular dysfunction
Acute aortic or mitral insufficiency with signs of ventricular
failure‡
Heart failure unresponsive to medical therapy‡
Valve perforation or rupture‡

Perivalvular extension
Valvular dehiscence, rupture, or fistula‡
New heart block‡
Large abscess, or extension of abscess despite appropriate FIGURE 19.3. Transthoracic echocardiogram, apical four-chamber
antimicrobial therapy‡ view. A highly mobile linear echodensity (arrow) suggestive of a
vegetation is seen within the left atrium (LA) and is attached to the
* See text for more complete discussion of indications for surgery based on mitral valve (MV) anterior leaflet. LV, left ventricle; RV, right ven-
vegetation characterizations. tricle); RA, right atrium.
† Surgery may be required because of risk of embolization.
‡ Surgery may be required because of heart failure or failure of medical
therapy.

rior mitral valve leaflets, premature closure of the mitral

Although these studies reported a high incidence of CHF
in patients with echocardiographic detection of vegetations
compared with those without vegetations, Lutas and associ-
ates38 reported that the presence or size of vegetations on
echocardiography did not significantly increase the incidence
of CHF or the need for cardiac valve replacement. O’Brien
and Geiser43 reported that 50% of patients without vegeta-
tions on echocardiogram developed heart failure. Patients
whose echocardiograms demonstrated fluttering of the ante-
valve, chordal (Fig. 19.4) or cusp rupture, or Doppler ultra-
sound evidence of moderate to severe valvular regurgitation
were at higher risk for the development of CHF and the need
for cardiac valve replacement.41–45
Echocardiographic imaging is operator dependent and is
influenced by such factors as obesity, chest wall deformity,
trauma, recent thoracic surgery, and the use of ventilating
equipment. Not surprisingly, considerable variability is
reported for the incidence of complications and the need for
cardiac valve replacement associated with the presence of

A B
FIGURE 19.4. Transesophageal echocardiogram, four-chamber (arrowheads). (B) The mass lesion appears more extensive during
view during diastole with mechanical mitral valve prosthesis open prosthetic valve closure (arrowheads). Prosthesis shadowing and
(A, arrows) and during systole with mechanical prosthesis closed reverberation artifacts obscure the left ventricle (LV) and the right
(B). A complex mobile mass lesion consistent with vegetation par- ventricle (RV). RA, right atrium; LA, left atrium.
tially occupies the left atrial appendage (LAA) and valve inflow zone
454 chapter 19

vegetations detected on echocardiography. Medical regimens First relapse

and indications for cardiac valve replacement differ among
institutions, and the detection of vegetations by echocardiog-
raphy may have in itself influenced the decision to intervene Staphylococci Other microorganism
Gram-negative bacilli
surgically. or other microorganism
In summary, we do not believe that patients should be resistant to multiple drugs
Q fever endocarditis Re-treat with
subjected to cardiac valve replacement only on the basis of antimicrobials
echocardiographic detection of cardiac valve vegetations.
The mere presence, location, size, or persistence of vegeta- Cardiac valve
Cure Second relapse
tions visualized by echocardiography do not necessarily replacement

imply that all of these patients will develop CHF. The hemo-
dynamic status of the patient and the response to medical
Gram-negative bacilli or Enterococci
therapy are the most important factors in the decision for unusual microorganisms Streptococci
surgical intervention. Echocardiography is useful as a means moderately resistant Penicillin-sensitive
to antimicrobials Nutritionally variant
to closely monitor patients with endocarditis during and Other highly antibiotic-
after the completion of antimicrobial therapy. Patients with sensitive microorganism

torn aortic cusps that produce severe aortic regurgitation and Cardiac valve
replacement
premature closure of mitral valve or ruptured mitral valve Re-treat with
antimicrobials
chordae that produce severe mitral regurgitation are at higher
risk for CHF and should be followed closely for early detec-
tion of left ventricular dysfunction and CHF so that prompt Cure Third relapse
surgical intervention can be performed.
Cardiac valve replacement can be performed successfully
in patients who have active IE and severe heart failure.46–49 Cardiac valve
Previously, we described 11 patients with active IE who replacement

underwent urgent cardiac valve replacement; eight of these
patients had positive blood cultures within 48 hours preop-
eratively.49 Three of the 11 patients died—two of complica-
tions of sudden-onset severe aortic regurgitation and one of
coagulase negative staphylococcal PVE. The risk of valve
dehiscence in PVE may be higher in patients with active IE
at the time of operation than in those who have completed
a course of antimicrobial therapy preoperatively, but this risk
is justified by the excessively high mortality rate in patients
with severe CHF who do not undergo early cardiac valve
replacement. For patients with sudden-onset severe aortic
insufficiency, urgent cardiac valve replacement offers the
only hope for survival.
Relapse
In a series of 629 consecutive cases of endocarditis in patients
seen at the Mayo Clinic, relapse occurred in 4%.1 All patients
with IE should be evaluated carefully to determine the portal
of entry of infection. If a source of infection is identified, it
should be eliminated while the patient is receiving antimi-
crobial therapy for IE. Because the oral cavity and urinary
tract are the most frequently identified portals of entry, urine
culture, urologic evaluation if necessary, and assessment of
dentition and any necessary dental procedures should be
performed. Metastatic infection is most likely to occur in
patients with S. aureus IE, and a diligent search for possible
metastatic foci of infection, especially located intraabdomi-
nally, using imaging techniques should be conducted.
Our approach to the management of patients with relapse
of IE is shown in Figure 19.5.30 We believe that in all patients
with bacterial IE who are stable hemodynamically and who
have not had recurrent multiple large emboli, at least one
attempt should be made to sterilize the infected valve by
antimicrobial therapy before cardiac valve replacement is
considered. Patients with S. aureus IE who experience a
FIGURE 19.5. Diagram of an approach to management of patients
with relapse of infective endocarditis.
relapse despite adequate antimicrobial therapy should be
considered for cardiac valve replacement, especially if a
second relapse occurs and if no metastatic focus of infection
to account for the relapse is identified.
Patients with penicillin-susceptible streptococcal IE or
enterococcal IE are usually responsive to antimicrobial
therapy, and relapses, when they occur, are usually cured by
a second course of antimicrobial therapy.
Perivalvular Extension of Infection, Myocardial
Abscess, Myocardial Conduction Defects,
Infarction, and Pericarditis
The extension of infection involving cardiac valves beyond
the valve annulus may result in conduction defects, myocar-
dial abscess, increased risk of valve dehiscence, and the
development of heart failure and is associated with a higher
mortality rate and need for cardiac surgery. In aortic valve
IE, infection may extend from the annulus into the membra-
nous septum and involve the atrioventricular node, resulting
in myocardial abscess or heart block. Perivalvular extension
of infection is more likely to occur in aortic valve IE than in
mitral or tricuspid valve IE. Prosthetic valve endocarditis is
especially susceptible to perivalvular extension of infection
and valvular dehiscence. Persistent bacteremia despite appro-
priate antimicrobial therapy, recurrent emboli, or the devel-
opment of heart block or worsening valvular insufficiency or
dehiscence suggests perivalvular extension of IE. The use of
TEE is more sensitive and specific than TTE for the detection
of perivalvular extension of infection.50 Moreover, TEE com-
bined with spectral and color Doppler echocardiography
may demonstrate fistulas, pseudoaneurysms, or myocardial
 in fectiv e en doca r ditis
abscess associated with perivalvular extension of infection.
Accordingly, TEE is the procedure of choice for the diagnosis
of perivalvular extension of infection in patients with IE.
Some patients with perivalvular extension of infection
may be successfully treated without surgical intervention;
these patients include those without heart block, echocardio-
graphically demonstrated progression of abscess during
appropriate antimicrobial therapy, or valvular dehiscence.
These patients should be monitored closely with serial echo-
cardiography during and after the completion of antimicro-
bial therapy.
At the Mayo Clinic, doctors have observed patients with
presumed myocardial abscess diagnosed by echocardiogra-
phy in which antimicrobial therapy alone resulted in disap-
pearance of the abscess. In addition, autopsies performed on
patients with previously healed endocarditis may demon-
strate healed abscess cavities after medical therapy alone.
Therefore, the detection of an abscess by echocardiography
is not an absolute indication for surgical intervention.
Daniel and colleagues50 reported their experience in
patients with myocardial abscesses documented at surgery
or autopsy. Transesophageal echocardiography in these
patients detected abscesses in 87% of cases, whereas only
28% were identified by two-dimensional echocardiography
(p < .001). In this study, patients with PVE had a higher per-
centage of abscesses than did those with native valve IE. In
patients with IE, we believe that two-dimensional echocar-
diography should be performed initially, followed by TEE if
necessary. The two procedures complement each other and
are not mutually exclusive. Patients with myocardial
abscesses diagnosed by echocardiography should be followed
closely for signs of extension of the abscess, valve dehis-
cence, development of heart block on electrocardiography,
CHF, or persistence of infection despite adequate medical
therapy. Patients who exhibit one or more of these complica-
tions of myocardial abscess should receive prompt surgical
intervention.
Cardiac rhythm disturbances or heart block may result
from involvement of the cardiac conduction system by exten-
sion of IE. Patients with conduction defects should be moni-
tored closely and may require the insertion of a transvenous
pacemaker or other surgical intervention. The goal of surgi-
cal intervention in patients with perivalvular extension of IE
is eradication of infection, correction of hemodynamic abnor-
malities including cardiac valve replacement, drainage of
abscess, and debridement and closure of fistulous tracts. In
patients with perivalvular infection who require cardiac
valve replacement, the use of aortic homografts may be asso-
ciated with a lower risk of persistence of infection than the
use of an artificial prosthesis.
Myocardial infarction results from vegetations that dis-
lodge and embolize to the coronary arteries. In our experi-
ence, the frequency of myocardial infarction associated with
IE is 3%. Patients with myocardial infarction associated
with IE should be treated similarly to those with infarction
associated with atherosclerosis. Pericarditis is most often
associated with S. aureus IE. Echocardiography is useful in
the detection of pericardial fluid, but the diagnosis of puru-
lent pericarditis must be established by pericardiocentesis.
Purulent pericarditis should be treated with prompt surgical
drainage and antimicrobial therapy.
455
Extracardiac Complications
Emboli
The frequency of clinically apparent emboli in patients with
IE has been reported to be from 22% to 50%.32,51 The highest
percentage of patients with major embolic events occurs in
association with S. aureus or those infections that produce
large bulky vegetations, such as those caused by the HACEK
group of microorganisms, nutritionally variant viridans
streptococci, group B streptococci, or fungi (especially Asper-
gillus).52,53 Because embolic events may result in irreversible
organ dysfunction or death, prevention is a desirable goal.
Elective cardiac valve replacement has been recommended
for patients who have recurrent emboli or who are at high
risk for additional emboli.40,54
The relationship between echocardiographically visual-
ized cardiac valve vegetations, systemic embolization, and
the need for cardiac valve replacement is controversial. Val-
vular vegetations have been detected by echocardiography in
13% to more than 78% of patients with endocarditis,32–34 and
their presence has been reported to increase the risk of embo-
lization in some studies,33,40,42–44,55 but not in others.32,56–59
Large, mobile vegetations detected by echocardiography,
especially those in excess of 10 mm in diameter, have also
been reported to increase the risk of embolization in some
reports,33,42,60 but not in others.32,38,44,58,59,61 The results of
these studies led to the controversial recommendation that
elective cardiac valve replacement be considered in patients
with vegetations detected by echocardiography on the pre-
sumption that the presence of vegetations is predictive of
future embolic events.
At the Mago Clinic, doctors reported the incidence of the
first embolic event after the onset of effective antimicrobial
therapy in more than 200 patients with left-sided native
valve IE.32 Vegetations were detected by echocardiography in
38% of patients and were absent in 40%. In the remaining
patients, vegetation status was indeterminate. We observed
no statistically significant difference in the incidence rate of
embolic events among patients with definite valve vegeta-
tions compared with those with absent or indeterminate
vegetation. Moreover, no increased rate of embolization was
noted with increasing vegetation size from 3 to 30 mm in
diameter, nor was there a statistically significant difference
in the rate of emboli among patients with vegetations greater
than 10 mm in diameter compared with those with smaller
vegetations. There was no significant effect of vegetation size
on the rate of embolization in subsets of patients with aortic
or mitral valve involvement except in patients with strepto-
coccal IE who had a higher rate of embolization. The inci-
dence rate of emboli decreased over time during antimicrobial
therapy (p < .001). The incidence of embolic events among all
patients fell from 13 per 1000 patient-days during week 1 of
antimicrobial therapy to fewer than 1.2 per 1000 patient-days
after week 2 of therapy (Fig. 19.6).
Many studies, including those cited earlier,32 have
attempted to identify patients with IE who are at high risk
of emboli who might benefit from surgical intervention to
avoid embolization. Mitral valve vegetations reportedly are
more likely to result in peripheral embolization (25%) than
in aortic valve vegetations (10%). The highest rate of
456
20
Definite vegetations
Embolic rate/1000 pt-days
All patients
15
Absent vegetations
10
5 ography may be useful for the diagnosis of intracranial
0 angiography. Accordingly, cerebral angiography remains the
1 2 3 4
Week of antimicrobial therapy
FIGURE 19.6. Incidence of embolic events in patients (pt) with
infective endocarditis.
embolization (37%) was observed when the vegetations were
located on the anterior leaflet rather than the posterior leaflet
of the mitral valve.62,63 This higher rate may be related to the
mechanical effects of the abrupt excursion of the anterior
mitral valve during the cardiac cycle, which subject vegeta-
tions located on the anterior leaflet to fragmentation and
embolization. The risk of emboli is greater when associated
with an increase in vegetation size demonstrable by TEE
during 4 to 8 weeks of antimicrobial therapy. The risk of
emboli in these patients was twice that of patients in whom
vegetations remained unchanged or decreased in size during
therapy.
The American Heart Association published guidelines
suggesting the potential need for surgical intervention in
patients with valvular vegetations demonstrable by echo-
cardiography (Table 19.11).15 Antimicrobial therapy reduces
the risk of embolization during the first 2 weeks of therapy.
Accordingly, benefit from surgery to prevent embolic events
is highest early in the course of antimicrobial therapy. In
selected patients, surgical intervention may prevent a
primary or recurrent serious embolic event. The decision
for surgical intervention to prevent embolization should
be individualized in each patient. Surgery should be con-
sidered when large vegetations are detected on the mitral
valve, especially the anterior leaflet, and in patients
whose vegetation increases in size after 4 weeks of anti-
microbial therapy or in patients who have one or more
embolic events during the first 2 weeks of antimicrobial
therapy or two or more embolic events during or after anti-
microbial therapy.
Mycotic Aneurysm
Mycotic aneurysm is a rare complication of IE. During a 16-
year period at the Mayo Clinic, we were able to identify only
32 patients with mycotic aneurysm among 628 patients with
IE (5%).12 Intercranial mycotic aneurysms are associated with
higher morbidity and mortality rates than mycotic aneu-
rysms located elsewhere. Patients with intracranial mycotic
aneurysms may be asymptomatic, and the diagnosis is
usually made after a sudden massive, often fatal subarach-
noid or intracerebral hemorrhage. Our experience suggests,
however, that the diagnosis of intracranial mycotic aneu-
chapter 19
rysm can be made early before massive hemorrhage occurs.
A severe unremitting localized headache or a homonymous
hemianopsia is a finding that is highly suggestive of intra-
cranial mycotic aneurysm. Contrast-enhanced computed
tomography scanning may detect an intracerebral bleed in
90% to 95% of instances and may indirectly suggest the
locations of a mycotic aneurysm.l5 Magnetic resonance angi-
mycotic aneurysm, but its sensitivity for the detection of an
aneurysm of less than 5 mm is less than that of cerebral
diagnostic procedure of choice. Cerebral angiography should
be performed in these patients.
Although many authorities believe that most intracra-
nial mycotic aneurysms will rupture if untreated, Bingham64
reported that the outcome of patients with intracranial
mycotic aneurysm is similar in those administered adequate
antimicrobial therapy compared with those treated with
both antibiotics and surgical excision of the aneurysm.
Some patients with mycotic aneurysm require both
cardiac valve replacement surgery and ligation of an intra-
cranial mycotic aneurysm. The more life-threatening
problem dictates the surgical procedure to be performed
first. The use of a bioprosthetic cardiac valve that does
not require the administration of anticoagulant therapy may
be preferable to mechanical valve prosthesis in these
patients.
Most, if not all, intrathoracic and intraabdominal mycotic
aneurysms will rupture if not excised. Peripheral mycotic
aneurysms are most accessible to early diagnosis and are
associated with the best prognosis. The risk of rupture of an
untreated peripheral mycotic aneurysm is high, and prompt
surgical intervention is imperative. Most authorities believe
that the treatment of choice for patients with peripheral
mycotic aneurysm is ligation and excision and that it is
preferable to sacrifice the limb, if necessary, rather than the
life of the patient.
Splenic Abscess
Splenic infarction is a common complication of left-sided IE
(approximately 40% of cases); however, only about 5% of
patients with splenic infarction develop splenic abscess.15
Viridans streptococci or S. aureus is the most common cause
of splenic abscess. Patients with persistent left upper quad-
rant pain and those with persistent or recurrent bacteremia
or fever despite appropriate antimicrobial therapy should be
suspected of having splenic abscess. Abdominal computed
tomography or magnetic resonance imaging is the most sen-
sitive test for the diagnosis of splenic abscess. Differentiation
of splenic abscess from infarction may be difficult with these
imaging tests. Persistent sepsis, positive blood cultures, or
enlargement of the splenic defect on computed tomography
or magnetic resonance imaging suggests an abscess rather
than an infarction. Percutaneous drainage of splenic abscess
has been performed successfully15 and, in experienced hands,
has replaced splenectomy as the treatment of choice. In
patients with splenic abscess who require cardiac valve
replacement surgery, splenectomy should be performed before
valve replacement surgery because of the risk of bacteremia
and infection of the valve prosthesis.
 in fectiv e en doca r ditis
Metastatic Infection
Patients with metastatic infection are at risk for relapse of
IE, which most often occurs in patients with staphylococcal
endocarditis. Imaging techniques such as computed tomog-
raphy, magnetic resonance imaging, and radioisotope scan-
ning may be helpful in localizing occult metastatic foci of
infection. The persistence of fever, localized pain or tender-
ness, persistently abnormal liver function tests, and break-
through bacteremia suggest the diagnosis of metastatic
abscess.
Central Nervous System Abnormalities
Central nervous system abnormalities have been reported to
occur in 9% to 80% of patients with IE; these include head-
ache, confusion, stroke, meningoencephalitis, brain abscess,
and mycotic aneurysm.12,13 The management of patients with
mycotic aneurysms or embolic events was discussed earlier.
Most patients with central nervous system abnormalities
show improvement with supportive care and appropriate
antimicrobial therapy. Patients with a large solitary brain
abscess may require stereotactic or open surgical drainage,
but most patients with small abscesses do not require neu-
rosurgical intervention. In patients with brain abscess, the
duration of antimicrobial therapy should often be extended
beyond that usually required for the treatment of uncompli-
cated IE.
Prosthetic Valve Endocarditis
Incidence
Prosthetic valve endocarditis (PVE) continues to be a rare but
life-threatening complication of cardiac valve surgery. The
prevalence is reported to be between 15% and 30% of all
cases of endocarditis.66–68
The risk of infection of a prosthetic heart valve is highest
within the first year after surgery (1% to 3%), particularly
within the first 3 months postoperatively.69 After the first 6
to 12 months, the rate stabilizes at 0.4% per year.70
Although there seems to be no difference in overall risk
for infection of these valves, there is an increased incidence
of PVE in the first 6 months with mechanical valves,71 and
an increase after 5 years with bioprosthetic valves.72
Pathogenesis
After cardiac valvular replacement, fibrin and platelets
attach at the operative site, particularly the sewing ring/
annulus area, producing a sticky bed for adherence of micro-
organisms reaching the bloodstream. Early postoperative
bacteremia is frequently associated with line sepsis or wound
infections.69,73
As this operative site heals and as the area becomes
endothelialized, the risk of infection is less. Late infections
mimic the pathogenesis of IE where valvular abnormalities
result in turbulence of blood flow with resulting formation
of the platelet-fibrin bed known as nonbacterial thrombotic
endocarditis. Organisms attach to this during bacteremia,
leading to IE and PVE.
457
Microbiology
Early-onset PVE (≤2 months postoperative) is most often
caused by staphylococci (Staphylococcus epidermidis and
other coagulase-negative staphylococci, frequently methicil-
lin-resistant as well as S. aureus, including many isolates
that are methicillin resistant).70,74
After staphylococci, gram-negative bacilli and fungi are
the etiology of early PVE. Prosthetic valve endocarditis
occurring late (≥12 months postoperative) is caused by
the same organisms that cause IE on native valves
(Table 19.4). There is also an increased incidence of entero-
cocci and coagulase-negative staphylococci as pathogens in
late PVE.
Clinical Picture
Any patient with a prosthetic heart valve and fever should
be assumed to have PVE until proven otherwise. The clinical
features of PVE are quite similar to those found in IE except
for the relative absence of signs of peripheral emboli early in
the course of the illness to help the physician make a clinical
diagnosis at the bedside.
The presentation of PVE, like that of IE, can vary from
an indolent subacute picture (more common in late PVE) to
fulminant sepsis and septic shock (more common with early-
onset S. aureus infection).
Diagnosis
The Duke Criteria14 using echocardiographic data in addition
to clinical and laboratory findings may be used in the diag-
nosis of PVE75, as well as IE (Tables 19.1 and 19.2).
The diagnosis of PVE is based on the clinical picture,
laboratory tests, and results of the echocardiogram. The clin-
ical suspicion must be confirmed with positive blood cul-
tures. The bacteremia in PVE is more or less continuous, so
blood cultures can be obtained without regard to timing
them with chills or fever spikes. In patients who are not
critically ill with sepsis or heart failure, it is preferable to
withhold antibiotic therapy until a microbiologic diagnosis
has been established. Most blood cultures obtained off anti-
biotics will be positive. The importance of having the organ-
ism isolated before treatment is that it is necessary to have
the organism for antibiotic sensitivity testing. Both PVE and
IE require a truly bactericidal antibiotic regimen for a cure,
and this can be designed only if you have reliable sensitivity
data.
Echocardiography
Echocardiography is critical in the diagnosis and manage-
ment of PVE. In this infection, TEE is superior to TTE both
for initial diagnosis and then serially for early recognition of
serious complications which may require surgical interven-
tion: annular abscesses, malfunction of the prosthetic valve
due to large vegetation, or early dehiscence of the prosthetic
valve.75,76
The sensitivity of the TEE in patients with PVE is reported
to be as high as 86% to 94% with a specificity of 88% to
458 chapter
100%. The negative predictive value of a TEE in PVE also
reaches 95%.
When the initial TEE is negative in a patient with clinical
and microbiologic data suggestive of PVE, simply repeat the
TEE after a week of antibiotic treatment.
Antimicrobial Therapy
Once the infecting organism for sensitivity testing has
been isolated, the antimicrobial treatment becomes straight-
forward. Treatment for IE has been discussed in detail for
IE in this chapter. Table 19.9 is a summary for treatment of
staphylococcal PVE. The recommendations concerning
treatment of other bacteria and fungi that can cause IE
also apply to the treatment of these pathogens when they
cause PVE. (See Tables 19.5 through 19.7 and Table 19.9 for
staphylococcal PVE, and Table 19.10 for the other organisms
causing IE and PVE and the recommended antibiotic
treatment.)
To convert these tables to regimens appropriate for PVE
treatment77 there are two corrections. In the duration of
treatment column always use the longer duration when a
range is given, or add 2 weeks if no range is given. In the
dosage column, always use the highest dose when a range is
given.
Other less frequent pathogens causing IE and PVE and
their treatment are discussed earlier in this chapter, as is the
approach to culture negative IE and PVE.
Surgical Treatment
The treatment of PVE should be a combined effort of cardiol-
ogy, cardiovascular surgery, and infectious disease. This is
particularly true in the decision concerning the need for
surgery and the type of surgery to be performed.
Most of the complications of PVE are associated with
spread of infection from the valve ring into perivalvular and
adjacent myocardial tissue. Perivalvular/annular abscesses
are common sources for persistent bacteremia in the face
of appropriate antibiotic therapy. Valvular dehiscence and
fistula formation or valvular obstruction or malfunction due
to a large vegetation can result in severe heart failure. New
conduction abnormalities can result from extension of infec-
tion to involve the conduction system.
All of these complications are indications for surgical
intervention.
In addition, surgery is indicated in the management of
any infecting organism for which there is no bactericidal
antibiotic regimen and in all fungal PVE since there are no
truly cidal antifungal agents.
Relapse of infection after an appropriate course of antibi-
otic treatment also requires valvular replacement and another
full course of antibiotic therapy.
Timing of surgery must be individualized for each patient,
but the most important factor is the hemodynamic status of
the patient. Early surgery as soon as one of these complica-
tions is recognized will lower the mortality. Mortality is
reported to be proportional to the degree of preoperative
congestive heart failure, hemodynamic instability, and end-
organ dysfunction, particularly renal failure.
19
Prevention
The American Heart Association publishes recommenda-
tions for IE as well as PVE prevention. These recommenda-
tions are found in Tables 19.12 to 19.15.
Another important aspect of prevention of PVE is the role
of the cardiologist in reeducating each patient on an annual
basis regarding the hazard of PVE in every patient with a
prosthetic valve. Patients need to be instructed that it is the
patient’s responsibility to avoid PVE by alerting physicians
and dentists about the presence of a prosthetic valve before
any manipulation is performed that could cause bleeding in
any area of the body normally colonized with bacteria, par-
ticularly the teeth, mouth, trachea/bronchi, esophagus, and
gastrointestinal and genitourinary tracts. The cardiologist
must also be mindful of the following:
1. Patients must be discouraged from treating febrile
illnesses at home. Medical evaluation and antibiotic
treatment should be sought early rather than after an
infection is allowed to progress to the point of producing a
bacteremia with the hazard of infection of the prosthetic
valve.
2. Patients must be discouraged from manipulating any
pustular of infected skin lesions including carbuncles, furun-
cles, or even styes on the eyelid. These lesions contain staph-
ylococci and can lead to transient bacteremia if manipulated
or drained without appropriate antibiotic coverage before and
after drainage procedures.
TABLE 19.12. Dental procedures and endocarditis prophylaxis
Endocarditis prophylaxis recommended*
Dental extractions
Periodontal procedures including surgery, scaling and root
planing, probing, and recall maintenance
Dental implant placement and reimplantation of avulsed teeth
Endodontic (root canal) instrumentation or surgery only beyond
the apex
Subgingival placement of antibiotic fibers or strips
Initial placement of orthodontic bands but not brackets
Intraligamentary local anesthetic injections
Prophylactic cleaning of teeth or implants where bleeding is
anticipated
Endocarditis prophylaxis not recommended
Restorative dentistry† (operative and prosthodontic) with or
without retraction cord‡
Local anesthetic injections (nonintraligamentary)
Intracanal endodontic treatment; postplacement and buildup
Placement of rubber dams
Postoperative suture removal
Placement of removable prosthodontic or orthodontic appliances
Taking of oral impressions
Fluoride treatments
Taking of oral radiographs
Orthodontic appliance adjustment
Shedding of primary teeth
* Prophylaxis is recommended for patients with high- and moderate-risk
cardiac conditions.
† This includes restoration of decayed teeth (filling cavities) and replacement
of missing teeth.
‡ Clinical judgment may indicate antibiotic use in selected circumstances
that may create significant bleeding.
 in fectiv e en doca r ditis 459
TABLE 19.13. Other procedures and endocarditis prophylaxis recommended
Respiratory tract Endocarditis prophylaxis not recommended
Tonsillectomy and/or adenoidectomy Respiratory tract
Surgical operations that involve respiratory mucosa Endotracheal intubation
Bronchoscopy with a rigid bronchoscope Bronchoscopy with a flexible bronchoscope, with or without biopsy†
Gastrointestinal tract* Tympanostomy tube insertion
Sclerotherapy for esophageal varices Gastrointestinal tract
Esophageal stricture dilatation Transesophageal echocardiography†
Endoscopic retrograde cholangiography with biliary Endoscopy with or without gastrointestinal biopsy†
obstruction Genitourinary tract
Biliary tract surgery Vaginal hysterectomy†
Surgical operations that involve intestinal mucosa Vaginal delivery†
Cesarean section
Genitourinary tract In uninfected tissue
Prostatic surgery Urethral catheterization
Cystoscopy Uterine dilatation and curettage
Urethral dilation Therapeutic abortion
Sterilization procedures
Insertion or removal of intrauterine devices
Other
Cardiac catheterization, including balloon angioplasty
Implanted cardiac pacemakers, implanted defibrillators, and
coronary stents
Incision or biopsy of surgically scrubbed skin
Circumcision
* Prophylaxis is recommended for high-risk patients; it is optional for medium-risk patients.
† Prophylaxis is optional for high-risk patients.

TABLE 19.14. Prophylactic regimens for dental, oral, respiratory tract, or esophageal procedures
Situation Agent Regimen

Standard general prophylaxis Amoxicillin
Unable to take oral medications Ampicillin
Allergic to penicillin Clindamycin or
Cephalexin† or cefadroxil† or
Azithromycin or clarithromycin
Allergic to penicillin and unable Clindamycin or
to take oral medications
Cefazolin†
* Total children’s dose should not exceed adult dose.
† Cephalosporins should not be used in individuals with immediate-type hypersensitivity reaction (urticaria, angioedema, or anaphylaxis) to penicillins.
Adults: 2.0 g; children: 50 mg/kg PO 1 h before procedure
Adults: 2.0 g IM or IV; children: 50 mg/kg IM or IV within
30 min before procedure
Adults: 600 mg; children: 20 mg/kg PO 1 h before procedure
Adults: 2.0 g; children: 50 mg/kg PO 1 h before procedure
Adults: 500 mg; children: 15 mg/kg PO 1 h before procedure
Adults: 600 mg; children: 20 mg/kg IV within 30 min before
procedure
Adults: 1.0 g; children: 25 mg/kg IM or IV within 30 min
before procedure

TABLE 19.15. Prophylactic regimens for genitourinary/gastrointestinal (excluding esophageal) procedures

Situation Agents* Regimen

High-risk patients Ampicillin plus gentamicin Adults: ampicillin 2.0 g IM or IV plus gentamicin 1.5 mg/kg (not to exceed
120 mg) within 30 min of starting procedure: 6 h later, ampicillin 1 g IM/
IV or amoxicillin 1 g PO
Children: ampicillin 50 mg/kg IM or IV (not to exceed 2.0 g) plus
gentamicin 1.5 mg/kg within 30 min of starting the procedure; 6 h later,
ampicillin 25 mg/kg IM/IV or amoxicillin 25 mg/kg orally
High-risk patients allergic Vancomycin plus gentamicin Adults: vancomycin 1.0 g IV over 1–2 h plus gentamicin 1.5 mg/kg IM/IV
to ampicillin/amoxicillin (not to exceed 120 mg): complete injection/infusion within 30 min of
starting procedure
Children: vancomycin 20 mg/kg IV over 1–2 h plus gentamicin 1.5 mg/kg
IM/IV; complete injection/infusion within 30 min of starting procedure
Moderate-risk patients Amoxicillin or ampicillin Adults: amoxicillin 2.0 g PO 1 h before procedure, or ampicillin 2.0 g
IM/IV within 30 min of starting procedure
Moderate-risk patients Vancomycin Adults: vancomycin 1.0 g IV over 1–2 h; complete infusion within 30 min
allergic to ampicillin/ of starting procedure
amoxicillin Children: vancomycin 20 mg/kg IV over 1–2 h; complete infusion within
30 min of starting procedure
* Total children’s dose should not exceed adult dose.
† No second dose of vancomycin or gentamicin is recommended.
460 chapter
3. In addition, early postoperative bacteremia can lead
to PVE, and these positive blood cultures must be
interpreted in the light of the clinical situation.73,78 If a
source of the bacteremia (line sepsis, wound infection) is
easily identified and responds promptly to appropriate
medical/surgical treatment and no evidence of PVE is found
by exam or echocardiography, the bacteremia can be treated
for the full 10 to 14 days appropriate for the organism. If the
patient has already seeded the prosthetic valve, this short
course of antibiotic treatment will not cure the PVE, and
relapse will occur within 24 to 48 hours of stopping the
antibiotics.
Prevention of Endocarditis
The American Heart Association published recommenda-
tions for prophylaxis of IE for patients with cardiac valve
abnormalities, congenital heart disease, intercardiac pros-
thesis, or other cardiac abnormalities (Tables 19.12 to 19.15).65
It is important for clinicians to be aware of the indications
for prophylaxis regimens. Patients should be provided with
the card that is published and distributed through the Ameri-
can Heart Association.
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 2 The Assessment and
0 Therapy of Valvular
Heart Disease in the
Cardiac Catheterization
Laboratory
Paul Sorajja and Rick A. Nishimura

Principles and Techniques . . . . . . . . . . . . . . . . . . . . . . . . 464 Prosthetic Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477

Aortic Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467 Balloon Mitral Valvotomy. . . . . . . . . . . . . . . . . . . . . . . . . 478
Mitral Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469 Balloon Aortic Valvotomy . . . . . . . . . . . . . . . . . . . . . . . . . 480
Valvular Regurgitation . . . . . . . . . . . . . . . . . . . . . . . . . . . 474 Percutaneous Valve Replacement and Repair . . . . . . . . . 481

Key Points
• The approach to catheterization should be individualized
for each patient, with knowledge of the clinical presenta-
tion to facilitate the planning of the procedure and the
acquisition of the relevant data.
• Determination of valve gradients may require direct
measurement of chamber pressures. The use of surrogate
measurements (e.g., femoral artery for central aorta; pul-
monary capillary wedge for left atrial pressure) may lead
to significant errors in the assessment of valve gradients.
• It is important to critically examine the absolute pressure
in each chamber, its contour, and the relation between
each of the pressures examined.
• Among patients with a discrepancy between the clinical
history and resting hemodynamic findings, exercise
testing with pressure measurements in the laboratory
can be helpful.
• Valve morphology is the primary determinant of outcome
in patients who undergo percutaneous mitral balloon
valvuloplasty.
In the 1960s, cardiac catheterization emerged as the princi-
pal diagnostic modality for the evaluation of the patient with
valvular heart disease. Two-dimensional echocardiography
subsequently allowed visualization of valve morphology and
motion as well as the assessment of the ventricular response
to the valvular lesions. The advent of Doppler echocardiog-
raphy in the 1980s provided a noninvasive method for deter-
mination of valve gradients, valve areas, and intracardiac
pressures. Thus, there has been a shift in the evaluation of
patients with valvular heart disease, with the initial diag-
nostic approach consisting of a comprehensive two-dimen-
sional and Doppler echocardiogram following the history
and physical examination. When the clinical and echocar-
diographic findings are concordant, catheterization is needed
only to assess the status of the coronary arteries.
Cardiac catheterization, however, still remains essential
for many patients with valvular heart disease. Although
echocardiography can diagnose the presence and severity of
valvular lesions, there are limitations to its accuracy. Thus,
the major indication for further assessment with hemody-
namic catheterization is when there is a discrepancy between
clinical and echocardiographic findings. Absolute intracar-
diac pressures cannot be assessed by Doppler echocardiogra-
phy, and cardiac catheterization needs to be performed when
this information is necessary. Finally, there has been the
evolution of catheter-based therapies for patients with valvu-
lar heart disease, which in many cases obviates the need for
open-heart surgery.
As the cardiac catheterization laboratory has focused
increasingly on acute and chronic coronary syndromes, less
attention has been focused on the proper performance and
understanding of the hemodynamic assessment of patients
with valvular heart disease. The patients with valvular heart
disease currently being evaluated in the catheterization labo-
ratory are now those with more complex problems, since
patients with straightforward valvular lesions can be assessed
primarily with noninvasive methods. Thus, accurate and

463
464 chapter
clinically relevant data from invasive catheterization has
become increasingly important for patients with valvular
heart disease.
Principles and Techniques
General Approach to the Patient with Valvular
Heart Disease in the Catheterization Laboratory
The approach to the hemodynamic assessment of valvular
heart disease should be individualized for each patient. The
invasive cardiologist performing the study should have full
knowledge of what tests has been performed previously, what
information is known, and what clinically relevant informa-
tion is required from the study. A comprehensive differential
diagnosis of the patient’s problems is needed and facilitates
the planning of the procedure. Before proceeding, the vascu-
lar access sites and approach to gathering data should be
delineated fully.
While all patients should be fasting for the catheteriza-
tion procedure, intravenous fluids should be administered to
patients who have a long waiting period between their last
oral intake and the procedure. This prevents the hemody-
namic measurements from being taken during a low-output,
low-volume state. Patients can be lightly sedated, but should
be awake to simulate the hemodynamic milieu of their out-
patient state with close approximation of the heart rate and
blood pressure that occurs in their usual daily activities. No
parenteral oxygen should be administered prior to the proce-
dure to allow measurements of oxygen saturations.
Accurate measurement of intracardiac pressures with
fluid-filled catheters requires the use of large-bore, rigid cath-
eters with minimization of the tubing length between the
catheter and pressure transducer. Attention to potential
errors of measurement due to damping, catheter whip, entrap-
ment, and other artifacts is always necessary during an inva-
sive hemodynamic study. Fluid-filled catheters can reliably
measure mean and absolute intracardiac pressures. However,
for analysis of pressure waveforms, instantaneous recordings
with high-fidelity micromanometer-tip catheters should be
utilized (Millar Instruments, Houston, TX). If possible, con-
tinuous recording of all hemodynamic pressures should be
made to allow retrospective review of these pressures
throughout the entire study.
All hemodynamic measurements should be made before
any contrast injections, as iodine contrast may affect the
hemodynamic milieu. Equilibration periods of at least 10
minutes should be used to allow hemodynamic stabilization
whenever there is any change in the hemodynamic state.
This equilibration period always should be applied to mea-
surements taken following infusion of a drug or other inter-
vention such as exercise. Spontaneous changes in heart rate
and blood pressure should always be noted during the proce-
dure and documented on the record.
Calculations
Cardiac Output Calculation
Indicator dilution (using thermodilution or indocyanine
green dye) and the Fick method constitute the main tech-
20
niques for measurement of cardiac output in the catheteriza-
tion laboratory. If available, simultaneous echocardiography
with measurement of the left ventricular outflow tract diam-
eter and Doppler-derived stroke volume also may be used.
The indicator dilution method uses a bolus infusion of
an indicator into the circulation with measurement of its
concentration over time at some point downstream from the
injection. The area under the concentration versus the time
curve is inversely proportional to the cardiac output. This
method requires the presence of a mixing chamber between
the injection and sampling chambers. In most laboratories,
this method is performed using cold saline injected into the
right atrium and sampling in the pulmonary artery using a
thermodilution balloon-tipped catheter. Indocyanine green
dye also can be used as the indicator, with injection into the
left atrium or pulmonary artery and sampling in the aorta.
The Fick principle utilizes the difference in oxygen
content in the arterial and venous system to measure flow.
In the absence of an intracardiac shunt, the saturation in the
pulmonary artery and the saturation in the systemic circula-
tion can be used to determine the systemic cardiac output.
Each gram of hemoglobin carries 1.34 mL of oxygen. Thus,
the oxygen content is the saturation · hemoglobin · 1.34. The
calculation of cardiac output by Fick also requires that either
direct measurement of the oxygen consumption or an
assumed number for oxygen consumption (derived from body
mass and heart rate) be obtained. The formula for cardiac
output by Fick is as follows:
Cardiac output (L/min)
Oxygen consumption (mL/min)
=
(A − VO2 ) ⋅ 1.34 mL/g ⋅ Hgb(g/dL) ⋅ 10(dL/L)
where A − V O2 is the difference in oxygen saturation between
the arterial and venous circulation.
There are advantages and disadvantages for each of the
different methods used. Cardiac output using the indicator
dilution method is inaccurate in the presence of low or high
heart rates, significant valvular regurgitation, and irregular
rhythms. The Fick method overcomes these limitations, but
its accuracy requires a steady state and thus it cannot be used
for measurement of acute changes (e.g., during pharmaco-
logic interventions). Furthermore, the Fick method requires
simultaneous measurement of oxygen consumption or its
assumption with one of several methods. Even under ideal
conditions, variability in cardiac output may approach 20%
when using thermodilution and 10% to 15% when using the
Fick method. If possible, both methods should be performed
in an individual study to identify outlier results.
Valve Area Determination
The severity of a stenotic valve lesion is measured directly
by the gradient across the valve. However, the gradient is
proportional not only to the severity of stenosis but also to
the flow across the valve. It is for this reason that a calculated
“valve area” is required for further assessment of severity.
The formula for calculation of stenotic valve areas was origi-
nally derived by Gorlin and Gorlin1 in 1951. This equation
is based on two fundamental hydraulic principles: (1) Torri-
celli’s law, which states that the area of an orifice is inversely
proportional to velocity of flow for a given amount of total
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y
flow across that orifice; and (2) the pressure gradient across
the orifice is directly proportional to the velocity of flow. The
Gorlin equation is as follows:
Flow (mL/sec )
(
Valve area cm2 = ) 44.3 ⋅ C ⋅ ΔP
where ΔP is the mean transvalvular pressure gradient (mm Hg)
and C is an empirical constant that encompasses two coef-
ficients: a coefficient of orifice contraction, which corrects
for the area of a jet through an orifice being smaller than the
true area of the orifice, and a coefficient of velocity, which
accounts for the energy loss as pressure energy is converted
to kinetic (or velocity) energy. For mitral valve area calcula-
tions, C was derived to be 0.85.2 For all other valve area cal-
culations, C is assumed to be 1.0. Flow refers to absolute
forward flow across the valve expressed in millimeters per
second and is derived from the cardiac output and the dura-
tion of forward flow, which is the diastolic filling period for
the mitral valve and the systolic ejection period for the aortic
valve (Fig. 20.1). In general, the total error in valve area cal-
FIGURE 20.1. Calculation of transvalvular flow and gradient. This
patient had both aortic and mitral stenosis. The forward flow rate is
derived from systolic ejection period (SEP) for calculation of aortic
stenosis and the diastolic filling period (DFP) for calculation of
mitral stenosis. The diastolic filling period encompasses the entire
duration of mitral valve opening, including periods of diastasis.
Shaded areas indicate areas for mean gradient across the aortic valve
(A) and mitral valve (B). Ao, aortic pressure; C, Gorlin constant; CO,
cardiac output; DFP, diastolic filling period; LA, left atrial pressure;
LV, left ventricular pressure; SEP, systolic ejection period.
465
culation using the Gorlin equation is 0.2 cm2. However, this
error increases significantly in patients with bradycardia or
tachycardia. Furthermore, the Gorlin equation is inaccurate
for patients with significant coexistent regurgitation because
the regurgitant flow is not factored into the measurement of
flow.
A simplified version of the Gorlin equation has been
derived.3 In the derivation of this formula, Hakki and cowork-
ers observed that the product of heart rate, forward flow, and
the Gorlin constants approximated 1 for most calculations.
The Hakki equation is as follows:
Cardiac output (L/min )
(
Valve area cm2 = ) ΔP
As in the Gorlin equation, the mean pressure gradient is used
for calculation of the valve area using the Hakki equation.
Because the proportions of diastolic and systolic flow vary
with heart rate, the major limitation of the Hakki equation
occurs in patients with bradycardia or tachycardia. Errors
also occur in patients with coexistent regurgitation.
Techniques
Right and Left Heart Catheterization
Right and left heart catheterization is the mainstay of the
hemodynamic assessment of the patient with valvular heart
disease. Although each patient requires an individualized
approach, there is a standard methodology that comprises
the basis for these procedures. Proper performance of the
right heart catheterization involves screening oximetry
for detection of intracardiac shunts, saturation confirmation
of pulmonary capillary wedge readings, cardiac output
determination, and calculation of the pulmonary arteriolar
resistance. For measurement of absolute pressures, a large
bore, single end-hole balloon wedge catheter is preferred for
the right heart catheterization. For patients who require
measurements of acute changes in pressure and simultane-
ous assessment of cardiac output, the multiport balloon-
tipped catheter with thermodilution capability may be used.
The left heart catheterization should include measurement
of ascending aortic pressure, left ventricular pressure, and
arterial saturation. These pressures may be obtained with a
pigtail or multipurpose catheter. If intraventricular pressure
gradients are suspected, an end-hole catheter should be used.
The Judkins coronary catheter should not be utilized for
obtaining left heart pressures.
A standard approach to left and right heart catheteriza-
tion begins with obtaining arterial and venous access. In
most situations, the femoral sites can be utilized. However,
in the presence of severe tricuspid regurgitation with large
right-sided chambers, the internal jugular approach enhances
the performance of the right heart catheterization. Also, the
internal jugular approach should be used when an endomyo-
cardial biopsy is required. Once vascular access has been
obtained, the right heart catheter is used to acquire oxygen
saturations in the inferior and superior vena cavae for calcu-
lation of mixed venous oxygen content and to screen for
intracardiac shunts. The right atrial pressure is measured
with the catheter in the midportion of the right atrium and
466 chapter 20

turned to its lateral wall to avoid prolapse across the tricus-

pid valve. Ascending aortic pressure is then measured by
placement of the left heart catheter, followed by advance-
ment of the catheter into the left ventricle to measure simul-
taneous left ventricular and right atrial pressures. The right
heart catheter is then advanced into the right ventricle to
measure simultaneous right ventricular and left ventricular
pressures. Finally, the right heart catheter is placed into the
pulmonary artery. This sequence of catheter placement and
advancement allows prospective examination of the relation
between the pressures of the left ventricle and right-sided
chambers, which may be particularly helpful in patients who
may have concomitant pericardial disease, restrictive cardio-
myopathy, or other diastolic dysfunction. With the catheter
in the pulmonary artery, simultaneous saturations from the
pulmonary artery and left ventricle are obtained for calcula-
tion of cardiac output by the Fick method. Finally, the pul-
monary artery wedge pressure is obtained with confirmation
of the oxygen saturation. Pulmonary arteriolar resistance
should then be calculated from these measurements.
In the presence of elevated pulmonary arteriolar resis-
tance, prognostic information may be obtained using phar-
macologic interventions. Several agents have been used for
this purpose. In general, selective pulmonary arteriolar
dilators (e.g., prostacyclin) are useful in determining the
response of the patient with pulmonary hypertension to
vasodilator therapy. These selective vasodilators should not
be used in patients with elevation of left atrial pressure
because of the potential for pulmonary edema. In these
instances, agents with capability for dilating both the pul-
monary and systemic vascular beds (e.g., nitroprusside)
should be utilized. The response of the pulmonary arteriolar
resistance to pharmacologic interventions is useful for pre-
dicting chronic response to vasodilator therapy, reduction of FIGURE 20.2. Landmarks for transseptal puncture. (Top left) The
pulmonary pressure with left-sided interventions, and candi- target puncture site is located at the intersection of these two lines
(A and B) on frontal fluoroscopy as described in the text. (Top right)
dacy for cardiac transplantation. In general, the target site is located two thirds of the distance (C)
between the aortic valve and posterior border of the left atrium.
(Middle left and right) Advancement of the assembly into the left
Transseptal Puncture atrium. (Bottom left and right) Rotation of the Mullins sheath coun-
terclockwise results in its placement into the left ventricle.
The main indications for transseptal puncture are direct
measurement of left atrial pressure, assessment of the left
ventricle to avoid catheter entrapment from a transaortic
approach, access to the left ventricle with an aortic valve
prosthesis, and performance of percutaneous mitral balloon tion of a horizontal line (M-line) from the tricuspid annulus
valvotomy. The ideal puncture site is the fossa ovalis. The to the lateral border of the right atrium and a vertical line
location of the puncture should be assessed by either biplane that divides the left atrium into anterior and posterior halves
fluoroscopy or echocardiography to avoid injury to adjacent (Fig. 20.2). On lateral fluoroscopy, the puncture site is located
structures (aorta, coronary sinus, tricuspid valve) (Fig. 20.2).4 two thirds of the distance from the aortic valve to the pos-
If fluoroscopy is used, a catheter in the ascending aorta terior border of the left atrium. Of note, in patients with
should be placed to ensure that the puncture is posterior to vertical hearts, the ideal puncture site may be superior to the
the aortic root. Both a Mullins sheath as well as a preformed horizontal M line. In patients with an enlarged left atrium,
Brockenbrough needle are tools that aid in proper perfor- the medial left atrial border may protrude beyond the right
mance of this technique. atrial free wall, thus precluding the use of the M line for
After venous access is obtained, a 0.032-inch straight landmarks. The atrial septum may lie in a more horizontal
wire via the right femoral vein is used to place an 8-French plane in patients with a large left atrium.
(F) Mullins sheath and dilator in the superior vena cava. The With the transseptal needle fixed inside the dilator, the
Brockenbrough needle is inserted into the dilator with the assembly is rotated posteromedially (around 4 o’clock on the
tip just within the end of dilator. The location of the aortic direction indicator) and moved inferiorly from the superior
valve is marked with an arterial diagnostic catheter, and vena cava to the atrial septum. The assembly will move
biplane fluoroscopy is used to guide the approach. On frontal rightward (toward the patient’s left) as it passes into the right
plane fluoroscopy, the puncture site is located at the intersec- atrium and as it moves over the superior limbus of the fossa
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y
ovalis. Slight flexion of the catheter tip with gentle advance-
ment of the catheter assembly will occur against the limbus
when it is located in the fossa ovalis. Advancement of the
assembly across the atrial septum is accomplished with
gentle pressure and slight protrusion of the Brockenbrough
needle beyond the introducer tip. The location of the assem-
bly in the left atrium is confirmed with pressure transduc-
tion, oximetry, or contrast injection. Anticoagulation with
heparin is administered once access into the left atrium has
been obtained. Following advancement of the sheath into the
left atrium, the introducer and needle are removed with
counterclockwise rotation of the sheath, resulting in an ante-
rior direction and facilitating access into the left ventricle.
The sheath is vigorously aspirated and then flushed with
heparinized saline. Injury of adjacent structures and cardiac
perforation with tamponade are the main complications
of transseptal puncture; these occur in less than 3% of
patients.5,6
Direct Apical Left Ventricular Puncture
(Brock Procedure)
The Brock procedure is reserved for patients who require
direct measurement of left ventricular pressure, such as
those who have both mitral and aortic mechanical valve
prostheses that prohibit transvalvular access. The puncture
site is at the left ventricular apex, which is located by fluo-
roscopy or echocardiography. Following location of the site
and scrubbing and draping it, local anesthesia is used to
infiltrate the region at a location superior to a rib. An 18- or
21-gauge needle with a multihole sheath and inner stylet is
advanced over the superior rib border and parallel to the long
axis of the left ventricle. Premature ventricular beats fol-
lowed by pulsatile flow after removal of the stylet indicate
access into the left ventricle. The sheath itself can then be
used to measure pressures. Complications of apical puncture
include tamponade or pneumothorax in 3%, pleuritic chest
discomfort in 10%, vagal-mediated hypotension in 5%, and
lower incidences (<1%) of hemothorax, ventricular fibrilla-
tion, and coronary artery laceration.7,8
Aortic Stenosis
Overview
Due to the aging population, senile degenerative aortic ste-
nosis has emerged as a common etiology of patients present-
ing with symptomatic severe valve disease requiring
intervention. The classic presentation of the triad of dyspnea,
angina, and syncope in conjunction with a harsh, late-
peaking murmur on auscultation provides the clinician with
the suspicion of critical aortic stenosis. Two-dimensional
echocardiography can identify the calcified stenotic aortic
valve, and Doppler echocardiography reliably estimates the
severity of aortic stenosis in the majority of patients.
When the noninvasive assessment demonstrates a high
mean aortic valve gradient (>50 mm Hg) that correlates with
the physical examination, no further hemodynamic assess-
ment is needed, as severe aortic stenosis is unequivocally
present. However, errors may occur in the noninvasive
4 67
assessment of the severity of the stenosis, mainly from poor
alignment of the Doppler signal with the aortic jet, which
results in underestimation of the gradient. When there is a
discrepancy between the clinical and echocardiographic
findings in these patients with aortic stenosis, invasive aortic
valve assessment is indicated.
Gradient Determination
The assessment of the severity of aortic stenosis requires
accurate measurement of the left ventricular and ascending
aortic pressures and of cardiac output. The left ventricular
and ascending aortic pressures should be measured simulta-
neously, either via two arterial accesses or a single arterial
access and a transseptal puncture for left ventricular pres-
sure. The mean aortic gradient should be measured from
these two simultaneous pressures, using the average of three
consecutive beats. In the presence of irregular rhythms, at
least eight to 10 sequential beats should be measured. The
mean aortic valve gradient alone can be used to help define
the severity of aortic valvular stenosis in patients with a
normal cardiac output in the absence of significant aortic
regurgitation (mild, <25 mm Hg; moderate, 25 to 49 mm Hg;
severe, ≥50 mm Hg).
The pullback of a single catheter from the left ventricle
to the aorta may sometimes be performed to determine the
peak-to-peak systolic gradient. However, this method is
subject to error because variation in the beat-to-beat pressure
can occur due to respiration changes and variations in the
R-R interval. Importantly, the peak-to-peak gradient is not
physiologic because it is derived from nonsimultaneous
recordings (Fig. 20.3). The peak-to-peak gradient may approx-
imate the true mean aortic valve gradient in some circum-
stances, particularly at high-pressure gradients (>50 mm Hg).
However, the peak-to-peak gradient does not accurately
reflect lower aortic valve gradients, and may be erroneous in
patients with low cardiac output or irregular arrhythmia.
In some laboratories, the femoral artery pressure obtained
from the sidearm of the sheath is substituted for the ascend-
ing aortic pressure. Errors in aortic valve assessment with
this method occur because of the time delay for the pressure
wave to travel from the ascending aorta to the periphery, and
because of the overshoot phenomenon that is characteristic
of peripheral artery pressures (Fig. 20.4). Pressure overshoot
is due to amplification of the pressure wavefront as it travels
from a large channel (i.e., aorta) to smaller conduits without
a proportional decrease in flow, and is especially prominent
in elderly patients with poorly compliant arteries. While
various methods have been proposed to adjust for the poten-
tial errors from the use of femoral artery pressure, they are
prone to inaccuracy and cannot be applied to an individual
patient.9 Although the femoral artery pressure should not
be used for determination of an aortic valve gradient, this
femoral artery pressure may be examined for the Carabello
sign, in which peripheral pressure increases during catheter
pullback from the left ventricle to the aorta.10 This phenom-
enon is believed to be due to partial obstruction of the aortic
valve orifice by the catheter, which resolves during its pull-
back into the aorta. A significant rise in femoral artery pres-
sure (>10 mm Hg) following catheter pullback has been
associated specifically with aortic valve areas of <0.6 cm2.
468 chapter 20

200 200
Overshoot

150 150
LV
Ao
FA
100 100
Delay

50 PA 50

LA LA
0 0
FIGURE 20.4. Central aortic and peripheral arterial pressure trac-
ings from one patient with aortic stenosis. (Left) Simultaneous left
ventricular (LV), left atrial (LA), pulmonary artery (PA), and femoral
artery (FA) recordings. There is a temporal delay in the femoral
artery tracing because of the transmission of pressure from the
central aorta to the periphery. This delay can lead to under- or over-
estimation of the gradient and erroneous calculation of the aortic
valve area. Also, due to the femoral artery overshoot, there does not
appear to be a “peak-to-peak” gradient. (Right) Simultaneous left
ventricular (LV), ascending aortic (Ao), and left atrial (LA) recordings
from the same patient. Note the presence of the aortic valve gradient
that was not evident on the tracings on the left-hand side.

Aortic Valve Area

FIGURE 20.3. Aortic valve gradients. Maximum instantaneous
gradient is the maximum pressure difference at any time between
the left ventricle and aorta. “Peak-to-peak” is a nonsimultaneous
measure of the aortic and left ventricular pressure difference. Shaded
area is the area of planimetry for calculation of mean valvular gradi-
ent. Ao, aortic pressure; LA, left atrial pressure; LV, left ventricular
pressure.
Single arterial access has been used for measurement of
the aortic valve gradient. One method utilizes an 8F double-
lumen pigtail catheter that is advanced retrograde into the
left ventricle.11 This catheter contains a side hole located
10 cm proximal to the distal end hole, enabling simultaneous
measurement of the left ventricle and aortic pressures. Care
must be taken to ensure location of the proximal side hole
above the aortic valve during pressure measurement.
Damping of the pressure may occur due to the small lumen
of the catheter, resulting in erroneous gradient determina-
tions. Another technique utilizes a 0.014-inch pressure wire
(RADI Medical Systems, Uppsala, Sweden) that has a high-
fidelity, wire-mounted pressure sensor in its distal end.12 The
calibrated pressure wire is placed into the left ventricle
through a retrograde diagnostic catheter. The catheter is
then withdrawn into the ascending aorta with the pressure
wire remaining in the ventricle for simultaneous aortic and
ventricular pressure measurements. While this method has
been examined in a small series of patients,13 validation
of the pressure wire technique against other standard
methods of aortic valve gradient assessment has not yet been
performed.
The gradient across the aortic valve is dependent not only on
the severity of obstruction but also on the flow through the
valve. Thus, calculation of the aortic valve area provides
incremental information to the mean gradient. Based on the
Gorlin equation, the aortic valve area is calculated from the
following formula:
CO ÷ [SEP ⋅ Heart rate ]
Valve area cm2 = ( ) 44.3 ⋅ ΔP
where CO is the cardiac output in mL/min, SEP is the sys-
tolic ejection period in seconds per beat, and heart rate is in
beats per minute. The systolic ejection period is the time
duration from the aortic valve opening to the dicrotic notch
(Fig. 20.1). Normal aortic valve areas range from 3.0 to 4.0 cm2.
In general, severe aortic stenosis is less than 1.0 cm2 (Table
20.1). In patients with a large or small body size, the valve
area may be normalized to body surface area (m2). In these
circumstances, severe aortic stenosis is commonly defined
as an indexed valve area of less than 0.5 cm2/m2.
The Hakki equation can be used to calculate aortic valve
area in the absence of significant bradycardia, tachycardia,
or a low output state. This method uses the mean gradient
across the aortic valve, and is usually within 10% of the valve
area calculated from the Gorlin equation.3 In both equations,
TABLE 20.1. Severity of aortic stenosis
Mild Moderate Severe
Valve area >1.5 cm2
1.0 to 1.5 cm 2
<1.0 cm2
Mean gradient <30 mm Hg 30 to 50 mm Hg >50 mm Hg
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y
concomitant aortic regurgitation causes an overestimation
of the true valve area.
Aortic Valve Resistance
Valvular resistance has been proposed as an adjunct measure
for determining the clinical severity of aortic stenosis.14,15
Laminar, nonviscous flow through a planar orifice is a limit-
ing assumption of the Gorlin equation, which theoretically
can be overcome by calculation of valvular resistance. The
formula for aortic valve resistance is as follows:
Mean gradient (mmHg ) ⋅ 1.33
( )
Resistance dynes ⋅ sec ⋅ cm−5 =
Systolic forward flow (mL/sec)
In patients with normal systolic function, a valve resistance
of >250 dynes · sec · cm−5 has been associated with clinically
significant aortic valvular stenosis, whereas a value of <200
dynes · sec · cm−5 likely indicates minimal obstruction.
However, the calculation of aortic valve resistance has not
been shown to provide incremental information to the mean
gradient and valve area.16
Caveats
Low-Output, Low-Gradient Stenosis
There is a subset of patients who present with left ventricular
systolic dysfunction and a low-output, low-gradient state.
The valve area will calculate to be in the range of severe
aortic stenosis. Some of these patients have severe aortic
stenosis and secondary left ventricular dysfunction due to
the long-standing severe pressure overload on the left ven-
tricle. However, other patients have a primary depression in
left ventricular systolic dysfunction and concomitant mild
aortic stenosis. These patients with only mild aortic stenosis
have an overestimation of the severity of stenosis due to the
flow dependency of the Gorlin equation in conjunction with
inadequate opening of the aortic valve from decreased ino-
tropic forces. It is essential to determine the true severity of
the aortic stenosis, as only patients with severe aortic steno-
sis will benefit from surgical intervention.
Dobutamine challenge has been used to differentiate
the two pathophysiologic processes in these patients with
low-output, low-gradient aortic stenosis.17 Dobutamine (5 to
40 μg/kg/min) is infused to normalize the cardiac output
during hemodynamic measurements of aortic valve gradient.
Figure 20.5 illustrates representative hemodynamic tracings
from three patients with low-output, low-gradient aortic ste-
nosis who underwent dobutamine infusion. If the cardiac
output normalizes and the valve gradient exceeds 40 mm Hg,
severe aortic stenosis is present. Alternatively, in those
patients with normalization of cardiac output and no increase
in mean gradient (less than 30 mm Hg), only mild aortic ste-
nosis is present. Finally, there is a subset of patients who are
not able to increase the cardiac output with dobutamine
infusion due to the lack of contractile reserve. This lack of
contractile reserve portends a very poor prognosis irrespec-
tive of therapy. In one study, all patients with a final valve
area of <1.2 cm2 and a mean gradient >30 mm Hg at peak
dobutamine infusion were found to have surgically con-
firmed, severe calcific aortic stenosis.17 Furthermore, patients
469
who had contractile reserve (>20% increase in stroke volume
with dobutamine) had a lower perioperative mortality and a
lower incidence of progressive heart failure and late mortal-
ity following aortic valve operation.
An alternative method of evaluating the patient with
low-output, low-gradient aortic stenosis utilizes nitroprus-
side to augment forward output, which leads to higher cal-
culated valve areas in patients without severe aortic stenosis.18
This may be potentially useful in patients with systemic
hypertension or resting tachycardia, in whom intravenous
dobutamine may be contraindicated.
Levels of Outflow Obstruction
Not all patients with left ventricular outflow tract obstruc-
tion have valvular aortic stenosis. The level of obstruction
may be subvalvular, valvular, or even supravalvular. Sub-
valvular obstruction may be fixed (discrete subaortic steno-
sis, abnormally high profile mitral prosthesis) or dynamic
(hypertrophic cardiomyopathy). Although the level of
obstruction should be diagnosed at echocardiography, these
other types of obstruction may be missed when there are
suboptimal echocardiographic images or limited Doppler
interrogation.
Other types of outflow tract obstruction should be sus-
pected whenever there is a high outflow tract gradient
without a heavily calcified aortic valve on fluoroscopy. In
the catheterization laboratory, the diagnosis of subvalvular
obstruction is made by a pullback of the catheter from the
left ventricular apex to the left ventricular base to the aorta,
preferably with the use of a single end-hole catheter. In
patients with subvalvular obstruction, a systolic gradient is
present without a change in diastolic pressure when moving
the catheter from the left ventricular apex to the left ven-
tricular base. This finding may be missed if the pullback is
performed too quickly or when a pigtail catheter with mul-
tiple side holes is utilized.
Attention to the aortic pressure contour may provide a
further clue to the presence of other types of outflow tract
obstruction. The aortic pressure contour of aortic stenosis is
distinctly different from that seen with the dynamic outflow
tract obstruction of hypertrophic cardiomyopathy (Fig. 20.6).
In patients with significant valvular aortic stenosis, the rise
in aortic pressure is delayed with a late systolic peak, in
contrast to the spike-and-dome configuration of obstructive
hypertrophic cardiomyopathy. A fall or failure to augment
the pulse pressure on a beat following a premature ventricu-
lar contraction (Brockenbrough response) is diagnostic of
dynamic outflow tract obstruction (Fig. 20.7).
Mitral Stenosis
Overview
The primary etiology of mitral stenosis is rheumatic heart
disease. As the incidence of rheumatic disease has decreased
in industrialized countries, mitral stenosis has become less
common. Nonetheless, mitral stenosis is still prevalent in
parts of the United States, particularly in areas with immi-
grant populations.
47 0 chapter 20

A B
Base Dobutamine
Base Dobutamine

AVA Mean LV
Mean
0.8 cm2 24 mm Hg AVA Mean 20 mm Hg
0.8 cm2 47 mm Hg
AVA Mean AVA
0.6 cm2 17 mm Hg 0.7 cm2
100
Ao 100

100 100
Ao Ao
Ao
LV LV
LA

LA
LA LA

0 0 0 0

C
Base Dobutamine
AVA Mean AVA Mean
0.9 cm2 37 mm Hg 0.7 cm2 26 mm Hg
LV LV
100 100
Ao
FIGURE 20.5. Representative hemodynamic findings from three
Ao LA patients demonstrating three different responses to dobutamine. (A)
LA There was an increase in both cardiac output and gradient in
response to dobutamine. The valve area remained 0.8 cm2. The
patient had severe aortic stenosis at operation and was in New York
Heart Association (NYHA) class I following surgery. (B) There was
an increase in cardiac output but only a mild change in the gradient.
This represents mild aortic stenosis. (C) There was no change in
cardiac output, a decrease in the valve gradient, and hypotension
0 0 occurred during the study. Severe aortic stenosis was found at opera-
tion, but the patient died of heart failure 2 years later.

In contrast to aortic stenosis, the hemodynamic assess- Transmitral Gradient

ment of mitral stenosis can be accurately and reliably assessed
with Doppler echocardiography, since the Doppler beam can
be directed parallel to the stenotic jet in nearly all patients.19
The transmitral gradient obtained by Doppler echocardiog-
raphy should be considered a “gold standard” in the evalua-
tion of these patients. Cardiac catheterization for the
hemodynamic severity of mitral stenosis is indicated only
when there is a discrepancy between a patient’s symptoms
and lesion severity by echocardiography. The additive infor-
mation from the results of the catheterization include the
measurement of absolute left ventricular, left atrial, and pul-
monary pressures as well as the response of these pressures
to exercise. The severity of concomitant mitral regurgitation
also may need to be determined by cardiac catheterization.
Proper assessment of the severity of mitral valve stenosis at
catheterization requires simultaneous left ventricular and
left atrial pressure recordings to obtain the mean transmitral
gradient. The pulmonary capillary wedge pressure from a
right heart catheterization has been used for an indirect mea-
surement of the left atrial pressure. The mean pulmonary
capillary wedge pressure accurately reflects mean left atrial
pressure in the absence of pulmonary veno-occlusive disease
or cor triatriatum. However, there is a significant overestima-
tion of the transmitral gradient (>50% in some cases) when
using the pulmonary capillary wedge pressure and left ven-
tricular pressure (Fig. 20.8). This overestimation may occur
in part because of the time delay (usually 50 to 70 ms) for the
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y 471

200 200

150 150

100 100

50 50

0 (200) 0
LV Subaortic Aortic
A
FIGURE 20.6. Left ventricular outflow tract obstruction. (A)
Single-catheter pullback from the left ventricle (LV), across the left
ventricular outflow tract (LVOT), and into the ascending aorta (Ao)
in a patient with subaortic stenosis. (B) Similar pullback in a
LV Aortic
patient with aortic valvular stenosis. B

LV

150 mm Hg Ao 150 mm Hg

Ao

LA

RA
0 mm Hg 0 mm Hg

FIGURE 20.7. Pressure tracings after a premature ventricular beat the premature ventricular beat in the patient with hypertrophic
in a patient with a fixed obstruction due to aortic stenosis (left) and cardiomyopathy (i.e., Brockenbrough response) that does not occur
dynamic outflow tract obstruction due to hypertrophic cardiomy- in the patient with aortic stenosis.
opathy (right). Note the decrease in aortic pulse pressure following

FIGURE 20.8. Simultaneous Doppler echocardiography and invasive

catheterization measurement of the transmitral gradient in a patient
with mitral stenosis. (Left) There is excellent correlation of the trans-
mitral gradient by Doppler echocardiography with that obtained by
direct catheterization because the Doppler transducer is easily lined
parallel to the mitral inflow. (Right) There is overestimation of the
true transmitral gradient when the pulmonary capillary wedge pres-
sure is used as a surrogate for left atrial pressure in patients with
mitral stenosis. Dopp, Doppler gradient; LA, left atrium; LV, left ven-
tricle; PCWP, pulmonary capillary wedge pressure.
47 2 chapter
A B
C D
pressure transmission from the left atrium to the pulmonary
capillaries (Fig. 20.9).19 Phase shifting to align the v-wave
peak of the wedge pressure curve to coincide with the relax-
ation phase of the left ventricular pressure tracing may be
performed to help correct for the temporal delay. However,
even with proper temporal alignment of the wedge pressure,
there is a blunting of the y descent, which results in a 20%
to 30% overestimation of the transmitral gradient. Thus if
catheterization is required for an accurate assessment of the
transmitral gradient, a transseptal approach is necessary to
obtain a direct measurement of left atrial pressure.
Mitral Valve Area and Diastolic Half-Time
As with aortic stenosis, the mean transmitral gradient is
dependent not only on the severity of the stenosis but also
on the flow through the mitral valve. Thus, a mitral valve
area should be calculated as part of the hemodynamic assess-
ment of a patient with mitral stenosis. Based on the Gorlin
equation, the mitral valve area is calculated from the follow-
ing formula:
CO ÷ [DFP ⋅ heart rate ]
( )
Mitral valve area cm2 =
44.3 ⋅ 0.85 ⋅ ΔP
where DFP is the diastolic filling period (seconds per beat).
The diastolic filling period is measured from the entire
period of mitral valve opening to closure. The normal mitral
valve has an area of 4.0 to 5.0 cm2. Exertional symptoms may
occur in patients with mitral valve areas of <2.5 cm2. Severe
mitral stenosis is usually defined as a valve area of ≤1.0 cm2,
when transmitral gradients >10 mm Hg are present with a
normal cardiac output (Table 20.2). An accurate invasive
assessment of valve area requires an accurate measurement
of transmitral gradient, which at catheterization is possible
only with direct left atrial pressure measurements.
20
FIGURE 20.9. Hemodynamic evalua-
tion of a patient with mitral stenosis. (A)
The mean pressures are obtained by the
pulmonary capillary wedge pressure
(PCWP) and left atrial recordings are the
same. However, note the significant
time delay and blunting of the y descent
in the PCWP tracing in comparison to
direct measurement of LA pressure.
These effects can lead to significant
errors in calculation of the mitral gradi-
ent and valve area. (B) Gradient between
PCWP and LV indicated by dark-shaded
area (false mitral valve gradient =
13 mm Hg). (C) Gradient between LA and
LV indicated by light-shaded area (true
mitral valve gradient = 8 mm Hg). (D)
Simultaneous recording of the LA,
PCWP, and LV pressures. Dark shade
indicates area of the false gradient; light
shade indicates area of the true
gradient.
The diastolic half-time is a semiquantitative, adjunctive
measure for assessing the severity of mitral stenosis.20 Its
principle is based on the observation that the rate of decay
in the transmitral gradient is exponentially and inversely
related to the degree of valvular obstruction.21 Diastolic half-
time is calculated as the time in which the peak transmitral
gradient declines by 50% (Fig. 20.10). Since the rate of pres-
sure gradient fall is not dependent on transmitral flow, the
diastolic half-time can be used to estimate the severity of
stenosis in patients with mitral regurgitation and irregular
arrhythmia (i.e., atrial fibrillation). The primary determi-
nants of diastolic half-time are the peak transmitral gradient
and the relative compliance between left atrium and left
ventricle. Thus, the half-time may be inaccurate when used
in patients with severe abnormalities of ventricular compli-
ance, such as restrictive or hypertrophic cardiomyopathy, or
after interventions that result in acute changes in net atrio-
ventricular compliance, such as percutaneous or surgical
valvotomy.22,23 Severe aortic regurgitation also abbreviates
the diastolic half-time. Values of diastolic half-time for
grading the severity of mitral stenosis are as follows: 100 ms,
mild; 200 ms, moderate; and 300 ms, severe.
Exercise Testing
For any given orifice area, the transmitral gradient is propor-
tional to the square of the transvalvular flow rate. Thus,
some patients who have relatively mild hemodynamic abnor-
TABLE 20.2. Severity of mitral stenosis
Mild Moderate Severe
Valve area >1.5 cm2
1.0 to 1.5 cm2
<1.0 cm2
Mean gradient <5 mm Hg 5 to 10 mm Hg >10 mm Hg
Pressure half time <100 ms 100 to 300 ms >300 ms
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y
FIGURE 20.10. Diastolic pressure half-time (PHT) measurement in
a patient with mitral stenosis.
malities at rest may experience symptoms related to their
mitral stenosis with exertion.24 For patients whose symp-
toms are out of proportion to the resting hemodynamics,
formal exercise testing with hemodynamics may be war-
ranted. Testing may be done invasively with right- and left-
heart catheterization or noninvasively with Doppler
echocardiography.25–28 The advantages of invasive catheter-
ization are the ability to directly measure the pulmonary
47 3
artery, left atrial or pulmonary capillary wedge, and left
ventricular diastolic pressures at rest and during exercise.
The optimal approach for exercise hemodynamics is to
utilize exercise that simulates physiologic stress, such as a
supine or upright bicycle. Other approaches have utilized
arm ergometry or pharmacologic stress, but these techniques
provide less relevant clinical information than exercise.
Arterial or ventricular pacing (if atrial fibrillation is present)
can be used to increase heart rate and decrease the diastolic
filling period, which is a primary determinant of the gradient
in patients with mitral stenosis.
The objective of the exercise hemodynamic study is
twofold. The first objective is to measure the transmitral
gradient at rest and exercise. A rise in transmitral gradient
to that exceeding 20 mm Hg during exercise associated with
symptoms may be considered an indication for percutaneous
or surgical relief of mitral obstruction.29 The second objective
is to examine the rise in absolute pressures and their relation
during exercise. In some patients, the left ventricular dia-
stolic pressure will rise significantly in conjunction with
only a mild increase in transmitral gradient, indicating left
ventricular diastolic dysfunction as an etiology for symp-
toms (Fig. 20.11). In other patients, there will be a rise in

FIGURE 20.11. Representative hemodynamic

tracings from two patients with mitral stenosis
illustrating two different responses to exercise.
(Top) This patient had marked exercise intolerance
but resting hemodynamics were consistent with
mild mitral stenosis. With an increase in heart
rate to 120 bpm, there was a significant increase in
the transmitral gradient (shaded area). (Bottom)
This patient also had symptoms of exercise intol-
erance. With exercise, there was a mild increase in
the transmitral gradient (shaded area). However,
there were marked increases in the left ventricular
(LV) diastolic pressure with relatively rapid filling
(arrows), as well as in the left atrial (LA), and pul-
monary artery (PA) pressure. The increases in LV,
LA, and PA pressures were proportional to the
increase in systemic hypertension, consistent
with exercise-induced diastolic dysfunction. Ao,
aortic pressure.
474 chapter
pulmonary artery pressure out of proportion to the rise in
the left atrial or pulmonary capillary wedge pressure, sup-
porting a pulmonary etiology for the symptoms.
Caveats
The valve area calculation derived by cardiac catheterization
may not be accurate in several circumstances. First, the valve
area calculation is dependent on accurate measurement of
the transmitral gradient. Thus, significant errors will occur
when the pulmonary capillary wedge pressure is used, fre-
quently leading to an overestimation of the transmitral gra-
dient and a falsely small valve area. The calculation of mitral
valve area using the Gorlin equation also is highly dependent
on accurate measurement of transvalvular flow (i.e., cardiac
output). Since patients with mitral stenosis may have atrial
fibrillation and tricuspid regurgitation, cardiac output
assessed by the thermodilution method may not be accurate
in such patients. Concomitant mitral regurgitation precludes
accurate measurement of the mitral valve area due to the
increased flow across the mitral valve. A large transmitral
gradient with a short half-time may be an indicator of severe
mitral regurgitation.
An elevation in pulmonary pressures that is out of pro-
portion to the transmitral gradient and mitral valve area
should alert the physician to the presence of concomitant
disorders such as pulmonary disease, mitral regurgitation, or
other causes of elevated left-sided diastolic pressures (Fig.
20.11). The pulmonary artery end diastolic pressure should
approximate the left atrial pressure. If the pulmonary artery
end diastolic pressure exceeds the left atrial pressure by
10 mm Hg, intrinsic pulmonary disease should be suspected.
Long-standing severe mitral stenosis may lead to pulmonary
arteriolar disease, in which the pulmonary pressure will
be elevated out of proportion to the elevation of left atrial
pressure.
Valvular Regurgitation
Overview
The workup of the patient with aortic and mitral regurgita-
tion requires an assessment of the etiology and severity of
the valve regurgitation as well as the ventricular response to
the volume overload. This is especially important in the
asymptomatic patient, as early valve operation is now being
recommended to prevent the detrimental long-term conse-
quences of the volume overload on left ventricular function.
Two-dimensional and Doppler echocardiography have
become standard for assessing the etiology of the valve lesion
and the status of the left ventricle. However, there are major
limitations to the Doppler assessment of the severity of the
regurgitation by current methods using only color flow
imaging.
In the patient with clinically severe mitral regurgitation
and definitive noninvasive evidence of severe mitral regurgi-
tation (e.g., an unsupported mitral leaflet on echocardiogra-
phy and a large eccentric jet of mitral regurgitation on color
flow imaging), no other hemodynamic information is
required. However, in the absence of any of these three find-
20
ings (clinical exam, two-dimensional echo findings compat-
ible with severe regurgitation, color flow Doppler findings of
severe regurgitation), further invasive evaluation is war-
ranted. This information obtained at cardiac catheterization
includes pressure measurements of the hemodynamic
consequences of the valve regurgitation, as well as assess-
ment of the severity of valve regurgitation by contrast
angiography.
Pressures and Pressure Contours
The severity of regurgitant valvular lesions can be assessed
indirectly by examination of pressure contours. In patients
with severe mitral regurgitation, the left atrial or pulmonary
capillary wedge pressure tracing may have a large v wave due
to a rise in left atrial pressure from systolic regurgitation
back into the left atrium (Fig. 20.12). However, the height of
the v wave is also inversely related to atrial compliance and
directly proportional to cardiac output and systemic vascular
resistance.30,31 Thus, there may be a large v wave in the
absence of severe mitral regurgitation in patients with severe
diastolic dysfunction. Severe mitral regurgitation also may
not produce a v wave if there is a compliant atrium. There-
fore, the finding of a large v wave is consistent but not diag-
nostic of severe mitral regurgitation.
The pulmonary pressure is also an indirect measurement
of mitral regurgitation. Although it may be elevated due to
a number of other reasons, an indication for intervention on
the patient with few or no symptoms and severe mitral regur-
gitation is the presence of pulmonary hypertension. Thus an
accurate measurement of the pulmonary pressure is helpful
for decision making regarding the timing of operation in
patients with mitral regurgitation.
Patients with chronic severe aortic regurgitation usually
have a widened aortic pulse pressure from augmented stroke
volume during systole and a large regurgitant volume during
diastole resulting in a rapid decline in aortic diastolic pres-
sure (Fig. 20.13). There will be a rapid rise in left ventricular
diastolic pressure, especially in patients with a decompen-
sated left ventricle. In patients with acute aortic regurgita-
tion, a widened aortic pulse pressure may not be present, but
there will be a rapid elevation of left ventricular diastolic
pressure.
In all patients with severe tricuspid regurgitation, the
right atrial pressure will be elevated. There usually is a large
v wave in the right atrial pressure tracing, which rises early
(i.e., cv wave) and, in extreme cases, may resemble the contour
of the right ventricle. When there is a high compliance of the
right atrium and adjacent vena cava, the cv wave due to tri-
cuspid regurgitation may be blunted (Fig. 20.14). Early rapid
filling in the right ventricular pressure tracing (i.e., dip-and-
plateau) occurs in severe tricuspid regurgitation due to
volume overload and a decreased effective operative compli-
ance of the right ventricle. Pericardial restraint occurs if
there is severe right ventricular enlargement, resulting in
elevation and equalization of diastolic pressures in the left
and right ventricular traces, which can simulate the hemo-
dynamic findings of restrictive cardiomyopathy and con-
strictive pericarditis (Fig. 20.15). The right atrial–right
ventricular gradient during diastole should be examined in
these patients to rule out concomitant tricuspid stenosis,
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y 475

100

LV
100

50
50 PA
LA
LA

0
0

FIGURE 20.12. Pressure recordings before and after percutaneous balloon mitral valvuloplasty, acute severe mitral regurgitation
balloon mitral valvuloplasty. (Left) At baseline, there is a mean occurs. The v wave in the left atrial tracing is markedly augmented
transmitral gradient of 8 mm Hg. (Right) Following percutaneous with a height that approaches 60 mm Hg.

particularly in patients with rheumatic disease. Patients

with tricuspid stenosis have large a waves and blunting of
the y descent on the right atrial pressure curve.

Angiographic Severity
Assessment of valvular regurgitation may be performed
with injection of contrast into the chamber or great vessel

FIGURE 20.13. Simultaneous ascending aortic and left ventricular
pressure recordings in a patient with severe aortic regurgitation.
Note the early rapid rise in left ventricular (LV) diastolic pressure
(arrows) and the concomitant fall in aortic diastolic pressure, which
approaches the LV pressure at end-diastole.
FIGURE 20.14. Right atrial pressure recordings from two patients
with severe tricuspid regurgitation. (Top) Large cv waves due to
severe tricuspid regurgitation. (Bottom) In contrast to the patient in
the top figure, this patient also had severe tricuspid regurgitation
but much less prominent v waves.
476 chapter
120
LV
80
40
RV
FIGURE 20.15. Pericardial restraint from tricuspid regurgitation
mimicking constrictive pericarditis. (Left) Right ventricular and left
ventricular pressure tracing from a patient with constrictive peri-
carditis. (Right) Right ventricular (RV) and left ventricular (LV) pres-
just distal to the regurgitant valve. Biplane angiography [60
degrees left anterior oblique (LAO), 30 to 40 degrees right
anterior oblique (RAO)] is preferred to allow two views of the
receiving chamber. Contrast volume and injection rates typi-
cally are 40 to 50 mL at 12 to 15 mL/sec for mitral or tricuspid
regurgitation, and 50 to 60 mL at 20 mL/sec for aortic regur-
gitation. It is important to use a large-bore catheter to avoid
“whip” of the catheter during the injection. In patients with
mitral and tricuspid regurgitation, a 6F or larger pigtail or
Rodriguez catheter is recommended. A 5F or larger pigtail
with a large bore is recommended for aortic root injections.
When performing left ventriculography for mitral regur-
gitation, it is important set up the RAO projection to ensure
that the left atrium and descending aorta do not overlap, as
this overlap may mask the entry of dye into the left atrium.
This setup may require increasing the RAO angle to 40 to
45 degrees. It is critical to position the catheter to avoid
ventricular ectopy during the injection. A pigtail catheter
should be placed at the base of the heart with the curve of
the pigtail away from the septum on the LAO view. Test
injections during deep inspiration are used to ensure optimal
position of the catheter without ectopy or catheter-induced
mitral regurgitation during the contrast injection.
The Sellers criterion for regurgitation severity is the stan-
dard for semiquantitation of valve regurgitation (Table 20.3).32
The degree of opacification of the receiving chamber by con-
trast is dependent not only on the severity of regurgitation
but also on the amount of contrast injected, rate of injection,
ventricular function, and size of the heart chambers. The
severity of regurgitation cannot be assessed if there is ven-
tricular ectopy produced during the injection. Although
there are many limitations to this angiographic technique,
20
120
LV
80
Ao
40
RV
sure tracing from a patient with severe tricuspid regurgitation. Note
the early dip-and-plateau with equalization of pressures between
the right ventricle and left ventricle in the diastolic phase.
this method has been used as the standard by which surgical
decisions have been made for decades, and current outcome
data for patients with valve disease is based on this method.
Similar angiographic methods are used to grade the severity
of aortic regurgitation and tricuspid regurgitation.
Regurgitant Fraction and Regurgitant Volume
Calculation of regurgitant fraction and regurgitant volume
provide a more quantitative method for determining the
severity of regurgitation. However, this is a method that can
be reliably performed only in laboratories that have expertise
in this measurement, and thus is not routinely done in con-
temporary practice. Regurgitant fraction is the proportion of
the volume of regurgitation to the total amount of blood
ejected from the left ventricle. The total amount of blood
TABLE 20.3. Severity of mitral regurgitation (Sellers criteria) 32
1+ Contrast does not completely fill left atrium
2+ Contrast completely opacifies left atrium but does not reach
the intensity of the contrast in the left ventricle
3+ Contrast completely opacifies left atrium and reaches
intensity of the contrast in the left ventricle after four heart
beats
4+ Contrast completely opacifies left atrium and reaches
intensity of contrast in the left ventricle within two or three
beats
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y
ejected (i.e., total volume) is derived from a left ventriculo-
gram by subtracting left ventricular end-systolic volume
from end-diastolic volume. Forward flow volume, the net
amount of blood moved to the systemic circulation, can be
derived from cardiac output obtained by the Fick method.
The regurgitant fraction calculation is as follows:
Forward flow volume = Cardiac output (from Fick equation)
÷ Heart rate
Regurgitant volume = Total volume − Forward flow volume
Regurgitant fraction = Regurgitant volume ÷ Total volume
In general, valvular regurgitation is graded as mild for regur-
gitation fraction <20%, moderate for 20 to 40%, moderately
severe for >40 to 60%, and severe for >60%. A regurgitant
fraction also cannot be used when both significant aortic and
mitral regurgitation are present. The major limitation of
regurgitant fraction is its reliance on ventriculography for
accurate volume assessment. Unless the laboratory has an
expertise in reliable reproducible measurement of ventricu-
lar volume, this method should not be used.
Prosthetic Valves
Overview
The implantation of a prosthetic valve is a lifesaving proce-
dure for the patient with severe valvular heart disease.
Prosthetic valves may eventually malfunction, either with
obstruction (from thrombosis or pannus formation) or regur-
gitation (periprosthetic or through a prosthesis). The nonin-
vasive assessment of prosthetic valve malfunction is more
difficult than with native valves. Thus, the catheterization
laboratory plays a major role in the hemodynamic evaluation
of the patients with suspected prosthetic valve malfunction.
However, the invasive evaluation of a patient with a pros-
thetic valve itself can be very challenging as the prosthesis
itself may prohibit access to the cardiac chambers.
The two-dimensional echocardiographic evaluation of
the patient with a suspected prosthetic malfunction is
limited by acoustic shadowing that is produced by the pros-
thesis. This shadowing decreases the ability to visualize disk
or poppet motion, and prevents assessment of prosthetic
valve regurgitation by color flow Doppler imaging. This is
particularly pertinent in patients with regurgitant mitral
prostheses, in whom imaging of color flow jets in the left
atrium is severely hampered by the acoustic shadowing of
the prosthesis.
As with native mitral valve stenosis, the Doppler trans-
mitral gradient in the patient with a mitral valve prosthesis
is reliable and accurate. The transmitral gradient by Doppler
is more accurate than that obtained by conventional cardiac
catheterization using a pulmonary capillary wedge pressure,
due to the inherent problems of the wedge pressure as previ-
ously described. However, the Doppler evaluation of an aortic
prosthetic valve may not accurately reflect the true degree of
obstruction, due to the phenomenon of pressure recovery.
This phenomenon refers to the recovery of kinetic energy of
blood into a pressure head following its acceleration through
the prosthetic orifice, which reduces the net pressure loss
47 7
across the valve.33 The high velocities within the prosthetic
valve detected by Doppler echocardiography will lead to an
overestimation of the true effective gradient. The amount of
pressure recovery that occurs is directly related to the ratio
of the effective orifice area to the aortic area at the level of
the prosthesis, as smaller ratios predispose toward the devel-
opment of flow eddies that dissipate the blood flow and result
in loss of the kinetic energy. The pressure recovery phenom-
enon is particularly prominent in patients with small bileaf-
let prosthesis (19 to 21 mm) and with small aortas (diameter
<3.0 cm).
Approach to Cardiac Catheterization
In patients with suspected prosthetic valve obstruction,
cardiac catheterization accurately determines the true
severity of obstruction, as the catheterization gradient is
not affected by pressure recovery. However, cardiac catheter-
ization in the patient with suspected prosthetic valve
malfunction can be challenging, given the obstruction to
access that may be presented by the prosthesis. Catheters
should not be placed retrograde across mechanical prosthe-
ses. Such placement causes hemodynamic alterations in
patients with ball-cage and disk prostheses from catheter-
induced regurgitation. In addition, placement of a catheter
may result in entrapment of the catheter, particularly if it is
placed in the minor orifice of the tilting disk prosthesis.
Retrograde catheterization should be avoided even with the
older tissue prostheses, due to calcific deposits on the valve
leaflets, which may become dislodged by the catheter. The
pulmonary capillary wedge pressure should not be used to
determine the transmitral gradient in patients with mitral
valve prosthesis. Thus the hemodynamic assessment of valve
prostheses may require alternative procedures, such as a
transseptal approach or a Brock procedure. It is particularly
important in this assessment to obtain simultaneous proxi-
mal and distal pressures as well as an accurate measurement
of cardiac output. Both the gradient as well as a calculated
effective orifice area should be obtained when obstruction is
suspected.
Fluoroscopy of the prosthetic valve is a useful adjunct to
the assessment of mechanical prosthetic valve dysfunction
in the cardiac catheterization laboratory. This should be
done on all patients to assess proper seating of the valve
prosthesis, and to assess disk or poppet motion. Proper fluo-
roscopic evaluation requires alignment of the x-ray beam
perpendicular to the valve ring and valve disks to permit
measurement of the opening, closing, and travel angles of
the leaflets. Normal values of these angles for each specific
valve type and size have been published (Table 20.4).34–37
Prosthetic dysfunction is usually defined as an opening angle
less than two standard deviations of the angles derived from
a normal prosthesis.
In patients with suspected prosthetic valve regurgita-
tion, contrast angiography may be necessary. Aortic root
angiography in patients with aortic prosthesis and left
ventriculography in patients with mitral prosthesis may
be a required diagnostic modality. As with native valve
regurgitation, the upstream pressures may be of additional
value in determining the hemodynamic consequence of the
regurgitation.
47 8 chapter 20

TABLE 20.4. Fluoroscopic characteristics of normal prosthetic heart valves35–37

Valve model Closing angle (degrees) Opening angle (degrees) Disk movement (degrees)

Sorin tilting disk 0 60 60

Björk-Shiley (spherical) 0 60 60
Björk-Shiley (convexo-concave 60 degrees) 0 60 60
Björk-Shiley (convexo-concave 70 degrees) 0 70 70
Björk-Shiley (Monostrut) 0 70 70
Medtronic Hall
Aortic 0 75 75
Mitral 0 70 70
Lillehei-Kaster 18 80 62
Omniscience 18 80 62
St. Jude Medical 10–13 120–124*; 130–135† 54–56.5*; 57.5–62.5†
CarboMedics 23–27 128–136 51.0–55.0
Sorin Bicarbon 20–25 136–141 56.5–60.0
Jyros 20–24 108–115 42.0–46.5
Edwards-Duromedics
Aortic 25–29 148 59.0–61.5
Mitral 32–38 148 55.0–58.0
* Valve ring 19–25 mm. † Valve ring 29–33 mm.

Balloon Mitral Valvotomy are assigned according to the morphologic characteristics of

Overview
The pathophysiologic abnormality in the patient with mitral
stenosis is obstruction to inflow due to fusion of the mitral
valve commissures. The treatment of mitral stenosis has
been either surgical valvotomy to split the commissures or
mitral valve replacement. Percutaneous balloon mitral val-
votomy was first introduced in the 1980s as an alternative
treatment for patients with isolated mitral stenosis. Because
of the significant improvements in its technique and the
equipment over the years, percutaneous balloon mitral val-
votomy presently is the procedure of choice for selected
patients with severe mitral stenosis.38
Patient Selection and Indications
The success of balloon mitral valvotomy relies on splitting
of the valve commissures without acute disruption of the
valve leaflets on the remaining supporting apparatus. Thus,
assessment of the valve morphology is crucial in the proper
selection of patients for this technique. Several methods for
examining the morphology of the mitral valve have been
proposed.39–41 The primary goal of these methods is to deter-
mine the mechanism of commissural fusion and the pliabil-
ity of the mitral valve, both of which directly correlate with
procedural success rate, acute complication rates, and long-
term outcome. It is also important to assess the subvalvular
apparatus, as retraction, shortening, and fusion of the chordae
and papillary muscles will preclude an adequate result from
balloon dilatation.
The Abascal score is a well-accepted semiquantitative
system that assesses the suitability of the valve morphology
for this procedure.40 In this scoring system, one to four points
the mitral valve and summated (Table 20.5). A score of ≤8 is
indicative of a pliable, noncalcified valve without significant
subvalvular fusion and has been shown to be predictive of
procedural success and long-term event free survival.39–41
In addition to the Abascal score, it is necessary to also
determine the presence or absence of calcification in the com-
missures, since it is the splitting of these commissures that
is the dominant mechanism by which balloon valvotomy
leads to relief of mitral stenosis. Calcification of the commis-
sures may result in tearing of the valve leaflets during balloon
TABLE 20.5. Abascal scoring system 39,40
Leaflet mobility
1 Highly mobile valve with restriction of only leaflet tips
2 Reduced mobility of the midportion and base of leaflets
3 Valve leaflets move forward in diastole mainly at the base
4 No or minimal forward movement of the leaflets in diastole
Valvular thickening
1 Near normal (4–5 mm)
2 Mid-leaflet thickening with marked thickening of the margins
3 Thickening extends through entire leaflets (5–8 mm)
4 Marked thickening of all leaflet tissue (>8–10 mm)
Subvalvular thickening
1 Minimal thickening of chordal structures below the valve
2 Chordae thickening extending less than one third of chordal
length
3 Thickening extending to the distal third of chordae
4 Extensive thickening, chordae shortening extending to papillary
muscle
Valvular calcification
1 Single area of increased echo brightness
2 Scattered areas of brightness confined to leaflet margins
3 Brightness extending into midportion of leaflets
4 Extensive brightness through most of the leaflet tissue
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y
inflation due to the differential stress effects of the inflated
balloon. The presence of commissural calcification is more
predictive of adverse events than the Abascal score.41 The 3-
year survival free of death, mitral valve replacement, or repeat
percutaneous mitral balloon valvotomy is 86% ± 4% among
patients without commissural calcium versus 40% ± 11% for
those with such calcium (p < .001) (Fig. 20.16). While the
Abascal score also is predictive of final mitral valve area and
long-term outcomes, patients with high Abascal scores may
still have a successful balloon valvotomy if there is no heavy
calcification of the valve commissures.
Candidates for balloon mitral valvotomy are those
patients with symptoms due to moderate or severe mitral
stenosis (mitral valve area <1.5 cm2) and a pliable valve that
is considered suitable for the procedure. Asymptomatic
patients with moderate or severe mitral stenosis also may be
considered is there is favorable valve morphology, especially
if there is pulmonary hypertension or new onset of atrial
fibrillation. In pregnant patients, balloon mitral valvotomy
has been used successfully to treat increasing symptoms of
heart failure.42
In patients with heavily calcified immobile mitral valve
leaflets with significant subvalvular fusion, percutaneous
mitral balloon valvotomy is associated with higher compli-
cation rates (mainly due to severe mitral regurgitation) and
lower acute success rates. There is a poorer long-term outcome
due to a high restenosis rate. In these patients the increased
risk of this procedure must be weighed against the risks of
a mitral valve replacement.
Ineligible patients are those with moderate or severe
mitral regurgitation because of the potential for worsening
of regurgitation that may occur with valvuloplasty. Patients
should all have a transesophageal echocardiogram prior to
procedure to rule out a left atrial thrombus. If a left atrial
thrombus is present, patients may be reconsidered for mitral
balloon valvotomy following anticoagulation with warfarin
and resolution of the thrombus. However, a persistent throm-
bus is a contraindication to percutaneous mitral balloon
valvotomy.
100 Abascal score ≤ 8
Probability of survival (%)
80
Abascal score > 8
60
40
20
0 0
0 1 2 3
Years from procedure
No. at risk
46 33 22 59 45 31
28 22 15 14 10 6
FIGURE 20.16. Survival according to the presence of commissural
calcium in patients undergoing balloon mitral valvuloplasty.
47 9
Technique
The most common technique for balloon mitral valvotomy
employs a transvenous, antegrade approach with a single
Inoue balloon system. Retrograde, transarterial approaches
have been utilized to obviate the need for a transseptal punc-
ture, but this technique is technically challenging with
higher complication rates.43 A double-balloon technique was
initially used in which two balloons are inflated across the
mitral valve. However, as compared to the Inoue balloon, the
double-balloon technique is associated with higher compli-
cation rates of clinically significant atrial septal defects and
left ventricular perforation, due to the movement of the bal-
loons during inflation.
The majority of centers now use the specially designed
Inoue balloon. This hourglass-shaped balloon is made so that
increasing inflation pressures will first inflate the distal end
of the balloon in the left ventricle, followed by the proximal
end of the balloon in the left atrium to ensure centering and
fixation of the balloon across the mitral valve. Full inflation
of the balloon inflates the center of the balloon, which dilates
the mitral valve. Comparable reduction in the mitral valve
gradient occurs with either the double- or single-balloon
(Inoue) method.44–47 A major advantage of the single-balloon
Inoue system over the double-balloon method is the ability
to gradually up-size the balloon, less fluoroscopy time during
positioning of the balloon, and the self-centering nature of
the Inoue balloon.48,49
The technique of performing a successful procedure
requires a transseptal puncture directly through the fossa
ovalis. Transseptal punctures superior or inferior to the fossa
ovalis may result in difficulty crossing the mitral valve with
the balloon catheter. Once the transseptal puncture is per-
formed, anticoagulation with heparin, and baseline assess-
ments of the mitral valve area, gradient, cardiac output,
pulmonary blood pressure, and severity of mitral regurgita-
tion are performed. Selection of Inoue balloon size is deter-
mined by the patient’s height according to the following
formula:
Balloon size (mm) = [height (cm) ÷ 10] + 10
Each Inoue balloon catheter is prepared and examined for
accuracy of inflation size prior to insertion. A heavy-duty
100 Calcification absent spring coil guidewire is placed through the transseptal sheath
into the left atrium. The transseptal sheath is exchanged
80 for a 14F long dilator, which is used to dilate the interatrial
septum. The Inoue balloon is elongated, passed over the
guidewire into the left atrium, and then shortened. The
60
spring coil guidewire is exchanged for a J-tipped stylet, which
40 Calcification present is used to guide the balloon through the mitral orifice with
care to avoid entanglement of the device and the subvalvular
apparatus.
20
Following removal of the stylet, the distal part of the
balloon is inflated in the left ventricle and pulled back to
appose the mitral valve. Sequential inflation of the proximal
0 1 2 3
compartment and midsection of the balloon follows, facili-
Years from procedure tating commissural splitting. During the procedure, repeat
assessment of the transmitral gradient, severity of mitral
regurgitation, and pulmonary pressures with echocardiogra-
phy or invasive monitoring is performed. Repeated or subse-
quent dilatation with larger inflation sizes with the Inoue
480 chapter 20

Before PMBV After PMBV
DOPP 10 mm Hg –20 mm Hg
20 mm Hg DOPP 4 mm Hg
Mean 11 mm Hg Mean 4 mm Hg
0 mm Hg –0 mm Hg
FIGURE 20.17. Acute hemodynamic effects of percutaneous mitral
balloon valvotomy (PMBV). Dopp, Mitral gradient by Doppler
echocardiography.
balloon can be performed in a stepwise fashion in 1- to 2-mm
increments until the desired mitral valve area is achieved.
After successful dilatation, the balloon is elongated in the
left atrium to prevent an atrial septal defect during with-
drawal of the balloon back into the right atrium. Following
removal of the balloon catheter, an oxygen saturation run is
performed to exclude significant left-to-right shunting, and
residual mitral regurgitation is assessed by either echocar-
diography or left ventriculography.
Outcome
Valve morphology is the predominant determinant of
outcome and complications after balloon valvotomy. Other
factors that are associated with the success rate include age,
functional class, ventricular diastolic pressure, severity of
stenosis, and cardiac output.50 In general, there is a doubling
of the mitral valve area (usually 1.0 cm2 to 2.0 cm2) and a 50%
to 60% reduction in the transmitral gradient (Fig. 20.17).
Procedure success has been defined as a final mitral valve
area >1.5 cm2 and decrease in left atrial pressure to <18 mm Hg
in the absence of complications, and it occurs in 70% to 95%
of patients, depending on the underlying valve morphology.51
Complications include acute severe mitral regurgitation in
2% to 10%, large residual atrial septal defect (Qp/Qs > 1.5)
in 12% with the double-balloon technique and <5% with the
single-balloon system, ventricular perforation in 0.5% to 4%,
systemic embolization in 0.5% to 3.0%, myocardial infarc-
tion in 0.3% to 0.5%, and mortality in <2%. Given the com-
plexity of the procedure, acute outcomes also have been
directly correlated with operator experience.48,52,53 Overall, in
patients with favorable morphology, the success rate in expe-
rienced hands is greater than 90% with a complication rate
of less than 3%.
Event-free survival (freedom from death, repeat valvot-
omy, or mitral valve replacement) over 3 to 7 years is 50% to
70% overall, but exceeds 90% in those with favorable valve
morphology. Randomized, albeit small, investigations have
demonstrated comparable clinical outcomes of balloon mitral
valvotomy and surgical mitral commissurotomy for selected
patients with mitral stenosis.54–58 These investigations
enrolled primarily young patients (mean age <30 years) with
favorable valve morphology) and are summarized in Table
20.6.
Balloon Aortic Valvotomy
Overview
Percutaneous balloon aortic valvotomy was introduced by
Lababidi et al.59 in 1984 and has become the treatment of
choice for noncalcified congenital aortic stenosis in children
and young adults. In the mid-1980s, Cribier et al. generated
great enthusiasm when they successfully performed this pro-
cedure in three elderly patients with critical aortic stenosis
due to calcific degenerative disease. Although there was an
acute improvement in hemodynamics and symptom relief in
these critically ill patients, subsequent follow-up studies
have shown a high restenosis rate and no improvement in
survival in these critically ill elderly patients. Thus percuta-
neous aortic balloon valvotomy in adults now has limited
indications and is rarely performed. The following discussion
focuses on aortic balloon valvotomy in the older adult.
Patient Selection
Patients with stenosis due to congenital abnormalities of the
aortic valve and no significant calcification may have signifi-
cant relief of obstruction due to splitting of the commis-
sures.60–62 However, in patients with senile degenerative aortic

TABLE 20.6. Clinical trials of percutaneous and surgical mitral commissurotomy

Mitral gradient MVA
Mean No. of Average Freedom from NYHA
Study follow-up Procedure patients score Pre Post Pre Post Restenosis reintervention FC I

Patel et al. Immediate PMBV 23 6.0 12 ± 4 4±3 0.8 ± 0.3 2.1 ± 0.7
(1991)54 CC 22 6.0 12 ± 5 6±4 0.7 ± 0.2 1.3 ± 0.3
Turi et al. 8 mo PMBV 20 7.2 18 ± 4 10 ± 2 0.8 ± 0.2 1.6 ± 0.2
(1991)57 CC 20 8.4 20 ± 6 12 ± 2 0.9 ± 0.4 1.7 ± 0.2
Arora et al. 22 mo PMBV 100 23 ± 5 5±3 0.9 ± 0.3 2.4 ± 0.9 5%
(1993)55 CC 100 26 ± 3 6±4 0.8 ± 0.2 2.2 ± 0.9 4%
Reyes et al. 3 yr PMBV 30 6.7 0.9 ± 0.3 2.4 ± 0.6 10% 72%
(1994)56 OC 30 1.0 0.9 ± 0.3 1.8 ± 0.4 13% 57%
Ben Farhat 7 yr PMBV 30 6.0 0.9 ± 0.2 2.2 ± 0.4 7% 90% 87%
et al. OC 30 6.0 0.9 ± 0.2 2.2 ± 0.4 7% 93% 90%
(1998)58 CC 30 6.1 0.9 ± 0.2 1.6 ± 0.4 37% 50% 33%
CC, closed commissurotomy; MVA, moral valve area; NYHA FC I, New York Heart Association Functional Class I; PMBV, percutaneous mitral balloon
valvotomy.
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y
stenosis, the mechanism of aortic valvotomy is annular
stretching and fracture of calcific deposits, resulting in only a
modest reduction in gradient. Restenosis occurs in nearly
100% of patients after 6 to 12 months and may cause acceler-
ated symptoms. Thus, the current main indication for aortic
balloon valvotomy is limited to patients who are hemody-
namically unstable as a bridge to aortic valve replacement.
Occasionally, aortic balloon valvotomy may be used as pallia-
tive therapy in those with significant comorbid conditions
and a limited life span, but this should not be considered a
primary indication for this procedure. Ineligible patients are
those with moderate or severe aortic regurgitation because of
the potential for worsening of regurgitation with valvotomy.
Technique
The retrograde aortic approach from femoral artery access is
most commonly used for balloon aortic valvotomy. Initial
measurements are made with one catheter in the left ventri-
cle and the other in the ascending aorta. Following baseline
hemodynamic assessment, the left ventricular catheter is
exchanged for a 0.038-inch heavy-duty, exchange length
(300 cm) guidewire with a “pigtail” curve made at the end of
the wire. The prepared, deflated balloon catheter is then
advanced over this guidewire to straddle the aortic valve
using the proximal and distal balloon markers. In general, a
balloon diameter less than 120% of the annulus size mea-
sured on echocardiography is utilized.63 Most operators start
with a 20-mm balloon, but smaller sizes (15 or 18 mm) may
be used for patients with smaller body surface area (<1.8 m2).
The balloon is inflated slowly with pressure on the catheter
to maintain stable positioning across the aortic valve, fol-
lowed by rapid inflation with the appropriate necessary force
to reach its maximum diameter. Inflation is usually less
than 10 seconds, using the disappearance of a “waist” on the
balloon as a sign that the valve has been adequately dilated.
Transient myocardial ischemia, as measured by coronary
sinus flow and metabolites, occurs during balloon inflation
that resolves immediately with deflation.64 Both the myocar-
dial ischemia and the increased afterload imposed by balloon
inflation lead to depression of ventricular function. Systolic
blood pressure usually decreases modestly, but can be pre-
cipitous in patients with left ventricular dysfunction. In the
event that the desired aortic valve area has not been achieved,
inflations can be repeated following a period of stability with
larger balloon (23 mm), or, in some instances, double bal-
loons (i.e., two 15- or 18-mm balloons). The double-balloon
approach allows venting during inflation as an attempt to
improve patient tolerance.65–67
Outcome
Several registries have documented the acute hemodynamic
benefits, complications, and long-term outcomes with
balloon aortic valvotomy. The Mansfield balloon aortic valve
registry reported on 492 patients who underwent the proce-
dure at 27 institutions from 1986 to 1987 in the United States
and Europe.68 The National Heart, Lung, and Blood Institute
(NHLBI) Balloon Valvotomy Registry examined the out-
comes of 674 patients from 24 institutions in the United
States from 1987 to 1989.69 Overall, these investigations
4 81
observed an increase in the aortic valve area from 0.5 cm2 to
0.8 cm2, a decrease in the gradient from 60 mm Hg to
30 mm Hg, and little increase in cardiac output.
For patients with degenerative aortic stenosis, complica-
tions are a major limitation of balloon aortic valvotomy. These
occur in approximately 20% of patients, including stroke in
1.4% to 5.5%, emergency aortic valve replacement in 1.2%,
ventricular perforation in 1.4% to 3.6%, local vascular injury
in 4.1% to 10.0%, and procedural death in 1.8% to 7.5%. Pro-
cedural complications are a strong predictor of in-hospital
mortality, occurring most commonly in patients with coro-
nary atherosclerosis, severe functional class, and those who
are female. Other important variables associated with in-hos-
pital mortality are left ventricular dysfunction, the severity of
aortic stenosis at baseline, and the final valve area.70
Restenosis of the aortic valve, defined as 50% reduction
in the acute gain in valve area, occurs in 50 to 65% of these
patients at 6 months and reaches nearly 100% at 1 year.71
There also is a continued high rate of late mortality that is
not different from untreated patients, likely due to the severe
comorbidities that are present in these highly selected
patients. Thus, balloon aortic valvotomy remains a palliative
measure rather than an alternative to aortic valve replace-
ment in patients with calcific aortic stenosis.
Percutaneous Valve Replacement and Repair
Surgical operation remains the standard approach for valve
replacement. Percutaneous valve replacement was first
attempted several decades ago, but significant technical
hurdles hindered its progress.72,73 Nonetheless, in 1992, Ander-
sen and coworkers74 demonstrated the feasibility of the percu-
taneous approach by attaching a porcine bioprosthesis to a
wire-mounted stent, and successfully implanting the device
in various aortic positions. Subsequently, Bonhoeffer and
coworkers75,76 tested a bovine valve mounted on an expandable
stent in animals, and then successfully implanted the device
into the pulmonary position in a 12-year-old boy.
In the first reported series in humans, Cribier and cowork-
ers77 performed percutaneous aortic valve implantation with
a 23-mm prosthesis (Cribier-Edwards) in six nonsurgical
patients (mean age, 75 years) with end-stage calcific aortic
stenosis. This prosthesis consists of three bovine pericardial
leaflets mounted on a 15-mm balloon-expandable stainless
steel stent (Edwards Lifesciences, Irvine California) delivered
via an antegrade approach (Fig. 20.18). Successful delivery
occurred in five patients with an increase in the effective
aortic valve area from 0.5 ± 0.1 cm2 to 1.70 ± 0.1 cm2, a
decrease in the gradient from 38 ± 11 mm Hg to 7 ± 3 mm Hg,
and an increase in left ventricular ejection fraction from 24%
± 10% to 41% ± 12% at follow-up. Complications included
one death due to early migration and severe paravalvular
regurgitation in two, but coronary artery patency was pre-
served in all patients. Other percutaneous aortic valve pros-
theses include the CoreValve self-expanding prosthesis,
which has been implanted in two patients in Europe. Tech-
nological development of suitable prostheses is ongoing, with
targeting of the major obstacles to successful percutaneous
treatment of aortic stenosis. These challenges include
(1) accurate placement within the native valve without
482 chapter 20

FIGURE 20.19. The Cardiac Dimensions (KirKland, Washington)

device for percutaneous mitral annuloplasty.

have been two main approaches, both of which emulate sur-

FIGURE 20.18. The Cribier-Edwards percutaneous aortic valve.
obstruction of the native coronary arteries; (2) minimizing
the risk of embolization of the prosthesis and native valve
debris; (3) retention of the prosthetic position without para-
valvular regurgitation; and (4) long-term durability.
While balloon valvotomy has become the preferred
therapy for selected patients with mitral stenosis, ongoing
studies are evaluating percutaneous techniques for mitral
valve repair for patients with mitral regurgitation. There
gical techniques. The first method employs one or two metal-
lic clips (Evalve Inc., Redwood City, CA) through an antegrade
approach. The clips attach the free edges of the midportions
of the anterior and posterior mitral valve leaflets to each
other, creating a double-orifice valve and reducing mitral
regurgitation similar to the surgical Alfieri repair.78,79 In a
report of the multicenter Endovascular Valve Edge-to-Edge
Repair Study (EVEREST) Phase 1 study, Feldman and cowork-
ers80 successfully deployed the Evalve clip in 17 symptomatic
patients with grade ≥3+ mitral regurgitation. There was a
significant reduction in mitral regurgitation with 13 of the
patients having residual regurgitation of grade 2+ or less.
The second method emulates surgical mitral annulo-
plasty by implanting devices in the coronary sinus, whose
course roughly parallels the plane of posterior mitral annulus.
These devices, when deployed, foreshorten the coronary
sinus and thereby plicate or straighten the posterior annulus,
leading to a reduction in the mitral annular diameter and
regurgitation (Figs. 20.19 and 20.20). There have been several

4 1.00
MR jet area/ LA area
MR grade (0–4)

3 0.75

2 0.50
* *
1 0.25

0 0.00
Baseline Post-device Baseline Post-device
Angiographic MR gade MR jet area/ LA area

0.25 20
Regurgitant volume (mL)

0.20
15
ERO (cm2)

0.15
10
0.10 * *
5 FIGURE 20.20. Acute effects of percutaneous
0.05
mitral annuloplasty with the Cardiac Dimen-
0.00 0 sions device in dogs. (A) Grouped data for all
Baseline Post-device Baseline Post-device parameters of mitral regurgitation (MR) sever-
ity at baseline and post-device (p < .05 vs.
A ERO Regurgitant volume baseline).
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y 483

B Baseline Post-device

C Baseline Post-device

D Baseline Post-device

FIGURE 20.20. Continued. ERO, effective

regurgitant orifice. Representative examples of
contrast ventriculography (B), MR jet area/left
atrial area (C), and proximal isovelocity surface
area measurements (D) before and after device
placement in a single dog are shown. In B,
arrows indicate reflux of contrast into pulmo-
nary veins.

animal studies demonstrating the potential efficacy of this
approach.81–83 The main challenges to this technique will be
reliance on the coronary sinus, which can be mobile and is
subject to thrombosis, erosions, and other complications as
has been demonstrated in studies of patients who undergo
biventricular placing; and the proximity of the coronary
sinus to the left circumflex artery, which may be injured
during device deployment. For either percutaneous approach
to mitral valve repair, efficacy as a stand-alone intervention
also will need to be compared to open surgery, which is fre-
quently supplemented with other adjunctive measures (e.g.,
leaflet resection, chordal surgery).
484 chapter
These new technologic advances are potentially a less
invasive therapeutic approach to the patient with valvular
heart disease. There has been great enthusiasm generated for
this concept of catheter-based therapy for these patients.
However, the ultimate role of this technology will need to
be determined by trials demonstrating the short- and long-
term results of these procedures.
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 2 Echocardiographic
1 Assessment of Valvular
Heart Disease
Raymond F. Stainback

Overview. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488 Mitral Valve Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508

Grading System for Valve Lesions . . . . . . . . . . . . . . . . . . 488 Tricuspid Valve Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . 525
Jet Lesion Anatomy by Color Doppler . . . . . . . . . . . . . . . 489 Pulmonary Valve Disease . . . . . . . . . . . . . . . . . . . . . . . . . 528
Aortic Valve Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490 Prosthetic Valve Dysfunction . . . . . . . . . . . . . . . . . . . . . . 529
Chronic Aortic Regurgitation . . . . . . . . . . . . . . . . . . . . . . 500 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533
Acute Severe Aortic Regurgitation. . . . . . . . . . . . . . . . . . 507

Key Points Aortic Stenosis

General • The degree of apparent cusp immobility does not always
reflect the degree of hemodynamic severity, and quantita-
• Echocardiography is the primary tool for the noninvasive
tive measures are needed.
detection, quantitation, and follow-up assessment of val-
• The echocardiography imaging window that will yield
vular heart disease.
the highest aortic valve velocity (most coaxial to the jet’s
• No single echocardiography method can be considered a
net vector within the vena contractor) is not predictable
robust “gold standard” for quantification of lesion sever-
from valve morphology or jet appearance by color
ity in all situations.
Doppler.
• Valve lesion severity is often diagnosed by a synthesis of
• Flow velocities and gradients can vary tremendously
several anatomic, qualitative, and quantitative echocar-
beat-to-beat with irregular rhythms.
diography severity indicators.
• Valve area by continuity equation: The left ventricular
• For best practice, laboratories should routinely obtain as
outflow tract (LVOT) diameter measurement is squared,
many severity parameters as possible, so that adequate
so that any significant LVOT diameter (D) measurement
scanning and interpretation skills are maintained for
error will also be squared, producing a potentially unac-
accurate diagnoses in difficult cases.
ceptable error in the aortic valve area calculation.
• Transesophageal echocardiography (TEE) may be needed
• For a given valve area, the measured aortic valve gradient
in conjunction with the transthoracic exam (TTE) for a
is strongly influenced by heart rate, stroke volume, ejec-
definitive diagnosis.
tion duration, left ventricle (LV) contractility and preload
and afterload. Therefore, peak and mean velocity and
Color Doppler pressure gradient measurements in isolation can be
misleading.
• Imaging the full extent of an expanding jet within the
receiving chamber using multiple views is necessary and
helpful for determining lesion severity.
Aortic Regurgitation
• The overall jet size within the receiving chamber viewed
in isolation can be one of the least effective parameters • Determining the severity of chronic aortic regurgitation
for judging lesion severity, unless it is very small or very can be one of the most challenging tasks for a cardiolo-
large. gist. The final diagnosis may be the result of an inte-
• Applying several of the described quantitative methods grated analysis of several parameters.
requires an understanding of all of the component parts • There are many potential pitfalls for using color Doppler
of a jet lesion as depicted by color Doppler. jet size as an indicator for regurgitation severity. With

487
488 chapter
good imaging practices are employed, however, a very
small aortic regurgitation (AR) jet by color Doppler likely
represents mild AR, and a very large AR jet likely repre-
sents severe AR.
• In AR, pressure half-time (PHT) values are generally
useful only in the extremes and when the continuous-
wave (CW) Doppler signal’s outer edge is clearly definable
and the interrogating beam is well aligned with the
regurgitant jet.
• Acute severe AR usually represents a surgical emer-
gency, in which case early TEE for confirmation of
the diagnosis, its mechanism, and surgical planning is
indicated.
Mitral Stenosis
• Severe mitral valve (MV) stenosis is most often rheumatic
in origin.
• Mitral valve areas that cause clinical symptoms can vary
markedly among patients depending on body size, cardiac
output, and heart rate.
• The MV area should be confirmed using two or three
methods, given the number of potential pitfalls of each.
• The mean MV gradient may be low in severe mitral
stenosis (MS) when there is low cardiac output or
bradycardia.
• In equivocal cases exercise stress Doppler may be useful.
Mitral Regurgitation
• Detection of mitral regurgitation (MR) by Doppler is rela-
tively easy. However, accurate grading of MR severity can
be technically challenging. No one method is sensitive
and specific in all cases.
• When several findings are in agreement regarding lesion
severity, an accurate “integrated diagnosis” is possible in
most situations.
Tricuspid Valve Disease
• Tricuspid valve stenosis is an uncommon diagnosis. It
should be considered in all symptomatic patients with
rheumatic heart disease.
• Clinically significant tricuspid stenosis (TS) is poorly tol-
erated and is associated with modest resting tricuspid
inflow gradients (mean gradient >5 mm Hg).
• Paradoxical septal motion by M-mode and two-
dimensional (2D) examination and hepatic vein systolic
flow reversal can be important signs of severe TR.
• Torrential “unobstructed” TR may be easily missed by
color Doppler alone.
Pulmonary Valve Disease
• Low-velocity severe PR can be easily missed by color
Doppler. Careful attention to the PV spectral Doppler
signal and recognition of the signs of RV volume overload
are important.
• PS is relatively uncommon in adult patients, although it
is relatively easily to diagnose in most cases by routine
PV Doppler examination.
21
Prosthetic Valve Assessment
• Distinctive imaging artifacts aid in recognition of
mechanical prosthetic valves.
• Shadowing and reverberation artifacts, however, also
hamper detection of either obstructive or insufficiency
lesions and make their mechanisms (thrombus, pannus,
vegetation, paravalvular leak, or leaflet malfunction) dif-
ficult to determine.
• Whenever prosthetic valve dysfunction is suspected,
comprehensive TTE and TEE are frequently needed in
order to address the situation.
Overview
Echocardiography is the primary tool for the noninvasive
detection, quantitation, and follow-up assessment of valvular
heart disease.1–4 In most cases, features of the two-dimen-
sional (2D) [increasingly three-dimensional (3D)5] and M-
mode and Doppler evaluation provide important measurable
parameters and indirect clues regarding lesion severity and
etiology.6,7 Because Doppler is used to evaluate a wide range
of non–valve-related cardiovascular pathology, basic Doppler
concepts are presented in Chapter 5. An echocardiogram can
often quickly and accurately define valve lesion as clearly
mild or clearly severe based upon certain highly specific
features. Frequently, however, valve disease is neither clearly
mild nor clearly severe. No single echocardiography method
can be considered a robust gold standard for quantification
of lesion severity in all situations. In challenging cases,
lesion severity is often diagnosed by a synthesis of several
anatomic, qualitative, and quantitative echocardiography
severity indicators that are outlined herein. Valve disease
can be simple (isolated obstructive or insufficiency lesions)
or complex. Examples of complex valve disease include
mixed stenosis and regurgitation of the same valve; multiple
valve involvement; associated dynamic obstructive lesions,
congenital malformations, and cardiomyopathies; or pros-
thetic valve dysfunction. Such complications and other vari-
ables (imaging artifacts, tachycardia, irregular rhythm, low
output states, and high or low afterload or preload) influence
the extent to which certain Doppler methods are applicable
or valid. Accordingly, the most common pitfalls of each
method will be addressed. For best practice, laboratories
should routinely obtain as many lesion severity parameters
as possible, so that adequate skills are maintained for accu-
rate diagnoses in difficult cases. Transesophageal echocar-
diography (TEE) may be needed in conjunction with the
transthoracic exam (TTE) for a definitive diagnosis.
Grading System for Valve Lesions
Valve lesions are reported as mild, moderate, or severe.8 The
use of “mild-to-moderate” or “moderate-to-severe” is desir-
able, when appropriate, because lesions frequently lie within
these gray zones. Left-sided valve regurgitant lesions (aortic
and mitral) that are just detectable by color or continuous-
wave (CW) Doppler and are of little or no hemodynamic sig-
nificance may be called “trace” or “trivial.” Trace or trivial
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e
and even mild right-sided (tricuspid and pulmonary) regurgi-
tant lesions are common in individuals with normal anatomy,
and reporting these often nonpathologic findings is not
always necessary unless there has been a change in compari-
son with a prior examination. A numerical classification
scheme (e.g., 1+, 2+, 3+, 4+) for regurgitation (or stenosis) is
potentially confusing because the definitions may vary
among laboratories (e.g., 3+ may mean “moderate” in one
laboratory and “moderate-to-severe” in another).
Jet Lesion Anatomy by Color Doppler
Applying several of the quantitative methods described
below requires an understanding of the component parts of
a jet lesion as depicted by color Doppler. As illustrated in
Figure 21.1, a jet lesion consists of a proximal flow conver-
gence (PFC) zone, flow within the anatomic orifice, a physi-
ologic orifice (vena contracta), and the expanding jet within
the receiving chamber.9 Many of the following comments
regarding jet anatomy by color Doppler apply more to regur-
gitant jets than to stenotic lesions.
Proximal Flow Convergence and Proximal
Isovelocity Surface Area10–12
Laminar blood flow exiting a pressurized chamber produces
a localized, uniform PFC pattern by color Doppler just proxi-
mal to a narrowed orifice. The PFC size varies directly with
the flow rate, which is related to the orifice size and driving
pressure. Discernible color bands are present within the PFC
zone due to a velocity gradient and progressive aliasing of
laminar blood flow proximal to the orifice. The geometric
area of the color transition surface is known as a proximal
PFC
VC
Jet
Anatomic orifice Physiologic orifice
FIGURE 21.1. Illustration of jet lesion “anatomy” by color flow
Doppler. PFC, proximal flow convergence; VC, vena contracta.
489
isovelocity surface area (PISA). The PISA and CW Doppler
signal of a regurgitant jet can be used to calculate the effec-
tive regurgitant orifice area (EROA)13 and regurgitant volume
(RV). Under ideal circumstances (relatively flat anatomic
orifice, relatively discrete opening, and appropriate color
Doppler Nyquist limit setting), the outer edge PISA assumes
a hemispheric shape with a measurable radius r. The area of
a hemisphere (PISA) is 2πr 2. Blood flow velocity at the site of
this hemisphere is the same as the aliasing velocity, Va,
which is obtained from the color map. Instantaneous flow is
the cross-sectional area (PISA) multiplied by the instanta-
neous flow velocity (Va):
Flow = 2πr 2 × Va
which is simplified as
Flow = 6.28r 2 × Va.
The EROA can be calculated by a modification of the conti-
nuity equation because instantaneous peak PISA flow must
equal instantaneous peak flow across the regurgitant orifice
(Vpk). Using the PISA radius (r), Va (from the color Doppler
map), and peak regurgitation velocity (Vpk) from the mitral
or aortic regurgitation CW Doppler signal, EROA can be
calculated:
EROA = 6.28r 2 × Va/Vpk
This method has been validated, when imaging conditions
permit, for the mitral, aortic, and tricuspid valves.
Regurgitant volume (RV) is the cross-sectional area of
flow (EROA) multiplied by the time-velocity integral (VTI) of
flow at the EROA, as measured by CW Doppler (see examples
below):
RV = EROA × VTI
Analysis of the PFC for derivation of the PISA radius, com-
bined with CW Doppler, can be used to calculate the area of
a stenotic mitral valve (see example below). Although a PISA
signal may not always be adequate for quantitative measure-
ment, the presence of a prominent PFC is a potentially
important finding that should raise suspicion for a hemody-
namically important lesion.
Vena Contracta by Color Doppler9,14–16
Immediately downstream from the anatomic orifice, is a
physiologic orifice, where the highest velocity laminar flow
occurs within an area slightly smaller than that of the
upstream anatomic orifice. This region of compressed
laminar flow is known as the vena contracta. The highest
flow velocities measured by CW Doppler occur within
the vena contracta and not within the anatomic orifice. The
cross-sectional area of the vena contracta is known as
the effective regurgitant orifice area (EROA), which too, is
slightly smaller than the anatomic orifice area. With careful
imaging [zooming the proximal jet region and applying color
Doppler at a high frame rate (small color sector)], the vena
contracta width can be measured (see examples below). The
vena contracta width increases with increasing regurgitation
severity, making this measurable parameter an important
severity indicator.
490 chapter
Expanding Jet by Color Doppler
Imaging the full extent of an expanding jet within the
receiving chamber using multiple views is necessary and
helpful for determining lesion severity.17–20 However, the
overall jet size within the receiving chamber viewed in iso-
lation can be one of the least effective parameters for judging
lesion severity, unless it is very small or very large. This is
because color Doppler represents a velocity map display and
not a volume map of blood flow. Due to convective forces,
nonregurgitant “bystander” blood within the receiving
chamber can be entrained by regurgitant blood contained in
the jet and labeled by color Doppler. Accordingly, relatively
small jets under high driving pressure (high velocity) can
entrain significant surrounding blood in the receiving
chamber, thereby producing a potentially misleadingly large
expanding jet lesion by color Doppler. By the same token,
severe regurgitation may produce a deceptively small color
Doppler jet within a receiving chamber if the driving pres-
sure is low [e.g., severe tricuspid regurgitation (TR) with
normal RV systolic pressure, or severe mitral regurgitation
(MR) with low systemic pressure and high left atrial (LA)
pressure]. The extent of receiving chamber enlargement
must be taken into account when thinking in terms of
regurgitant jet area. “Wall hugging” jets do not entrain as
much blood as “free jets,” which may lead to “undercalling”
of lesion severity when color Doppler area methods are
used.21,22 In all such cases, analyses of the PFC zone and vena
contracta sizes, along with quantitative flow methods, will
help to establish lesion severity more accurately than by jet
area size alone.
Technical Notes on Color Jet Area
Jet size is inversely related to the color Doppler Nyquist limit
setting. As a standard, the color Doppler Nyquist limit
should be set in the range of 50 to 60 cm/s. Color gain settings
also influence jet size. The color gain should be increased
until there are a few color pixels overlying areas having no
blood flow. Then the gain should be decreased gradually until
these color “noise” speckles just disappear. Other factors
may also affect the appearance of the jet size by color Doppler
[size and depth of the image sector, pulse repetition fre-
quency (prf), manufacturer]. Operators should be familiar
with these and other variables that may affect the color
Doppler signal.23
The sonographer should evaluate the possibility of sepa-
rate (multiple) or geometrically complex proximal flow con-
vergence zones. Using color Doppler in both short axis and
multiple long axis and “off-axis” imaging planes along the
entire extent of leaflet coaptation zones, the sonographer can
often demonstrate all components of the jet lesion (PFC,
anatomic orifice, vena contracta, expanding jet) within a
single or a few “best” imaging planes. With eccentric jets,
the proximal components of a lesion may be best viewed in
one imaging plane and the expanding jet lesion in another.
However, all elements should ultimately be included. Three-
dimensional color Doppler imaging offers a potential means
for the more expedient analysis of complex jet geometries
and overall jet size.
21
Aortic Valve Disease
Aortic Stenosis
Two-Dimensional and M-Mode Exam and
Differential Diagnosis
The normal, trileaflet aortic valve (AoV) is an almost per-
fectly symmetrical structure. Leaflet number and symmetry
are best appreciated in the parasternal short axis view (Fig.
21.2). Normal aortic leaflets, also known as cusps, are thin
and highly pliable and have a deeply semilunar or “cupped”
conformation upon diastolic coaptation. During rapid sys-
tolic excursion, adjacent aortic cusps come into parallel
alignment within the bloodstream (Fig. 21.3A) while simul-
taneously undergoing partial inversion so that the leaflets,
in short axis, assume a circular (cylindrical) conformation
corresponding to the circular aortic annulus (Fig. 21.2A).
This overall “tubular” systolic valve shape minimizes blood
flow resistance and shear forces within the leaflets. Some
portions of thin and normal aortic valve leaflets may be dif-
ficult to visualize. On the other hand, certain portions of the
normal semilunar-shaped aortic cusps behave as parabolic
reflectors of the ultrasound beam, producing characteristic
regional areas of increased echogenicity, which should not be
mistaken for fibrosis or calcification. Diseased or “degenera-
tive” leaflets become increasingly thickened and well visual-
ized throughout, except in advanced disease, in which case
severe calcification can produce shadowing artifacts and
leaflet dropout.
Calcific Aortic Stenosis
Calcific degeneration of a previously normal, trileaflet valve
is the most common cause of acquired aortic stenosis (AS)
in adults older than 65, and it is frequently encountered in
almost all adult echocardiography laboratories. Aortic scle-
rosis is an even more common, possibly related, precursor
lesion that is differentiated from AS because it produces no
significant resting gradient (peak velocity <2.5 m/s). Aortic
sclerosis (without significant stenosis) is noteworthy in echo-
cardiography reporting because it may be a marker for a more
generalized atherosclerotic process24 and increased risk,25,26
including possible progression to AS. Aortic valve sclerosis
is recognizable on the 2D exam as leaflet thickening and
increased echogenicity with focal minimal or mildly reduced
systolic cusp separation (Figs. 21.2B and 21.3B). Focal hyper-
echoic regions indicating fibrosis and calcium deposits may
occur throughout the leaflets, but they are typically more
pronounced in the leaflet bases. Decreased cusp mobility
also typically occurs first in the leaflet bases (Fig. 21.2B) and
gradually works its way into the body of the leaflets
(Fig. 21.3C,D). The degenerative process can be balanced
among the three cusps or it may involve one or two cusps
predominantly.
Insidiously, over decades, sclerotic aortic valve cusps can
become increasingly thickened and immobilized, sometimes
with bulky, protruding calcific lesions that can cause promi-
nent shadowing and side lobe artifacts within the left ven-
tricular outflow tract (LVOT) (Fig. 21.3D). Reduced aortic
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 4 91

A B

C D
FIGURE 21.2. (A) Transthoracic echocardiography (TTE), short axis geal echocardiography (TEE), moderate-to-severe aortic stenosis
view of normal aortic valve, with nearly circular opening at the cusp (AS) with larger focal calcifications and planimetered orifice
level. (B) Aortic valve sclerosis. The orifice is triangular shaped with area (0.93 cm2). (D) TEE, heavily calcified aortic cusps with severe
small focal calcifications evident within the cusps. (C) Transesopha- (critical) AS and almost complete cusp immobility.

cusp separation is easily detected by M-mode of the aortic
cusps (Fig. 21.4). In severe AS, the aortic cusps can appear
almost “frozen” in a near closed position throughout the
cardiac cycle (Fig. 21.3D).
Calcific aortic stenosis is frequently accompanied by
some lesser degree of aortic regurgitation due to inadequate
closure of the dysmorphic leaflets. Mitral regurgitation also
frequently accompanies calcific AS due to commonly associ-
ated degenerative mitral annular and mitral leaflet calcifica-
tion (Fig. 21.3D).
Congenitally Bicuspid Aortic Valves
Congenitally bicuspid aortic valves are common (1% to 2%
of all individuals, predominantly in males27). Although not
all are destined to develop important hemodynamic lesions,
calcific degeneration of a congenitally bicuspid aortic valve
is the most common cause of AS in adults younger than 65,
and the second most common cause of severe AS overall.
Bicuspid aortic valves can also exhibit predominant aortic
regurgitation (AR) or mixed AS and AR. Congenital AS diag-
nosed in childhood, adolescence, or early adulthood is more
commonly associated with a unicuspid or a commissural
valve. The majority of bicuspid aortic valves appear to have
fusion of any two of the three aortic cusps along a single
“would be” coaptation line. This thickened fusion zone,
between two aortic sinuses of Valsalva, is known as a
“pseudo-raphe,” which can often exhibit prominent focal
thickening or calcification. The pseudo-raphe’s presence can
sometimes deceptively give the valve a normal trileaflet
appearance in the parasternal short axis view upon diastolic
closure, potentially resulting in a missed diagnosis. Upon
492 chapter 21

A B

C D
FIGURE 21.3. Parasternal long axis views of the aortic valve with basal cusp straightening (same patient as in Fig. 21.2B). (C) Moder-
progressive reduction in cusp separation. (A) Normal aortic valve ate-to-severely reduced cusp separation. (D) Severely reduced cusp
with cusps fully straightened. Line indicates aortic annulus diame- separation from severe calcific AS. Arrowhead, associated mitral
ter measured at cusp “hinge” point. (B) Sclerotic valve with reduced annular calcification.

systolic opening, however, the two asymmetrical leaflets
typically form an almond- or football-shaped opening (Fig.
21.5). Truly bicuspid valves (two symmetrical sinuses of Val-
salva with two symmetrical cusps) are less commonly
encountered. Because bicuspid valves cannot undergo normal
systolic leaflet straightening within the bloodstream, shear
forces within the leaflet can be great, producing early degen-
eration. In the late stages of bicuspid valve AS, the valve can
become heavily calcified and dysmorphic to the point of
being indistinguishable on echocardiography from trileaflet
degenerative calcific AS.
OTHER DIAGNOSTIC CLUES FOR BICUSPID AORTIC VALVES
Abnormal dilatation of the aortic root, ascending aorta, or
both are commonly associated with bicuspid aortic valves28
(Fig. 21.5A). When a dilated aortic root or dilated ascending
aorta or both are encountered, without hypertension, par-
ticularly in young adults, a bicuspid aortic valve should be
suspected. Efforts to clearly image the ascending aorta must
always be carefully undertaken because the degree of aortic
dilatation may influence surgical timing as much as, or
more than, the presence of aortic valve stenosis (or regurgita-
tion). Bicuspid aortic valves may exhibit relatively preserved
mobility in their bases, resulting in systolic doming in the
parasternal long axis view (Fig. 21.5B). M-mode evaluation
may show an eccentric closure line, owing to asymmetrical
leaflet size and orientation in the parasternal long axis view
(Fig. 21.5D). Bicuspid valves may be severely stenotic due to
small slit-like orifices, even though, by planar imaging, the
overall cusp mobility and separation may appear deceptively
adequate.
Rheumatic Aortic Stenosis
Rheumatic aortic stenosis is the third most common
cause of adult valvular AS in Europe and North America.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 493
Rheumatic AS rarely occurs in the absence of associated
rheumatic mitral valve disease. In rheumatic AS, leaflet
thickening due to inflammation occurs primarily in the
leaflet leading edges and not the bases as with calcific AS
(Fig. 21.6). Commissural fusion eventually produces a small,
immobile “fish-mouth” orifice that may also produce signifi-
cant AR. Systolic doming of the leaflets (Fig. 21.7B) may be
present because of relatively preserved mobility of the leaflet
bases. In advanced disease, severe cusp calcification, thick-
ening, and immobility can render rheumatic AS indistin-
guishable from the other forms of advanced valvular AS.

OTHER MORPHOLOGIC FEATURES OF AORTIC STENOSIS

FIGURE 21.4. M-mode tracing of aortic valve (arrow), showing
moderately reduced systolic cusp separation due to calcific AS.
RVOT, right ventricular outflow tract; LA, left atrium.
Concentric left ventricular hypertrophy in the presence of a
morphologically abnormal aortic valve that has reduced sys-
tolic opening should always raise suspicion for clinically
important AS or severe LVOT obstruction of any type.
However, because hypertension is a frequent comorbid con-
dition, this is a nonspecific finding. In the late stages of
valvular AS, more often in men, the ventricle can become
dilated.

A B

C D
FIGURE 21.5. Congenitally bicuspid aortic valve by surface echo. orifice area due to cusp systolic doming (see image B). (D) M-mode,
(A) Dilated aortic root (3.8 cm, red line). (B) Systolic doming of the eccentric cusp closure line (arrow), typical of a bicuspid aortic
cusps (arrow). (C) Short axis view shows ovoid or almond-shaped valve.
systolic opening. Note: This view likely represents exaggerated
 494 chapter 21

A B

FIGURE 21.6. Rheumatic AS by surface echo. (A) Parasternal long axis

shows subtle systolic cusp doming (arrow). (B) Parasternal short axis,
systole, shows commissural thickening and fusion (arrows) and a reduced
systolic opening. (C) Diastolic image shows severe thickening localized
C to the cusp margins and commissures.

Nonvalvular Left Ventricular Outflow Valve Area by Planimetry

Tract Obstruction
Some patients referred to the lab for possible valvular AS are
found to have nonvalvular LVOT obstruction. Nonvalvular
LVOT obstructive lesions identifiable by echocardiography
include dynamic subaortic stenosis, caused by systolic ante-
rior motion (SAM) of the mitral leaflets; fixed subaortic ste-
nosis; and supravalvular aortic stenosis. These entities are
discussed in other chapters.
Severity Assessment by Two-Dimensional
Imaging
Cusp Mobility
When the aortic valve is abnormal, the echocardiogram
report should generally include a statement regarding the
degree of leaflet thickening and the extent to which cusp
mobility or separation is reduced (mildly, moderately, or
severely). However, the degree of apparent cusp immobility
does not always reflect the degree of hemodynamic severity,
and quantitative measures are needed.
Although aortic valve planimetry by surface imaging may be
possible using state-of-the-art surface echocardiography, the
method has been validated with TEE29,30 (Fig. 21.2D). Aortic
valve area by planimetry is most reliable in calcific AS
because the relatively flat stenotic orifice is more likely to
lie within a 2D imaging plane. Aortic valve area by TEE is
most often employed when Doppler data (below) are indeter-
minate (e.g., irregular rhythm) or felt to be unreliable, when
mixed AS and aortic insufficiency (AI) are present, or when
Doppler and catheterization discrepancies are unexplained.
T ECHNICAL CONSIDERATIONS AND PITFALLS
Planimetry by TEE is frequently not possible when severe
calcification shadows the leaflet’s leading edges. When the
cusp margins are clearly defined, a dedicated effort should be
made to obtain the most symmetrical short axis view possi-
ble, ideally with acquisition of three relatively reproducible
area measurements. If gain settings are too low, leaflet
“dropout” can lead to area overestimation of the aortic valve.
If 2D gain settings are too high, “blooming” of the signal
into the orifice can cause an underestimation of valve area.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e
D1 = 1.8 cm
D2 = 2.1 cm
A B
VTI AoV = 101.8 cm Peak Grad = 58.7 mm Hg
V AoV = 3.8 m/s Mean Grad = 34.8 mm Hg
C
FIGURE 21.7. Aortic valve area (AVA) calculation using the conti-
nuity equation. (A) Left ventricular outflow tract (LVOT) diameter,
parasternal long axis view. The mid-LVOT diameter is mildly nar-
rowed by “protruding” basal septal hypertrophy (D1, smaller red
line). The calcified aortic annulus diameter is larger (D2, larger red
line). (B) Pulse-wave (PW) Doppler of the LVOT, apical five-chamber
view, for obtaining V LVOT and VTILVOT. (C) Continuous-wave (CW)
Doppler of the aortic valve (AoV), apical five-chamber view for
obtaining VAoV and VAoV. Application: The AVA is calculated using
The method is not reliable in congenital AS (bicuspid valves)
because the stenotic orifice may be curvilinear and not lying
within a single imaging plane. In this situation, attempted
imaging planes that cut across a relatively funnel-shaped
valve will overestimate valve area. The area of the systolic
color Doppler flow map in short axis should not be measured
by planimetry due to the low spatial resolution of color
Doppler.
Doppler Evaluation for Aortic Stenosis
Continuous-Wave Doppler
The LVOT obstructive gradients are detected and measured
using CW Doppler. Basic Doppler concepts, the pressure-
velocity relationship, and sites of data acquisition are
reviewed in Chapter 5. Spectral Doppler is accurate for clini-
cal purposes when the vectors of the interrogating ultra-
sound beam and the jet lesion are approximately coaxial
495
VTIlvot = 19.8 cm
Vlvot = 0.8 m/s
either the velocity-time integral (VTI) data or the velocity (V)
data:
AVA = (D 2 × 0.785) × (VTILVOT/VTI AoV) or
AVA = (D 2 × 0.785) × (V LVOT/VAoV).
Result: AVA using D1 (1.8 cm) = 0.5 cm2; AVA using D2 (2.1 cm) =
0.7 cm2 (severe AS in both cases, see Table 21.1). Small LVOT diam-
eter differences affect calculated AVA.
(within 20 degrees). Continuous-wave Doppler is needed for
measuring pathologic velocities (2.5 to 7 m/s) that exceed the
Nyquist limit of pulsed Doppler. Doppler-derived instanta-
neous velocity measurements are converted to a pressure
drop or pressure gradient across the valve using the modified
Bernoulli equation:
ΔP = 4V 2
Using Doppler, the calculated peak pressure gradient occurs
simultaneously with the maximum transvalvular flow veloc-
ity. The mean pressure gradient is derived by averaging
instantaneously sampled gradients throughout the ejection
period:
ΔPmean = 4V12 + 4V22 + 4V32 + . . . + 4Vn2 /n
The peak and mean gradients are automatically calculated
by the ultrasound system or off-line analysis program when
the user electronically “traces” the outer edges of the CW
spectral Doppler envelope (Figs. 21.7C and 21.8). Both peak
and mean gradients should be reported.
496 chapter
A B
C
FIGURE 21.8. (A,B) Variable AS gradients from different transducer
types. (A) Suboptimal AS spectral Doppler signal obtained using the
“steerable” imaging transducer CW Doppler, modified apical view.
Peak gradient = 46.8 mm Hg. (B) Optimal AS CW Doppler signal in
the same patient, using the smaller dedicated CW (Pedoff) trans-
ducer. Peak gradient = 78.3 mm Hg. (C) Variable AS gradients due to
arrhythmia: CW Doppler of LVOT, apical window, in calcific AS.
COMPARISON WITH CATHETERIZATION
Hemodynamic “loading conditions” and heart rate may be
vastly different at the time of catheterization versus echocar-
diography, leading to potentially conflicting results. It is
important to bear in mind that the peak instantaneous pres-
sure gradient obtained by Doppler is not comparable to a
reported catheter-derived peak-to-peak gradient. A catheter-
derived peak-to-peak gradient is simply the difference
between the peak pressure recorded in the left ventricle (LV)
and in the aorta using either simultaneous fluid-filled trans-
ducer recordings or the “pull-back” method. Because peak
left ventricular and aortic pressures do not occur simultane-
ously (left ventricular peak pressure occurs sooner than the
aortic peak pressure), the peak-to-peak gradient is not, in
fact, a gradient, but rather a useful clinical parameter that is
not comparable to the physiologic Doppler-derived peak
instantaneous pressure gradient. A better correlation is
observed between Doppler and “cath” data, when the cathe-
ter-derived maximum instantaneous pressure gradient
(occurring just before the peak ventricular pressure record-
ing) and the mean systolic pressure gradient are compared
with the Doppler-derived peak and mean instantaneous pres-
sure gradients. Additionally, the phenomenon of pressure
21
Cycle “a” peak gradient = 81 mm Hg, mean gradient = 56 mm Hg.
Cycle “b” peak gradient = 37 mm Hg, mean gradient = 24 mm Hg.
Because sequential regular beats were not acquired, whether or not
cycle “a” is a postectopic beat cannot be determined. Therefore,
neither cycle “a” nor “b” [a PVC (premature ventricular contraction)]
is acceptable for valve area calculation.
recovery can lead to overestimated gradients by Doppler as
compared with catheterization.31 With good technique, AS
velocities and gradients by CW Doppler have been shown to
correlate well with simultaneous catheterization data over a
broad range of pressures.32
K EY T ECHNICAL CONSIDERATIONS
The echocardiography imaging window that will yield the
highest aortic valve velocity (most coaxial to the jet’s net
vector within the anatomic orifice) is not predictable from
valve morphology or jet appearance by color Doppler. There-
fore, when AS is suspected, the sonographer must interrogate
the aortic valve with CW Doppler from several acoustic
windows, including apical, right parasternal, subcostal, and
suprasternal notch. In many patients (hypertensive and older
patients), the aortic valve plane can be abnormally rotated
anteriorly (Fig. 21.9), which makes Doppler interrogation
from the LV apical region inaccurate because of a poorly
aligned interrogation angle (Ø). In addition, severe aortic
calcification can strongly shadow a jet lesion’s vena con-
tracta (zone of highest velocity, located on the aortic side of
the valve) from apical views, making the right parasternal
and sometimes the sternal notch windows more successful.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e
FIGURE 21.9. Aortic root angiography, left anterior oblique (LAO)
projection, in a 62-year-old woman with congenitally bicuspid aortic
valve. The aortic root and ascending aorta are dilated and “angu-
lated.” There is an anteriorly directed negative contrast jet (dark
arrow) of aortic stenosis. The aortic cusps are heavily calcified
(white arrows). This fluoroscopic image shows the potential vari-
ability of an AS jet vector within the chest, and the potential for
aortic valve calcification to shadow the vena contracta zone (aortic
side of valve) when Doppler interrogation is made from the ventricu-
lar side of the valve.
The smaller, nonimaging CW transducer should be employed
routinely in AS cases, because this device provides a superior
spectral Doppler envelope, often with higher velocity, than
that achieved with the imaging transducer in part due to its
smaller footprint with easier maneuverability. Although it
may be argued that the dedicated nonimaging CW trans-
ducer is not needed in every case, its routine use ensures that
a sonographer possesses the necessary skills when confronted
with a technically challenging case of AS, which is not infre-
quent in adult echocardiography laboratories.
T ECHNICAL QUALITY OF THE CONTINUOUS-WAVE DOPPLER
SIGNAL AND OTHER CLUES TO AORTIC STENOSIS SEVERITY
Signs of a technically good CW Doppler signal are uniformed
signal density and a clearly defined envelope (Fig. 21.7C). An
early-peaking signal usually occurs with mild AS, and a mid-
peaking signal is a sign of severe AS (Fig. 21.8). Continuous-
wave Doppler signals appearing much denser in the base may
indicate that the interrogating beam is cutting across the jet
lesion rather than being coaxial (Fig. 21.7D). Therefore, one
should be highly suspicious of a late-peaking, possibly severe
AS signal that is relatively low in velocity with reduced
signal density, because the interrogating beam may be in
poor alignment, possibly “missing” severe AS.
OTHER POTENTIAL PITFALLS
From apical windows, CW spectral Doppler signals from
atrioventricular valve regurgitation (MR and TR) can be con-
497
fused with the aortic valve Doppler signal, because each is a
systolic signal, moving in roughly the same direction (below
the baseline) and occasionally at similar peak velocities. If
an MR CW Doppler signal (high velocity) is mistaken for an
aortic valve CW Doppler signal, severe AS could be errone-
ously diagnosed. Key observation: The aortic valve spectral
Doppler envelope is distinguished from atrioventricular
valve regurgitation lesions (MR or TR) because of its shorter
duration. Both MR and TR occur throughout the isovolumic
contraction and isovolumic relaxation phases, in addition to
the systolic ejection phase. Therefore, MR and TR start
earlier and last longer than aortic outflow. These differences
in signal onset and duration can be easily determined using
the simultaneous ECG and time calibration display.
IRREGULAR R HYTHMS
Flow velocities and gradients can vary tremendously beat to
beat with irregular rhythms as demonstrated in Figure 21.8.
With irregular rhythms, velocity and gradient determina-
tions should be based on an average of five to 10 different
samples. In sinus rhythm, measurement of ectopic beats or
postectopic beats should be excluded by recording three or
more regularly spaced sequential beats.
Pulsed Doppler
Techniques for determining flow and stroke volume within
the LVOT using pulsed Doppler are discussed in Chapter 5.
In a “best” apical view, the pulsed Doppler sample volume
is placed within the LVOT, very close to the aortic valve,
without placing it actually within the jet lesion. If the sample
volume is placed too far away from the aortic valve, the
pulsed Doppler signal will be erroneously small. A LVOT
pulsed Doppler velocity measurement (Fig. 21.7B) is neces-
sary for calculating the aortic valve area by the continuity
equation.
Valve Area by Continuity Equation33,34
As discussed in Chapter 5, stroke volume (SV) within a
conduit having laminar flow is the product of the cross-
sectional area (CSA) and the VTI of flow measured at a
defined site. The SV just proximal to the aortic valve (LVOT)
and the stroke volume within the AoV must be equal. Flow
within a normal (unobstructed) LVOT and flow within the
aortic stenosis vena contracta (immediately distal to the ana-
tomic orifice) is laminar. Therefore, the following set of
equations can be applied to derive the simplified continuity
equation:
SV = CSA × VTI
SV LVOT = SVAoV
CSA LVOT × VTILVOT = CSA AoV × VTI AoV
CSA AoV = CSA LVOT × (VTILVOT/VTI AoV)
The LVOT is assumed to be circular. The area of a circle =
πr 2. And π ≈ 3.14. Because radius (r) is one half of the
diameter (D), the more conveniently measured LVOT diam-
eter can be inserted directly into the formula with the fol-
lowing conversion:
498 chapter 21

LVOT area = πr 2 = π(D/2)2 = D 2 × 0.785

For aortic valve area, either of the following equations may
be used:
AoV Area = π(D/2)2 × (VTILVOT/VTI AoV)
simplified:
AoV Area = (D 2 × 0.785) × (VTILVOT/VTI AoV)
The ratio of LVOT and AoV velocity-time integrals (VTIs) and
the ratio of LVOT and AoV peak velocities should be equal
since the peak velocity at each site occurs simultaneously;
and the instantaneous velocity ratios should be the same at
any point during the ejection phase.
VTILVOT/VTI AoV = VLVOT/VAoV
Therefore, for clinical purposes, the continuity equation can
be further simplified by substituting the VTIs with the peak
velocity measurements:
AoV Area = (D 2 × 0.785) × (VLVOT/VAoV)
FIGURE 21.10. Severe calcific AS with “sigmoid septum” and dis-
See Figure 21.8 for an illustration of aortic valve area calcula- crete basal septal hypertrophy that markedly impinges on the mid-
tion using the continuity equation. LVOT diameter (D1 = 1.3 cm), which is much narrower than the
aortic annulus diameter (D2 = 1.9 cm). LVOT obstruction of this
degree may cause significantly accelerated blood flow within the
POTENTIAL PITFALL LVOT. This situation may cause a significantly overestimated AVA
by the continuity equation because the LVOT Doppler data (acceler-
In all cases, the LVOT diameter measurement is squared, so ated within the LVOT) is placed in the numerator (see equations in
that any significant LVOT diameter (D) measurement error Fig. 21.7).
will also be squared, producing a potentially unacceptable
error in the aortic valve area calculation. Therefore, accurate
LVOT imaging and diameter measurements are critical. The
LVOT diameter can be difficult to measure when excessive
aortic valve area less than one-fourth the reference LVOT
aortic root and annular calcification is present or if paraster-
area. The dimensionless velocity index can be a quick, useful
nal images are poor. The LVOT diameter and the aortic
method for identifying potentially significant obstruction in
annulus diameter are not always interchangeable (Figs. 21.7A
either high- or low-output states when the area calculation
and 21.10). The aortic annulus diameter is measured at the
by continuity equation is not possible or is in doubt (i.e., the
base or “hinge point” of the aortic valve leaflets (Fig. 21.3A).
LVOT diameter cannot be reliably measured). This index can
This annular measurement may be useful for prosthetic
be helpful in the assessment of possible prosthetic aortic
valve selection. Frequently, however, the LVOT, immediately
valve obstruction (Figs. 21.11 and 21.12).
proximal to the aortic annulus (site of pulsed Doppler sample
Calculations of aortic valve resistance 35 and left ventricu-
volume placement) is impinged by an angulated basal septum,
lar stroke work loss36 are other indices of AS severity that
making the LVOT diameter smaller than the aortic valve
may be useful but have not yet emerged as being clinically
annular diameter (Fig. 21.10). When the LVOT is very small
superior to the aortic valve area calculation.
or when there is turbulent or high-velocity LVOT flow proxi-
mal to the aortic annulus due to dynamic LVOT obstruction
Dobutamine Stress Echocardiography
(systolic anterior motion of the mitral valve), the aortic valve
area calculation by simplified continuity equation is not A patient with dilated cardiomyopathy, heart failure, and
reliable, and the aortic valve area by continuity equation will severe AS based on valve area calculation by the continuity
likely be overestimated (Fig. 21.10). equation but with a low-velocity aortic valve gradient (peak
velocity <4 m/s) can present a difficult clinical management
situation. In some such individuals, the cardiomyopathy may
Dimensionless Velocity Index (VLVOT : VAoV)
be secondary to severe AS, with possible benefit to be had
Velocity is proportional to flow across a fixed orifice. In the from aortic valve replacement surgery. Others, however, may
case of a completely normal aortic valve orifice, there should have a primary cardiomyopathy with only mild or moderate
be no significant difference between the peak LVOT velocity AS but reduced calculated valve area (and severely reduced
(VLVOT) by pulsed Doppler and the peak AoV velocity by CW visible cusp separation) due to low cardiac output. Patients in
Doppler (VAoV). Under normal conditions, therefore, the peak the latter group would not benefit from aortic valve replace-
velocities, VLVOT : VAoV, should be close to 1.0 regardless of flow ment surgery. Dobutamine stress echocardiography has been
rate. On the other hand, VLVOT : VAoV will be <1.0 in the pres- used to differentiate these two populations of heart failure
ence of aortic stenosis, because of increased flow velocity patients.37 If the aortic valve area calculation remains in the
across the aortic valve relative to that within the LVOT. severe range with a dobutamine-induced increase in stroke
Severe obstruction is likely if VLVOT : VAoV ≤0.25, indicating an volume, the cardiomyopathy may be secondary to severe AS.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 499

VAoV = 3.6 m/s

Grad pk = 51.8 mm Hg
DVI = 0.44

FIGURE 21.11. Dimensionless velo-

city index (DVI) method used to show
an acceptably increased biologic
aortic valve prosthesis gradient in the
setting of increased stroke volume.
(A) LVOT peak velocity, V LVOT =
1.6 m/s. (B) Aortic valve biologic pros-
thesis peak velocity VAoV = 3.6 m/s;
DVI = 1.6 m/s ÷ 3.6 m/s = 0.44—no
significant obstruction. A B

If ventricular contractile reserve is demonstrated, 38,39 valve
replacement surgery may be beneficial.
Useful Values for Clinical Management
Asymptomatic patients with isolated AS are managed medi-
cally and followed closely for signs of LV dysfunction or the
emergence of symptoms. Surgery is the only effective therapy
for symptomatic severe AS. With normal ventricular func-
tion and normal stroke volume, a peak aortic valve velocity
of >4 m/s (64 mm Hg) is a clinically important value, because
such patients likely have anatomically severe AS and are
likely to reach a surgical end point within 2 years.40 Such
patients should be monitored more frequently at this stage
for the development of symptoms, at which point surgery
would typically be indicated. For a given valve area, the
measured aortic valve gradient is strongly influenced by
heart rate, stroke volume, ejection duration, LV contractility,
preload, and afterload. Therefore, peak and mean velocity and
pressure gradient measurements in isolation are not helpful
for clinical management. With normal LV contractility and
heart rate, an aortic valve peak velocity ≤2.5 m/s almost
always indicates mild AS, and an area calculation may not
be necessary. When peak velocities are between 2.5–4.0 m/s,
the valve area by continuity equation or by planimetry
should be calculated with careful consideration given to the
quality of the obtained data. As a general rule, a mean aortic
valve gradient ≥50 mm Hg almost always indicates severe
aortic valve stenosis, and an area calculation may not be
necessary.

VAoV = 4.8 m/s

Grad pk = 92 mm Hg
DVI = 0.25 (obstructed)
FIGURE 21.12. Dimensionless velo-
city index (DVI) demonstrates an
obstructive gradient in a patient with
a mechanical aortic valve prosthesis.
(A) LVOT peak velocity, V LVOT = 1.1 m/
s. (B) Aortic valve mechanical pros-
thesis peak velocity VAoV = 4.8 m/s;
DVI = 1.1 m/s ÷ 4.8 m/s = 0.25—patho- VLVOT = 1.2 m/s
logic obstruction. Arrow indicates
mechanical prosthesis disk opening
and closure artifacts. A B
500 chapter
TABLE 21.1A. Severity of aortic stenosis (AS) by aortic valve
(AoV) area and valve area index
AS severity AoV area (cm 2) AoV index (cm 2/BSA)
None >2.0 >1.10
Mild 1.6–2.0 0.90–1.10
Mild-to-moderate 1.3–1.6 0.75–0.90
Moderate 1.0–1.3 0.6–0.75
Moderate-to-severe 0.7–1.0 0.4–0.60
Severe <0.70 <0.40
Note: Normal aortic valve area = 3.0–4.0.
BSA, body surface area.
Aortic Valve Area
Valve area remains the best clinical indicator of AS sever-
ity.35, 41 With a valve area of >1.0 cm2, symptoms are probably
not due to AS alone. At a valve area of approximately 1.0 cm2,
flow velocities (and gradients) increase significantly with
physiologic flow. Valve areas in the range of 0.8 to 1.0 cm2
represent a “gray zone” in which symptoms may indeed be
due to AS, yet other clinical factors (concomitant AR, MR,
coronary artery disease, patient body size, high output state,
etc.) should be considered. Typical symptoms are almost
always due to AS when the valve area is <0.8 cm2 (severe), in
which case surgery is indicated.42 An aortic valve area index
[valve area/body surface area (BSA)] may be of clinical utility
in dealing with large or small patients. Table 21.1A, from
the University of Chicago,43 and Table 21.1B, adapted from
American College of Cardiology (ACC)/American Heart
Association (AHA) practice guidelines,3 each show slightly
different grading systems. The ACC/AHA practice guide-
lines3 recommendations are less precise, and this may be
more applicable across different laboratories, given the
underlying margin for potential measurement error and
varying patient sizes.
Chronic Aortic Regurgitation
Two-Dimensional and M-Mode Exam and
Differential Diagnosis
The 2D exam is useful for determining the etiology of AR
to the extent that cusp size, number, coaptation characteris-
tics, and aortic root size can be evaluated. Native valve AR
may be secondary to abnormalities of the aortic leaflets, the
aortic root, or both. Understanding the mechanism for AR
FIGURE 21.13. Chronic severe aortic regurgitation (AR) due to
bicuspid aortic valve: various surface echocardiography images in
the same patient. (A) Reverse diastolic doming (prolapse) of the
aortic cusps (arrow). (B) Eccentric AR jet by color Doppler. (C) Left
(L) and right (R) cusp orientation with elliptical orifice (arrows). (D)
Pathologically large LVOT stroke volume as indicated by pulsed
Doppler, VTILVOT = 38.1 cm. (E) Pulsed Doppler, proximal descending
21
TABLE 21.1B. Aortic stenosis severity by valve area
AS severity AoV area (cm 2)
Mild 1.5
Moderate 1.0–1.5
Severe ≤1.0
can be useful for surgical planning.44 Disease may be acquired
or congenital. Any of the above-mentioned common causes
of aortic stenosis [calcific degeneration, bicuspid valve (Fig.
21.13), rheumatic (Fig. 21.14)] can also be associated with
either mixed disease or a predominant aortic regurgitation
lesion due to cusp prolapse, malcoaptation of the cusp
margins, or leaflet destruction from superimposed bacterial
endocarditis (Fig. 21.15). Chronic AR can be associated with
aortic root enlargement, particularly in the elderly, but also
in younger individuals with Marfan syndrome or annuloaor-
tic ectasia (Fig. 21.16) or in association with congenitally bi-
cuspid aortic valves. Congenitally bicuspid aortic valves may
exhibit obvious prolapse in the parasternal long axis view
(reverse diastolic doming), which may be obvious (Fig.
21.13A). Frequently, however, the degree of cusp prolapse is
subtle and involves one cusp, producing a highly eccentric
AR jet, the severity of which can be difficult to assess and
easily underestimated by color Doppler. Subtle congenital
prolapse of an otherwise normal trileaflet valve also occa-
sionally causes significant AR, as can focal fenestrations
along the leaflet margins (tattered flag appearance on sur-
gical inspection), which may be difficult to discern echo-
cardiographically. Associated valve conditions include
myxomatous degeneration, which can infrequently cause
marked prolapse and regurgitation of the otherwise normal
trileaflet aortic valve, although this condition is usually
found in association with the more commonly affected
mitral and tricuspid valves (see below). Characteristic 2D and
M-mode rheumatic mitral valve abnormalities (MS and MR)
strongly suggest a rheumatic etiology of associated AR.
Other congential abnormalities include unicuspid aortic
valves, which may have significant AR, AS, or both, as is the
case with bicuspid valves. Rare quadricuspid aortic valves are
more often regurgitant than stenotic and frequently become
“surgical” by the fourth or fifth decade. In congenital “fixed”
subaortic membrane or tunnel stenosis, the subvalvular jet
lesion can traumatize the aortic cusps, leading to aortic
insufficiency. Supracristal or subarterial ventricular septal
defects (adjacent to the aortic annulus) can cause severe AR
due to inadequate cusp support.
thoracic aorta, shows pan-diastolic flow reversal (downward arrows);
forward flow systolic flow (single arrow). (F) Simpson’s rule: severely
increased left ventricle end diastolic volume (LVEDV) = 244 mL. (G)
Severely increased LV end systolic volume (LVESV) = 155 mL. Cal-
culation: LVEF = (LVEDV − LVESV)/LVEDV = 36%, moderately
reduced LVEF (see Tables 21.2 and 21.3).
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 5 01

A B

VTI LVOT = 38 cm

C D

E F

G
502 chapter 21

A B

C D
FIGURE 21.14. Rheumatic AR. In this case the mechanism of AR of (A), thickened leaflet margins with central diastolic malcoapta-
could not be determined due to signal attenuation. TEE images in tion (A,B) and a visible central regurgitant orifice (C,D).
the same patient (B–D) demonstrate typical early rheumatic changes

Aortic Root Size Left Ventricular Size and Systolic

Aortic regurgitation is associated with the presence of aortic
root enlargement,45 particularly if there is expansion (efface-
ment) of the sinotubular junction (Fig. 21.16). The aortic root
is measured using the 2D image at the maximum sinus of
Valsalva diameter, perpendicular to the aortic long axis (Fig.
21.5A). Normal values for aortic root size, based on patient
age ranges, have been published [American Society of Echo-
cardiography (ASE) guidelines46,47]. An aortic root diameter
indexed for body surface area of >2.1 mm/m2 is highly spe-
cific for aortic root enlargement.46
M-Mode Measurements
M-mode measurements are pertinent for AR assessment
when used for LV diameter assessment. Diastolic fluttering
of the mitral valve’s anterior leaflet can be a sign of an eccen-
tric AR jet striking this leaflet (Fig. 21.17).
Function Assessment
Increased left ventricular dimensions are a hallmark of
chronic significant AR. Recognizing and following abnormal
LV remodeling by echocardiography is important for clinical
decision making. Parasternal long axis measurements of LV
end-diastolic and end-systolic diameters (LVEDD and
LVESD)47 can be highly reproducible and reflective of overall
LV size and contractility in the absence of concomitant
regional wall motion abnormalities from coronary artery
disease or other cardiomyopathies.
In the past, echocardiography-derived LV volume and
ejection fraction measurements have been thought to be dif-
ficult to reproduce, if not unreliable, because of variable
imaging quality and technique. Because echocardiography
technology has improved in recent years (improved 2D
imaging and use of left-sided contrast agents), quantitative
measures of LV size (volume and mass) and function (ejection
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 503

A B

C D

E F
FIGURE 21.15. TEE: acute, severe AR. This 24-year-old man with descending thoracic aorta shows sinusoidal appearance of forward
a bicuspid aortic valve had mild AR by echocardiography 10 months systolic flow (arrow) and pan-diastolic reverse flow (double arrow).
earlier. (A) Linear whip-like vegetation (arrow) attached to a prolaps- (E) Prominent diastolic mitral regurgitation (MR) by CW Doppler
ing cusp with early aortic root abscess formation (arrowhead); left (upward arrow), a sign of acute severe AR, associated with premature
atrium (LA); left ventricle (LV); aorta (Ao). (B) Severe AR completely mitral valve (MV) closure (downward arrow). (F) TEE gastric window:
fills the LVOT by color Doppler imaging. (C) In a different similar AR deceleration slope (line) by CW Doppler quickly reaches baseline
case, color M-mode helps to display the diastolic timing of the tur- [short pressure half-time (PHT), <200 ms] indicating almost equal
bulent AR jet during tachycardia (brackets). (D) Pulsed Doppler, aortic and ventricular diastolic pressure (severe acute AR).
504 chapter 21

TABLE 21.2. Left ventricular volume and volume index

Normal Mildly Moderately Severely
range dilated dilated dilated

A: Women
Diastolic
LVEDV (mL) 56–104 105–117 118–130 ≥131
Indexed
LVEDV/BSA (mL/m2) 35–75 76–86 87–96 ≥97
Systolic
LVEDV (mL) 19–49 50–59 60–69 ≥70
Indexed
LVEDV/BSA (mL/m2) 12–30 31–36 37–42 ≥43
B: Men
Diastolic
LVEDV (mL) 67–155 156–178 179–201 ≥201
Indexed
LVEDV/BSA (mL/m2) 35–75 76–86 87–96 ≥97
Systolic
LVEDV (mL) 22–58 59–70 71–82 ≥83
Indexed
LVEDV/BSA (mL/m2) 12–30 31–36 37–42 ≥43
Note: The LVEDV and LVESV indexes (mL/m 2) are the most validated
measures.
BSA, body surface area; LVEDV, left ventricular end diastolic volume; LVESV,
FIGURE 21.16. Severely dilated aortic root and ascending thoracic left ventricular end systolic volume (not shown).
aorta (dotted line). Complete effacement (obliteration) of the sinotu-
bular junction (solid line). Prominent proximal flow convergence
zone by color Doppler (arrowhead) and wide vena contracta >0.6 cm
(black arrow) indicate severe AR (see Table 21.4).

LV Ejection Fraction = (LVEDV − LVESV)/LVEDV

fraction) have become increasingly reliable. Accordingly, rec-
ommendations for cardiac chamber quantification by echo-
cardiography were recently updated.47 Although several
methods for LV volume assessment exist47 and are applicable
in varying situations, the biplane method of disks (modified
Simpson’s rule48) is recommended when apical foreshorten-
ing can be eliminated and the endocardial surfaces are
visible. The method uses summation of elliptical disk
volumes derived from the apical four- and two-chamber
views (Fig. 21.13F,G). When the LV cavity is relatively sym-
metrical and with uniform contractility, the method can also
be applied to a single plane if either one of the two views is
technically suboptimal.
Reference limits for LV volumes are shown in Table 21.2, and
reference limits for LV ejection fractions are shown in
Table 21.3.
Doppler Evaluation for Aortic Regurgitation
Severity Assessment
Continuous-Wave Doppler
In the presence of AR, CW Doppler interrogation of the
LVOT reveals a characteristic spectral Doppler velocity enve-
lope produced by diastolic decay of the pressure gradient
between the aortic root and aorta (Fig. 21.18). In some techni-

A B
FIGURE 21.17. (A) Eccentric AR jet, striking the mitral anterior leaflet. (B) M-mode of the mitral valve, same patient, shows anterior leaflet
diastolic fluttering from the jet impact (arrows). LA, left atrium; LV, left ventricle.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e
TABLE 21.3. Left ventricular function by left ventricular ejection
fraction (LVEF)
Normal Mildly Moderately Severely
range reduced reduced reduced
LVEF (%) >55 45–55 30–44 <30
No gender differences.
cally difficult exams, detection of the characteristic appear-
ance of AR by spectral Doppler may be the first or only clue
to its presence. When the signal is well aligned with the
interrogating beam, the density of the spectral Doppler signal
can be used as a rough qualitative indicator of severity. Mild
degrees of AR produce a faint signal, and moderate or severe
jets produce a dense signal. This is because signal density
correlates with the number of regurgitant red blood cells
within the path of the interrogating beam. In many cases,
the observer is unable to differentiate moderate from severe
AR using jet density. Nonetheless, a dense jet by CW war-
rants further investigation.
PRESSURE H ALF -T IME 49
The AR velocity by CW Doppler decays in a linear fashion
according to the rate of pressure equilibration between the
aortic root and left ventricle. The rate of pressure decay can
be described by a deceleration time (DT), which is the time
from initial peak velocity to zero velocity when the velocity
slope is extended to the baseline. Pressure half-time (PHT)
is the time for the AR velocity to decline to half of its origi-
nal peak value. Both the DT and PHT are automatically cal-
culated when the operator electronically defines the AR
velocity deceleration slope (Fig. 21.18). When AR is severe,
the aorta-to-LV pressure declines rapidly, producing a short
PHT (Figs. 21.15F and 21.18B). When AR is mild, or mild-to-
moderate (Fig. 21.18A), the PHT is long because the regurgi-
tant volume is not sufficient to significantly affect either the
aortic or ventricular diastolic pressures. A PHT <200 almost
always indicates severe AR, and a PHT of >500 almost always
indicates mild AR.7 The PHT for moderate AR usually lies
within a wide range (200–500 ms). Mild and severe AR can
also lie within this gray zone, depending on ventricular
loading conditions.
PHT = 561 ms
A B
FIGURE 21.18. Pressure half time (PHT) measurement in aortic
regurgitation. (A) Mild AR: mildly dense Doppler signal (relative to
background noise), long PHT = 561 ms. Early peaking mild AS signal
505
PHT T ECHNICAL NOTES AND PITFALLS
The PHT measurements are valid only when the CW inter-
rogating beam is coaxial to flow and a clear linear spectral
velocity envelope “edge” is present. Quality CW signals and
acceptable PHT measurements are simply not possible with
many eccentric or poorly aligned AR jets. The PHT can be
relatively long (significantly >200 ms) with compensated
chronic severe AR. This is because adaptive remodeling
allows the LV to accept a large regurgitant volume without
a significant rise in LV diastolic pressure. Another potential
pitfall is that for a given degree of AR, the PHT will appear
shortened in a patient with high LV filling pressures due to
an underlying cardiomyopathy. In this situation, the LV dia-
stolic pressure rises more rapidly for a given regurgitant
volume, quickly reducing the aorta-to-LV diastolic pressure
difference and shortening the PHT. Systemic vasodilator
therapy can also shorten the PHT by decreasing the aortic
pressure (low afterload).
Pulsed Doppler-Derived Regurgitant Volume and
Regurgitant Fraction50,51
Left ventricular outflow tract flow as measured by pulsed
Doppler is increased in AR. This is because LVOT flow
includes both the useful forward stroke volume and the
“wasted” regurgitant volume. When a very high LVOT VTI
measurement is encountered (e.g., LVOT VTI >30 cm), severe
AR should be suspected (see Fig. 21.13D). The regurgitant
volume (RV) can be obtained by subtracting a reference
forward stroke volume (SV from mitral annulus or RV outflow
tract) when there is no important concomitant reference
valve regurgitation.52
RVAR = SV LVOT − SVref valve
Details for calculating LVOT, mitral annulus, and RVOT
stroke volume are found in Chapter 5. The regurgitant frac-
tion (RF) is the regurgitant volume divided by the total LVOT
stroke volume ×100.
RF = RV/SV LVOT × 100
PHT = 273 ms
ms
(2.8 m/s, vertical red line). (B) Moderate-to-severe AR with relatively
dense CW signal and short PHT = 273 ms. Deceleration slope (slanted
red line). Automatically derived PHT (horizontal green lines).
506 chapter
TABLE 21.4. Grading aortic regurgitation: quantitative
parameters
Parameter Mild Severe
Vena contracta (cm) <0.03 ≥0.6
Jet height/LVOT (%) <25 ≥65
Pressure half-time (ms) >500 <200
Regurgitant volume (mL) 30 ≥60
Regurgitant fraction (%) <30 ≥50
Regurgitant orifice area (cm2) <0.1 >0.3
LVOT, left ventricular outflow tract.
The regurgitant fraction is a useful parameter when the total
stroke volume is reduced because of cardiomyopathy. Refer-
ence values appear in Table 21.4. As an additional check (in
the absence of significant MR), the total LV stroke volume
can also be calculated using the modified Simpson’s rule.51
This type of quantitative analysis can be time-consuming,
but it is useful in selected cases.
EFFECTIVE R EGURGITANT ORIFICE A REA (EROA) USING
SPECTRAL DOPPLER
After calculating the aortic regurgitant volume (see above),
the EROA (a useful severity indicator) (Table 21.4) can then
be calculated. Forward systolic stroke volumes or diastolic
RV is the product of the cross-sectional area of the flow
(EROA) and the VTI measured at the same site (by CW
Doppler of the AR jet in this case).
RVAR = EROA × VTI AR
EROA = RVAR/VTI AR
This method for EROA calculation is reliable only in regular
rhythm and when there is a clear, well-aligned CW Doppler
signal.
Aortic Diastolic Flow Reversal by
Pulsed Doppler53–55
As discussed in Chapter 5, the routine pulsed Doppler exam
includes interrogation of the proximal descending thoracic
aorta from the sternal notch window. In normal individuals
(no AR), a normal low-velocity (<40 cm/s) early diastolic flow
can be seen. In chronic, compensated severe AR, the early
diastolic flow velocity peak is higher (usually >40 cm/s), and
flow reversal becomes pan-diastolic (Fig. 21.13G). Unfortu-
nately, the sternal notch window is not available in all sub-
jects. Pan-diastolic flow reversal in the abdominal aorta, if
present, is a more specific sign of severe AR. Pan-diastolic
flow reversal is often more evident in acute severe AR (below),
but it may be less evident in patients with poor aortic
compliance.
Aortic Regurgitation Severity by Color Doppler
Jet Size
Trace and mild AR are frequently detected by color Doppler
in many otherwise normal, older individuals.56 Careful
imaging of the entire proximal jet lesion by color Doppler,
along with a corroborating CW Doppler signal typical of
21
FIGURE 21.19. TEE: rheumatic central AR jet by color Doppler.
Anatomic orifice (+); vena contractor width (A) = 0.36 cm; jet height
(B) approximately 50% of LVOT diameter. AR is moderate by these
criteria (see Table 21.4).
mild AR, may be all that is required to make the diagnosis
in many such cases. As previously mentioned, there are
many potential pitfalls for using color Doppler jet size as an
indicator for regurgitation severity. With good imaging prac-
tices, however, a very small AR jet by color Doppler likely
represents mild AR, and a very large AR jet likely represents
severe AR (Table 21.4). For jets that are neither clearly small
nor clearly large, further evaluation is needed. When assess-
ing color Doppler jet size, length and area measurements
within the left ventricle can be misleading and unreliable
indicators of severity. The height of jet within the LVOT, just
below the aortic cusps18 and the more proximal vena con-
tracta (VC) size57 (Fig. 21.19), can be a useful and readily
measurable parameter (Table 21.4). The AR vena contracta
and LVOT jet dimensions should not be based on one “freeze
frame” but on the best assessment of the sustained jet during
the diastolic period using a zoomed parasternal long axis
image and a small color sector for high sample rate and
improved color Doppler spatial resolution. Central jets are
easier to measure (Fig. 21.19). Eccentric AR jets can be diffi-
cult to measure. The area of the AR jet in short axis view at
or slightly below the cusp coaptation zone can be very useful
for assessing the 3D characteristics of the jet origin and the
AR mechanism (e.g., central cusp malcoaptation, valve cusp
perforation, valve extension along a cusp commissural zone,
valve prolapse). Cross-sectional area measurements can be
challenging to interpret in rapidly expanding or eccentric
jets and because of aortic root motion through the imaging
plane. Cross-sectional area as a percentage of aortic root size
may be difficult to interpret if the aortic root size is
abnormal.
Proximal Isovelocity Surface Area for
Effective Regurgitant Orifice Area and
Regurgitant Volume58
When a sizable proximal flow convergence zone is visualized
(Figs. 21.16 and 21.20), severe AR should be suspected, and
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e
A B
FIGURE 21.20. (A) Rheumatic MS. Modified parasternal long axis
view showing diastolic “doming” of the mitral leaflets; anterior
mitral leaflet “hockey-stick” deformity (arrow); thickened, fused
this finding alone should prompt a more careful and detailed
overall assessment using the other methods discussed.
Although often technically challenging, because of calcific
shadowing within the aortic root or eccentric jet, calculating
the EROA and RV using PISA has been validated, using the
formulas presented in the introductory part of this chapter.
EROA AR = 6.28r 2 × Va/VpkAR
RVAR = EROA × VTI AR
In summary, assessment of the severity of chronic aortic
regurgitation can be one of the most challenging tasks for
the echocardiographer. The final diagnosis may be the result
of an integrated analysis of several supportive parameters
without reliance upon only one or two severity indicators.
When there are indirect signs of possible severe AR, but the
aortic leaflets or the proximal jet cannot be clearly visualized
by TTE, adjunctive TEE can play a valuable role (Figs. 21.14,
21.15, and 21.19). TEE, cardiac catheterization with aortic
root injection, and, increasingly, cardiac magnetic resonance
imaging (MRI) can be particularly useful in selected cases.
Acute Severe Aortic Regurgitation
Acute severe aortic regurgitation can be due to aortic valve
endocarditis (Fig. 21.15), acute aortic dissection with propaga-
tion into an aortic cusp, an aortic cusp tear from a decelera-
tion injury (uncommon), or partial sewing ring dehiscence
or leaflet malfunction in a prosthetic aortic valve. Patients
with true acute severe AR represent surgical emergencies
and usually present with a relatively narrow pulse pressure
and cardiogenic shock (pulmonary edema, tachycardia, low-
output state). In hemodynamically unstable or intubated
patients, surface echocardiography is frequently suboptimal
for a variety of reasons, including tachycardia and signal
attenuation. In the presence of cardiogenic shock, a TEE
should be performed as soon as possible after endotracheal
intubation and establishment of mechanical ventilation.
Transesophageal echocardiography is used to firmly estab-
lish the diagnosis, rule out important associated valve disease
507
chordae tendineae, thickened leaflet margins, dilated left atrium
(LA). (B) M-mode of the mitral valve shows anterior diastolic motion
of the retracted posterior leaflet (arrows).
(particularly with endocarditis), determine ventricular con-
tractility, and assist with surgical planning. Patients with
baseline poor LV compliance from severe AS or LV hypertro-
phy or other causes will demonstrate signs of hemodynamic
collapse more quickly for a given acute AR volume load. This
is because of a steeper LVEDV pressure-volume relationship
curve.
Two-Dimensional and M-Mode Signs
The aortic cusps and aortic root should be imaged first in
long axis, short axis, and in oblique imaging planes for signs
of vegetation, leaflet perforation or prolapse, aortic root
abscess, aortic root dissection, prosthetic valve rocking
motion, thrombosis, or prosthetic valve biologic cusp or
mechanical disk opening or closure abnormalities in a
pathology-directed exam. Expedient, systematic evaluation
of the other valves should then be performed. In acute severe
AI, the thoracic aorta may exhibit exaggerated pulsatility,
though this clue may not be present in older patients with
stiffer aortas. Evaluation of LV size and function and the
pericardium is important. In aortic root dissection, pericar-
dial effusion or myocardial ischemia may also be present if
dissection involves a coronary ostium (more commonly the
right). The LV size may not be dilated as in chronic AR. Left
ventricle contractility may be hyperdynamic from a hyper-
adrenergic state and increased preload, unless there is also a
complicating preexisting cardiomyopathy.
Diastolic (premature) closure of the mitral valve is a sign
of steep increase in the left ventricular end diastolic pressure
that exceeds the left atrial pressure.59 Occasionally, end dia-
stolic (premature) opening of the aortic leaflets can be dem-
onstrated by M-mode due to aortic and left ventricular
pressure equalization.59 As with chronic AR, the mitral valve
M-mode image may show reduced valve opening and high-
frequency diastolic fluttering of the mitral anterior leaflet
from eccentric AR impact. Because of a fast sample rate,
color M-mode may be particularly useful in acute severe AR
with tachycardia (Fig. 21.15C), in which case routine color
Doppler of the LVOT (slower sample rate) may appear confus-
ing because of turbulent, high-volume systolic and diastolic
508 chapter
flow. Color M-mode can quickly confirm the diastolic timing
of the AR lesion and show an approximate jet height just
below the aortic valve.
Doppler Signs
With severe AR, color Doppler may almost fill the LVOT (Fig.
21.15B). The color Doppler flow convergence zone and the
associated vena contracta should be displayed simultane-
ously, if possible, and correlated with leaflet abnormalities.
The aortic valve PHT by CW Doppler obtained in a gastric
view is short because of rapid aorta-to-left ventricular dias-
tolic pressure equalization (Fig. 21.15D). Diastolic MR, in the
absence of prolonged PR interval, is another supportive sign
of acute severe AR, and it can be demonstrated by CW
Doppler60 (Fig. 21.15E). Pan-diastolic flow reversal in the
descending thoracic aorta is usually readily apparent by
either surface echo or TEE (Fig. 21.15F).
Quantitative Measures
All of the above-mentioned semiquantitative methods can
confirm the diagnosis of acute severe AR, particularly when
the anatomic regurgitant orifice is clearly visualized and the
mechanism has been discerned. Calculations of the aortic
regurgitant volume and regurgitant fraction are often not
feasible or necessary for the diagnosis of acute severe AR.
Acute AR Superimposed on Chronic
Aortic Regurgitation
On some occasions, patients present with many of the fea-
tures of acute severe AR (tachycardia, dyspnea, fever), though
cardiogenic shock is not present on initial evaluation. In
such cases, acute severe AR may have complicated underly-
ing chronic AR (likely moderate) for which some degree of
underlying physiologic adaptation and ventricular remodel-
ing had previously occurred. A relatively wide pulse pressure
may be present with some degree of LV dilatation. Preexist-
ing valve abnormalities may be linked to the mechanism of
acute severe AR (e.g., bicuspid aortic valve as a nidus for
endocarditis or acute aortic dissection complicating a previ-
ously dilated aortic root with some degree of baseline AR).
A B
FIGURE 21.21. (A) Parasternal short axis view, same patient as in Fig. 21.20), with commissural fusion and “fish-mouth” deformity of the
mitral orifice. (B) Planimetry, “zoomed” mode with planimetry of the mitral orifice (1.2 cm2 = moderate MS, see Table 21.6).
21
Mitral Valve Disease
Mitral Stenosis
Two-Dimensional and M-Mode Examination and
Differential Diagnosis
Mitral valve stenosis can be acquired or congenital. In adult
echocardiography laboratories, the most common causes of
acquired mitral stenosis (MS) are rheumatic and degenerative
calcification of the native mitral valve. Mechanical pros-
thetic mitral valves can become obstructed (stenotic) because
of thrombus or pannus formation. A biologic mitral prosthe-
sis can undergo calcific degeneration with stenosis due to
reduced cusp mobility. Echocardiographic findings of MS
from right atrial tumor and congenital MS are discussed in
other chapters.
R HEUMATIC M ITRAL STENOSIS
Stenosis is usually the predominant hemodynamic lesion in
rheumatic mitral valve disease. However, varying degrees of
mitral regurgitation are frequently present, with MR some-
times being the predominant lesion. Even in the early disease
stage, when stenosis may be mild, several echocardiographic
features of rheumatic mitral valve disease are usually
present.
Rheumatic Leaflet Deformity. Classic rheumatic
changes include leaflet thickening that is more prominent in
the leaflet leading edges with relatively preserved mobility
of the leaflet bases. Relatively preserved basal leaflet mobil-
ity and a reduced orifice area produce a characteristic dia-
stolic “doming” appearance of the valve and a diastolic
“hockey-stick deformity” of the anterior mitral leaflet in the
parasternal long axis view (Fig. 21.20A). Leaflet leading-edge
inflammation causes commissural fusion, which is the
primary mechanism for stenosis. Commissural fusion and
thickened leaflet margins produce an ovoid or circular “fish-
mouth” orifice, appreciated in the parasternal short axis
view (Fig. 21.21). Degenerative calcification can occur within
the leaflets. In advanced disease, the entire leaflet can even-
tually become severely thickened and calcified with little
apparent residual mobility.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 509

Submitral Apparatus. Rheumatic inflammation extends TABLE 21.5. Percutaneous balloon mitral valvuloplasty score
into the chordae tendineae and often into the papillary Mobility
muscles. A variable degree of chordal thickening, fusion, and Grade 1 Highly mobile valve; restricted leaflet tips only
shortening occurs. This deformity can be mild, moderate, or Grade 2 Normal mobility; basal and mid-leaflet portions
Grade 3 Mobility limited to the leaflet base
so extreme that the primary region of stenosis is actually
Grade 4 Relatively immobile leaflets throughout
within the fused chords and not at the leaflet level. Chordal
Leaflet thickening
shortening in advanced disease can be so extreme that dis- Grade 1 Leaflets near normal (4–5 mm)
crete chords cannot be differentiated from the brightly echoic Grade 2 Mid-leaflets normal; marked thickening of margins
papillary muscles that seemingly fuse directly into the leaf- (5–8 mm)
lets. Even in mild disease, posterior leaflet tethering and Grade 3 Thickening throughout leaflets (5–8 mm)
Grade 4 Marked thickening throughout the leaflets
immobility relative to the anterior leaflet is a specific feature
(>8–10 mm)
of rheumatic mitral valve disease. On M-mode examination,
Subvalvular thickening
there is a characteristic and highly specific posterior leaflet Grade 1 Minimal thickening just below the leaflets
“anterior diastolic motion” (Fig. 21.20B) because the tethered Grade 2 Thickening up to one third of the chordal length
posterior leaflet must “track” the anterior leaflet instead of Grade 3 Thickening extending to the distal one third of the
exhibiting normal diastolic leaflet separation (see Chapter chords
Grade 4 Extensive thickening and shortening of the papillary
5).
muscles
Rheumatic Left Atrium. The left atrium is often Calcification
severely dilated in rheumatic MS. Swirling left atrial spon- Grade 1 Single area of increased echo brightness
Grade 2 Scattered areas of brightness confined to leaflet
taneous echocardiography contrast (“smoke”) and left atrial margins
or left atrial appendage thrombus are common in rheumatic Grade 3 Brightness extending into the midportion of the
MS. Left atrial thrombus is usually apparent only by TEE. leaflets
In some cases, calcification of the left atrial wall, probably Grade 4 Extensive brightness throughout much of the leaflet
related to pancarditis, results in even suboptimal TEE images tissue
in rheumatic heart disease. Based on surface echocardiography examination.

Percutaneous Balloon Mitral Valvuloplasty Assess-

ment by Echocardiography.61– 63 In properly selected symp-
tomatic rheumatic MS patients, a durable result, comparable
to surgical mitral commissurotomy, can be achieved with
percutaneous balloon mitral valvuloplasty (PBMV). Morpho-
logic features, as evaluated by surface echocardiography, have
been divided into four categories and rated on a scale of 1 to 4
for each feature (Table 21.5).61 It has been shown that the best
PBMV results are achieved in young patients having a com-
bined mitral stenosis or ≤8, mild-to-moderate MR, and no
previous surgery. Other patients with less favorable valve
anatomy (score >8) may also benefit from the procedure, but
they may be more likely to have significant residual gradients
or mitral regurgitation. The palliative mechanism of PBMV
is separation of the fused mitral commissures. Focal commis-
sural calcification (not included in the above-mentioned
scoring scheme) may also reduce the success rate and predis-
pose to MR development. Its presence is usually discernible
on the mitral valve (MV) short axis view.62 Percutaneous
balloon mitral valvuloplasty carries a risk of stroke. A TEE is
performed in advance of PBMV to ensure that LA or left atrial
appendage (LAA) thrombus is not present. At some centers,
TEE is used to guide the procedure.
M ITRAL A NNULAR CALCIFICATION
This degenerative change is very commonly seen in the
elderly and in chronic renal failure or hemodialysis patients
and possibly in association with coronary artery disease
(Figs. 21.3D and 21.22). Some degree of associated MR is also

A B
FIGURE 21.22. Severe mitral annular calcification. (A) Apical bulky annular calcification. The thin chords and “straight” anterior
three-chamber view, TTE, severe annular calcification, involving MV leaflet in diastole (no doming) distinguish this from rheumatic
the leaflet bases (arrow) with associated calcific AS (arrowhead). (B) MV disease. RV, right ventricle.
Apical four-chamber view, same patient shows circumferential
510
TABLE 21.6. Mitral stenosis by valve area (cm2)
Very mild
Mild
Moderate
Severe
* Clinically severe MS can occur in this range because of variability of patient
size, heart rate, and stroke volume at rest and with exercise.
common. Mitral annular calcification (MAC) is usually dif-
ferentiated from rheumatic mitral disease by echocardiogra-
phy because leaflet thickening, calcification, and immobility
begin in the leaflet bases (Fig. 21.22), with relatively pre-
served mobility in the leaflet leading edges. With severe
posterior annular calcification, the posterior leaflet can
appear almost completely obscured on surface echocardiog-
raphy. Relatively thin chordae tendineae, absence of mitral
leaflet diastolic doming, or hockey-stick deformity (Fig.
21.22) can help to distinguish mitral calcific degeneration
from rheumatic disease. Even in relatively advanced MAC,
the hemodynamic severity of the associated mitral stenosis
generally remains in the mild or mild-to-moderate range.
Severe MAC-related mitral stenosis requiring surgery does
occur, in which case the risk for periprosthetic MR is
increased. Because commissural fusion is not the mecha-
nism for stenosis in MAC, percutaneous balloon valvulo-
plasty is not a palliative option.
Echocardiographic Parameters for Mitral
Stenosis Severity
VALVE A REA BY PLANIMETRY IN R HEUMATIC M ITRAL
STENOSIS 64 (Fig. 21.21 and Table 21.6)
With good technique and adequate imaging windows (para-
sternal short axis view), direct mitral orifice planimetry can
be the most accurate method for rheumatic mitral valve area
assessment.65 Using fine adjustment of the imaging plane,
the sonographer should make a concerted effort to image the
smallest, most distal anatomic orifice. Because the rheu-
matic valve can be somewhat funnel shaped, cutting through
the body of the leaflets and not the leaflet margins is a
A B
FIGURE 21.23. Mitral stenosis assessment by CW Doppler, atrial
fibrillation. Mean gradient varies (A), consistent PHT. Despite dif-
ferent RR intervals (B), the PHT measurement (green line) is the
chapter 21
common mistake that produces an erroneously large valve
>2.0 area. Ideally, three reproducible measurements are obtained.
>1.5–2.0 Newer 3D echocardiography techniques may be used to
facilitate anatomic orifice location and planimetry.66–68 It
>1.0–1.5*
should be noted that the planimetered MV area (anatomic
≤1.0
orifice) may be slightly larger than the Doppler-derived
mitral valve area (MVA) in the same patient since the latter
is a measure of the physiologic orifice (site of vena
contracta).
PITFALLS
Planimetry, even by 3D imaging, may not be possible when
there is shadowing artifact from severe calcification or image
dropout from poor imaging windows. In some cases, the
smallest apparent valve orifice area is disproportionately
large relative to the transvalvular gradient by Doppler. This
may be due to stenosis that occurs primarily in the submitral
region because of chordal fusion. In such cases, other methods
(below) must be applied. Note: Mitral valve sizes that cause
clinical symptoms (rest or exercise pulmonary congestion)
can vary markedly among patients depending on body size,
cardiac output, and heart rate.69
Doppler Evaluation
CONTINUOUS-WAVE DOPPLER: PEAK AND
M EAN GRADIENTS
Transmitral inflow velocity is measured from apical
views using CW Doppler. Color Doppler guidance can help
determine the best beam alignment for “directed” jets.
Mitral stenosis is suspected by visual inspection of
the spectral Doppler signal whenever the velocity remains
substantially above the baseline throughout diastole,
because at normal heart rates, the transmitral pressure gra-
dient normally becomes zero, or very close to zero during
mid-diastole. The valve peak and mean velocities and
gradients are automatically derived by tracing the spectral
signal’s outer edge (Fig. 21.23A). Table 21.7 shows
mean resting gradients that typically accompany mild-,
moderate-, and severe-range MS. The mean MV gradient is
strongly influenced by heart rate. Tachycardia shortens the
diastolic time available for transmitral pressure gradient
PHT = .29 (DT)
DT = 760 ms
PHT = 220 ms
MVA = 220÷PHT =1.0 cm2
same in both cycles. See image for mitral valve area (MVA) calcula-
tion by PHT method.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e
TABLE 21.7. Mitral stenosis by mean gradient (mm Hg)
Mild
Moderate
Severe
Note: Rough guidelines for “resting” Doppler assessment of MS. Gradients
are strongly affected by heart rate and cardiac output.
resolution. Mean gradients that may appear consistent with
mild-to-moderate or moderate MS at rest can quickly
increase into the severe range with increased heart rate (e.
g., exercise, tachycardia). The mean gradient can vary mark-
edly beat-to-beat in irregular rhythms (Fig. 21.23A). Accord-
ingly, Table 21.7 is only a rough guide that may be applied
to patients with normal-range heart rates and stroke
volumes. In irregular rhythm (atrial fibrillation) five to 10
cycles should be averaged for gradient assessment. The peak
gradient may be increased from high LV filling pressures
not related to MS or from concomitant MR.
M ITRAL VALVE A REA BY PRESSURE H ALF -T IME M ETHOD 70
During diastole, there is a relatively linear decay of the LA-
to-LV pressure gradient that is inversely proportional to the
MV area. The time from MV peak velocity to zero velocity
(extending the straight spectral Doppler velocity slope to
baseline) is known as the deceleration time (DT). The DT
can be visually estimated using the spectral Doppler image
time scale. Mitral stenosis is also described by the PHT—
time from initial peak pressure difference to half or the peak
pressure difference. The PHT cannot be determined by visual
inspection of the Doppler signal, but it is automatically cal-
culated by echocardiography systems when the linear decel-
eration slope is electronically defined (Fig. 21.23B). One of
the earliest and most clinically useful applications for the
Doppler exam was validation of the following empirically
derived formula:
MVA = 220/PHT
Because PHT = (0.29) DT, MVA is also easily calculated using
the DT. The advantages are as follows: The mitral inflow DT
(and PHT) by CW Doppler is easily obtained in many cases.
Because the PHT is relatively independent of flow, this
method is useful in patients with atrial fibrillation (Fig.
21.23B) or concomitant MR.70,71 The pitfalls are as follows:
With rapid heart rate (atrial fibrillation) or a large terminal
A-wave, the deceleration slope may be too short to accurately
define (Fig. 21.24C). The PHT method should be used with
caution or not at all in patients with potentially significant
left ventricular diastolic pressure elevation (e.g., advanced
cardiomyopathy or significant concomitant AR72). In such
cases, progressive pressure rise in the receiving chamber
hastens the decay of the LA-LV pressure gradient, and the
calculated MV area will be erroneously large. The PHT may
appear long secondary to impaired LV relaxation (LV dia-
stolic dysfunction) in the absence of significant MS. In addi-
tion, the PHT method is not valid in the first day or two after
percutaneous balloon valvuloplasty.73
VALVE A REA BY CONTINUITY EQUATION 74
See aortic stenosis (above) for derivation of the continuity
equation, which can also be applied to the mitral valve for
area calculation (MVA). Stroke volume is the product of CSA
511
and VTI. Flow across the mitral valve must equal flow across
<5 a reference valve or conduit, such as the LVOT:
5–10 CSA MV × VTI MV = CSA LVOT × VTILVOT
>10
MVA = (D 2 × 0.785) × (VTILVOT/VTI MV)
VTI MV is derived by electronically outlining the mitral dia-
stolic CW spectral Doppler signal. All variables for the
continuity equation are obtained during a standard Doppler
examination. Therefore, the method is easily applied. Refer-
ence flow in the right ventricular outflow tract (RVOT) can
also be used provided that the RVOT diameter can be accu-
rately measured. The continuity equation method is useful
when there is chordal level stenosis, when valve planimetry
is not possible, or if the PHT measurement is in doubt. The
pitfalls of this method are as follows: It cannot be used when
there is also significant MR because this will increase VTI MV
relative to the reference valve VTI, resulting in an errone-
ously small MV area calculation. The method cannot be
used with significant reference valve regurgitation [i.e., AR
or pulmonary regurgitation (PR)] because the increased
VTI ref. relative to VTI MV will result in an erroneously large
MVA calculation. The method may be unreliable in irregu-
lar rhythms because the stoke volume will vary markedly
from beat to beat, and simultaneous mitral and reference
valve flows cannot be compared. Averaging multiple
cycles (5 to 10) can be attempted or selecting cycles with a
similar R-R interval, although this is somewhat more
time-consuming.
PROXIMAL ISOVELOCITY SURFACE A REA M ETHOD 75,76
A prominent PFC zone is often apparent on the atrial surface
of the valve, particularly by TEE. The PISA formula for deriv-
ing valvular EROA was explained in the introduction (see
above). The same formula can be used to calculate the MVA
in MS using forward flow. Because the rheumatic MV inflow
surface is frequently funnel-shaped and not flat, the PISA
may not be hemispheric. Therefore, a correction factor
(α/180) must be applied. Alpha (α) is the angle formed by
lines running roughly parallel to the distal valve leaflets
(Fig. 21.25).
MVA = (α/180)6.28r 2 × Va/Vpk
The MV area by PISA is useful when other methods fail, and
it is a reasonably accurate method in atrial fibrillation. The
pitfalls of this method are as follows: The PFC zone may be
difficult to visualize by surface echo. In addition, an “α
measurement” tool is not provided on most analysis systems,
though a reasonable estimate can sometimes be made by
visual inspection.
T RICUSPID R EGURGITATION VELOCITY
Pulmonary hypertension either at rest (in the absence of
other causes) or during exercise (Fig. 21.24E), is a hallmark
of clinically significant MS. An estimate of the systolic pul-
monary artery pressure (SPAP) using the TR velocity by CW
Doppler (see Chapter 5) is an important element of the
exam.
E XERCISE DOPPLER ECHOCARDIOGRAPHY 77,78
Exertional dyspnea, the cardinal clinical symptom of MS,
can also be caused by a number of conditions not related to
512 chapter
REST
HR = 54
Grad Mn = 6.1 mm Hg
A B
SPAP = 50 mm Hg
HR = 54
Rest
VTR = 3.5 m/s
SPAP = 90 mm Hg
HR = 90
25 Watts Bike
E
FIGURE 21.24. Bicycle stress echocardiography in a large male
with chronic obstructive pulmonary disease (COPD) and NY Heart
Assoc. Functional Cass III (NYHAFC III) exertional dyspnea. At rest
(A–C) moderate mitral stenosis by valve area from PHT method and
mean gradient (see Tables 21.6 and 21.7). Moderate pulmonary
MS (e.g., primary pulmonary disease). A diagnostic dilemma
arises when a patient with exertional dyspnea is also found
to have MS with only mild-to-moderate range resting MV
gradients or valve area. As in the cardiac catheterization
laboratory, repeat hemodynamic measurements during exer-
cise may clarify the situation. With modest exercise (staged
supine bicycle protocol or immediately post treadmill), the
mean mitral valve gradient and systolic pulmonary artery
pressure will both increase markedly in clinically signifi-
21
Rest
HR = 54
MVA PHT = 1.2 cm2
Grad. MEAN = 15.5 mm Hg
HR = 90
25 Watts Bike
hypertension at rest, possibly from severe COPD. At low workload
(25 W, bicycle ergometry; D,E), increased mean MV gradient =
15.5 mm Hg and peak systolic positive airway pressure (PAP) =
90 mm Hg (HR = 90 bpm), suggesting clinically severe MS. (NYHAFC
I following percutaneous mitral balloon valvuloplasty.)
cant MS (Fig. 21.24), although the valve area calculation
should remain constant. Dobutamine echocardiography in
rheumatic MS has also been described.79
Conclusion
The MV area should be confirmed using two or three methods,
given the number of potential pitfalls of each. The valve area
may be mild by planimetry when there is severe chordal level
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 513

Va = 28 cm/s
r = 1.0 cm

A B

Vpk ~
– 200 cm/s
PHT = 266 ms

C
FIGURE 21.25. TEE images illustrate agreement of MVA calcula- 6.28 r 2 × Va/Vpk = 0.8 cm2 (rounded). MVA PHT = 220 ÷ PHT = 0.8 cm2
tion using the proximal isovelocity surface area (PISA) method and (rounded). See images for variables.
PHT method in a patient with atrial fibrillation. MVA PISA = (α/180)

stenosis. The mean MV gradient may be low in severe MS
with low cardiac output or bradycardia. The mean MV gradi-
ent may be high in mild MS with high cardiac output or with
tachycardia. A shortened PHT is possible with severe MS
with concomitant significant AR or cardiomyopathy. In mild
MS, the PHT may appear long if there is impaired LV relax-
ation. The planimetry, PHT, and PISA methods are relatively
reliable in atrial fibrillation. The PHT method should not be
used early after mitral balloon valvuloplasty. When reporting
gradients and when using the continuity equation in atrial
fibrillation, measurements from five to 10 cycles should be
averaged. In problematic cases, an exercise Doppler examina-
tion may be helpful.
Mitral Regurgitation
Detection of mitral regurgitation (MR) by Doppler is rela-
tively easy. However, accurate grading of MR severity can be
technically challenging.80 As previously mentioned, no one
method is sensitive and specific in all cases. This section
reviews the 2D and Doppler supportive signs and semiquan-
titative and quantitative methods for diagnosing the degree
of MR. When several of these findings are in agreement
regarding lesion severity, an accurate integrated diagnosis is
possible in most situations.7 Laboratories should ideally
apply as many methods as possible in each case, both for
confirmation and to maintain the skills needed for difficult
cases.
Two-Dimensional and M-Mode Examination and
Differential Diagnosis
The asymmetrical atrioventricular valves (mitral and tricus-
pid) are structurally and functionally more complex than the
arterial valves (aortic and pulmonic). Normal mitral valve
function depends on both normal structure and function of
each component of the so-called mitral apparatus. The mitral
apparatus consists of the mitral annulus and left atrium, the
leaflets, chordae tendineae, the papillary muscles, and the
left ventricle. Structural abnormalities of any component,
visible by 2D or M-mode evaluation, raises the possibility for
valve malfunction and provide clues as to etiology.
L EFT VENTRICULAR AND L EFT ATRIAL SIZE
A dilated left ventricle or left atrium47 should always heighten
the suspicion for the presence of significant MR, because
this condition imposes a volume load on both chambers.
In patients with known moderate-to-severe or severe MR,
514 chapter 21

measurement of LV size and function are important for sur-
gical timing. In chronic, compensated MR, without cardio-
myopathy, the left ventricular end systolic volume should be
normal and the left ventricular ejection fraction should be
≥60% due to low afterload. Left atrial enlargement accom-
panies chronic MR. In acute severe MR, the LA may be
normal in size. Many comorbid conditions can also enlarge
the left ventricle (e.g., cardiomyopathy, AR) or the left atrium
(e.g., LV diastolic dysfunction, atrial fibrillation, etc.). See
Tables 21.3 to 21.5 for left ventricular size and function by
echocardiography.
M ITRAL VALVE PROLAPSE AND
MYXOMATOUS DEGENERATION
The mitral leaflet systolic coaptation zone normally lies on
the ventricular side of an imaginary mitral annular plane, as
visualized in the parasternal long axis view or apical three-
chamber view. The mitral leaflets are said to “prolapse”
when leaflet closure is followed by a late systolic excursion
of one or both of the mitral leaflets beyond this imaginary
plane, into the left atrial space (Fig. 21.26). The mitral annulus
is not planar but “saddle-shaped.” Orientation of the valve in
the four-chamber view can sometimes give the appearance
of mitral valve prolapse (MVP) when there is none. Therefore,
the four-chamber view is not used for diagnosing MVP.
Mitral valve prolapse can be functional and transient because
of hypovolemia and a hyperdynamic state (reduced LV and
mitral annular size leading to leaflet redundancy) or myxo-
matous mitral valve degeneration. Mitral valve prolapse can
be provoked or accentuated by performing a Valsalva maneu-
ver during imaging. In myxomatous MV disease, prolapse
usually results from combined leaflet redundancy and
chordal elongation (Fig. 21.27). The degree of leaflet thicken-
ing can vary markedly among affected patients. Mitral
annular dilatation is often present. A characteristic “myxo-
matous deformity” may include a hypermobile systolic bil-
lowing or parachute-like appearance of the leaflets (Figs.
21.27 and 21.28). In advanced disease, the leaflets can be
excessively thickened and calcified, which reduces leaflet
mobility. Myxomatous changes can be generalized, involv-
ing both leaflets, or be highly localized, sometimes involving
only a single segment of one leaflet. Therefore, careful sys-

A B

C D
FIGURE 21.26. Mitral valve prolapse (MVP), posterior leaflet. (A) in isolation. (D) CW Doppler demonstrates that late systolic MR
Parasternal long axis view. The posterior leaflet (arrow) crosses the (double arrows) is a transient event and unlikely to represent a sig-
annular plane (red line). (B) M-mode shows late systolic hammock nificant regurgitant volume. Single arrow shows onset of systole
sign of MVP. (C) Color Doppler (same patient) suggests significant (MV closure artifact).
MR when a late systolic frame (see arrow, ECG tracing) is viewed
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 515

A B
FIGURE 21.27. Myxomatous degeneration of the mitral and tricus- Gastric long axis view of the LV shows markedly elongated chordae
pid valves and other structures by TEE. (A) MV and tricuspid valve tendineae (arrows) with “parachute” appearance of the two MV
(TV) annular dilatation, “billowing” MV and TV systolic prolapse leaflets.
(albeit in four-chamber view), aneurysmal interatrial septum. (B)

tematic scanning across the entire mitral coaptation line is
required to rule out MVP. Mitral valve prolapse can be a
subtle and rapid event, particularly during tachycardia.
Therefore, the M-mode exam (parasternal long axis views)
can be helpful in making the diagnosis (Fig. 21.26B). Associ-
ated tricuspid valve prolapse is not uncommon. Aortic valve
myxomatous degeneration is occasionally seen.
Mitral valve prolapse can produce any degree of regurgita-
tion (or none at all), depending on whether prolapse is mild,
moderate, or severe and to what extent the prolapse is bal-
anced between the two leaflets so that systolic coaptation is
maintained. Myxomatous valve disease predisposes patients
to chordal rupture, which can result in sudden, severe MR.
Ruptured chords can sometimes be detected by surface echo-
cardiography (Fig. 21.29) but are more easily identified by
TEE (Figs. 21.30 and 21.31). Highly eccentric MR is common
in MVP and particularly when chordal rupture is present,
though central MR can occur with balanced prolapse, usually
without chordal rupture (Fig. 21.28). Eccentric jet lesions
generally flow away from the dysfunctional leaflet (i.e., pos-
teriorly directed jet from anterior leaflet prolapse or anterior
jet from posterior leaflet prolapse). Chordal rupture is
suspected when a leaflet flail segment is seen partially
underriding the opposing leaflet, usually with an attached
mobile linear echo density (the liberated chord).
Surgical Repair of Mitral Valve Prolapse. Use of the
standard TTE and TEE views presented in Chapter 5 can
identify all segments of both the posterior and anterior leaf-
lets and the exact site of MR origin (Figs. 21.30 to 21.32).
Anatomic imaging, combined with color Doppler, will show
the primary site and mechanism of MR (e.g., leaflet

A B
FIGURE 21.28. Bileaflet MV prolapse by TEE, three-chamber view lapse with visible leaflet malcoaptation (no chordal rupture). a, ante-
showing redundant, billowing leaflets with mild central MR due to rior leaflet; p, posterior leaflet; Ao, aortic root; LV, left ventricle.
balanced bileaflet prolapse (A) and severe MR (B) from severe pro-
516 chapter
A B
C
FIGURE 21.29. (A) Severe MR due to flail posterior leaflet segment
(arrow) from chordal rupture, parasternal long axis view. (B) Massive
highly eccentric MR jet by color Doppler directed away from the
flail leaflet segment, encircling a severely enlarged left atrium (LA),
tethering, perforation, prolapse, or ruptured chord). Isolated
posterior mitral leaflet prolapse or flail segment is generally
most amenable to surgical repair (Fig. 21.30). Prolapse or flail
segments of the anterior leaflet can be more difficult to
correct surgically (Fig. 21.32). Many additional factors,
including local experience, leaflet calcification, mobility,
annular size, chordal length, and presence of coronary artery
disease, go into the decision-making process. Intraoperative
TEE is typically performed whenever MV repair is contem-
plated in order to confirm the diagnosis, and to assess the
results in the operating room immediately after cardiopul-
monary bypass (Fig. 21.30E).
M ITRAL A NNULAR CALCIFICATION
Calcific degeneration of the mitral valve is common, particu-
larly in the elderly, and can be present prematurely in chronic
renal failure patients. Calcium deposits most commonly
infiltrate the posterior aspects of the mitral annulus, though
the process can become circumferential and begin to invade
the bases of the leaflets where mobility is most notably
21
apical three-chamber view. (C) Markedly increased mitral inflow E
wave by pulsed Doppler = 1.5 cm/s (see Table 21.8) indicating severe
MR. Other quantitative methods are not required. Note: chronic
MR, patient relatively asymptomatic.
impaired. The degree of MR can be challenging to diagnose
because of shadowing of the left atrium. At least mild associ-
ated mitral stenosis is common, and this can affect mitral
inflow gradient peak and mean velocities. As with prosthetic
valve MR, TEE is frequently required for adequate MR evalu-
ation in advanced calcific degeneration of the mitral valve.
R HEUMATIC M ITRAL R EGURGITATION
Although mitral stenosis is more commonly associated with
rheumatic mitral valve disease, MR can be the predominant
hemodynamic lesion in some cases. Rheumatic MR can
result from scarred, restricted leaflets that appear almost
frozen in a semiopen position or from additional leaflet
destruction from superimposed endocarditis. Although
rheumatic MS can produce severe left atrial enlargement,
particularly with atrial fibrillation, historically it is rheu-
matic MR (usually with mixed MS) that has produced the
largest of the left atria—“giant left atrium.” The giant left
atrium is actually defined by chest x-ray (left atrium touch-
ing the right thoracic wall).81
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 517

A B

C D

E F
FIGURE 21.30. Intraoperative TEE, showing the mechanism for
severe anteriorly directed eccentric MR due to myxomatous mitral
valve disease primarily affecting the posterior leaflet with a flail
middle scallop (P2) due to chordal rupture. (A) TEE five-chember
view. The flail myxomatous-appearing P2 segment and attached
ruptured chorda tendina (arrow) resembles a duck’s head (a common
appearance). (B) TEE bicommissural view (see Chapter 5 for standard
views) confirms isolated involvement of the P2 segment. (C) Poste-
rior leaflet, P2 and the ruptured chord (arrow) override the mid
portion of the relatively normal anterior mitral leaflet. (D) Large
color Doppler proximal flow convergence (PFC) zone and a severe,
wall-hugging left atrial jet (Coanda effect) are seen. This eccentric
jet lesion is consistent with severe MR although the overall color
Doppler jet areas is not as large as a comparable central jet lesion
created by bileaflet prolapse (compare with Fig. 21.28B). The PISA
method for EROA quantation cannot be used in this case due to the
complex regurgitant orifice shape and a PFC zone that is “con-
strained” by the LV posterior wall. (E) Surgical specimen (excised P2
segment and ruptured chord (black arrow) in the same patient. (F)
Intraoperative TEE immediately after successful quadratic P2
scallop resection with annular reduction [mitral annuloplastiy ring
seen in cross exaction (arrows) with no residual MR].
518 chapter 21

A B
FIGURE 21.31. Intraoperative TEE showing the mechanism for severe posteriorly directed MR due to flail anterior leaflet segment A2 from
chordal rupture (arrow).

OTHER INFLAMMATORY CONDITIONS
Chordal thickening, shortening, and the resultant systolic
leaflet tethering causing severe MR can be seen in a number
of other inflammatory conditions (scleroderma; radiation
valvulitis; anorexigenic- and ergotamine-induced valve
disease; and hypereosinophilia). These other etiologies may
be difficult, if not impossible, to distinguish echocardio-
graphically (or even on surgical inspection) from rheumatic
MR. Minimal or no stenosis and the lack of commissural
fusion weigh against rheumatic disease.
release of collagenase and other destructive enzymes. Chordal
rupture can occur, in which case mobile chords or flail leaflet
segments may be difficult to distinguish from the vegetation
material. Pseudoaneurysms of the mitral valve leaflets can
perforate or impair leaflet function. Perforation may be
visible as a segment of leaflet discontinuity or, if punctate,
be apparent by turbulent color Doppler jet lesions arising
from areas outside the normal coaptation zones. A perforated
mitral annular abscess can produce an annular echo-free
space and annular MR.

ENDOCARDITIS FUNCTIONAL M ITRAL R EGURGITATION

A variety of anatomic abnormalities may be present on the
2D or M-mode exam. On M-mode, a mobile echodensity
adjacent or attached to the leaflets exhibiting independent
motion suggests vegetation. Small vegetations are frequently
visible by TTE, but this is highly dependent on imaging
conditions. The presence of possible valve vegetations should
raise suspicion for significant MR, and a confirmatory TEE
may be indicated. Microbial pathogens (Staphylococcus
aureus, most notably) can cause leaflet destruction from the
Functional MR exists when all elements of the mitral appa-
ratus appear morphologically normal, but their function is
impaired, usually because of dilated cardiomyopathy (Fig.
21.33). The classic identifiable feature by 2D exam is incom-
plete closure of the mitral leaflet due to leaflet tethering due
to papillary muscle displacement,82 although annular dys-
function may also play a role. Appreciated more recently is
the role of LV contractile dyssynergy (detectable and quantifi-
able echocardiographically, see other chapters) in patients

A B
FIGURE 21.32. TEE showing severe MR due to unusual cleft defor- view (B) imaging of the mitral valve confirms the regurgitant orifice
mity (confirmed surgically) in the anteromedial commissure region location and lack of associated chordal rupture or prolapse.
(arrowhead). Combined bicommissural (A) and gastric short axis
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e
A B
C
FIGURE 21.33. Moderate-to-severe functional MR by vena con-
tracta (VC) method in a patient with dilated cardiomyopathy. The
leaflets are tethered toward the LV (A). The VC is measured just
distal to the anatomic orifice (VC = 0.6 cm, see Table 21.8) after
with cardiomyopathy and left bundle branch block. In these
patients, functional MR can sometimes be improved sub-
stantially by cardiac resynchronization therapy.83
CORONARY A RTERY DISEASE 84
Left ventricular segmental wall motion abnormalities should
heighten suspicion for MR. Ischemic MR is a common but
not always easily defined entity. Ischemia can transiently
affect papillary muscle function, leading to an eccentric MR
jet from leaflet malcoaptation. Myocardial infarction can
cause acute severe MR from a papillary muscle tear (leaflet
prolapse) or complete avulsion (flail leaflets). Dysfunction of
a scarred and retracted papillary muscle can produce severe
MR from leaflet tethering.85 Extensive ventricular scarring
can lead to adverse remodeling and functional MR instead
of ischemic MR. A basal myocardial segment scar can distort
mitral annular geometry and function.
OTHER CAUSES OF M ITRAL R EGURGITATION R ECOGNIZABLE
BY ECHOCARDIOGRAPHY
Systolic anterior motion (SAM) of the mitral valve can cause
significant MR. Signs of this abnormality are covered in
Chapter 35.
519
applying a smaller but magnified (zoom mode) color sector. (C) Line
indicates orthogonal planes A and B, and the presence of a single
regurgitant orifice.
Doppler Evaluation of Mitral Regurgitation
PULSED -WAVE DOPPLER
As described in Chapter 5, the complete exam includes a
pulsed wave (PW) Doppler signal acquired at the mitral
leaflet tips, the mitral annulus, and the pulmonary vein.
This simple routine provides important information for MR
assessment by Doppler flow assessment.
Mitral E Velocity. In severe MR, the mitral
forward flow is markedly increased due to the additive
forward stroke volume and the “wasted” regurgitant
volume. The increased diastolic flow increases the mitral E
velocity. In patients with normal ejection fraction, a
mitral leaflet tip E-wave velocity ≥1.2 cm/s (Fig. 21.29C) is a
sensitive and moderately specific sign of severe MR.86
Increased mitral E velocity is not a reliable sign in patients
with cardiomyopathy. However, when the mitral inflow
pattern is A-wave dominant, there is little likelihood of
severe MR.
520 chapter
Pulmonary Vein Systolic Flow Reversal. By TTE and
TEE (Fig. 21.34), the PW Doppler sample volume is placed
approximately 1 cm into the right superior pulmonary vein
(TTE, apical four-chamber view) or in all TEE-visualized
pulmonary veins. For a time, based primarily on early TEE
reports, pulmonary vein systolic flow reversal was thought
to be a highly sensitive and specific sign of severe MR. Later
reports have shown that pulmonary vein systolic flow rever-
sal is neither highly sensitive nor highly specific for severe
MR.87,88 Directed jets that are not severe may enter a pulmo-
nary vein. In chronic severe MR, the remodeled LA may
accommodate severe MR without actual pulmonary vein
systolic reversal. Nonetheless, pulmonary vein inflow sys-
tolic blunting or systolic flow reversal should raise the ques-
tion of possibly severe MR, which should be confirmed using
other methods.
Pulsed Doppler of the Left Atrial Appendage. Occa-
sionally, a highly eccentric severe MR jet travels directly into
the LAA, where its energy is largely absorbed. Left atrial
appendage MR jets may be due to paravalvular leaks in the
adjacent prosthetic valves sewing ring or unusual cases of
native valve MVP or endocarditis. This possibility should be
borne in mind during TEE evaluation.
CONTINUOUS-WAVE DOPPLER
Continuous-wave CW Doppler density (brightness of the
spectral Doppler signal) is proportional to the number of
regurgitant red blood cells within the path of the interrogat-
ing beam. The faint signal of trivial or mild MR can be dis-
tinguished from the dense signal of moderate to severe MR.
The bright density of all forward flow in the mitral valve
(above the baseline) is a useful benchmark for determining
the relative regurgitant density (Fig. 21.35). With MVP or
functional MR, the signal may be dense only in late or in
early stole, respectively. In these two situations, the CW
FIGURE 21.34. TEE, pulmonary vein systolic flow reversal (arrows
below baseline). Diastolic dominant pulmonary vein forward flow
(arrow above baseline) in a patient with significant MR.
21
signal can be useful for demonstrating that the MR is not
sustained and is unlikely to be severe, even if dense (Fig.
21.26D). The CW signal can exhibit a V-wave “cut-off” in
severe MR with cardiomyopathy and a high left atrial pres-
sure in acute severe MR (see below). The pitfalls are as
follows: CW density is a helpful supportive sign and not a
true quantitative measure. The CW Doppler signal can be
shadowed in calcified or prosthetic valves. The CW beam
may not be accurately placed within the jet, potentially
resulting in a faint jet despite severe MR. In curvilinear,
eccentric jets, CW Doppler cannot be brought into coaxial
alignment, so that jet CW Doppler density and peak velocity
may be low, even in severe lesions.
L EFT ATRIAL JET A REA BY COLOR DOPPLER
Overall jet size (maximum area) within the left atrium is
useful only in extreme circumstances. The area generally
includes only the zone of sustained “mosaic” color Doppler.
A mosaic is the appearance of alternating, colored, adjacent
pixels, signifying a zone of high-velocity turbulent flow. A
very small left atrial jet usually means mild MR. A very
large jet that almost fills the left atrium usually means
severe MR (Table 21.8). The pitfalls are as follows: A common
pitfall is an inappropriate Nyquist limit setting. The color
Doppler Nyquist limit setting should be in the range of 50
to 60 m/s. Lower or higher settings increase or decrease the
mosaic jet area, respectively. Many other factors (described
earlier) affect the size and appearance of the jet. Mild-to-
moderate volume “high-energy” central jets can entrain sur-
rounding blood and appear severe by color Doppler. Severe
MR can appear mild to moderate by color Doppler if hypo-
tension or high left atrial pressure (unobstructed MR) are
present. Severe eccentric MR with a “wall-hugging” jet may
appear only mild to moderate based on area assessment.89
The tendency for high-energy jets to “cling” to an adjacent
solid boundaries surface is known as the Coanda effect (Figs.
21.29 to 21.31). In the future, left atrial jet volume assess-
ment using 3D echocardiography may be of incremental
value.
VENA CONTRACTA WIDTH BY COLOR DOPPLER 90,91
When the sonographer confirms that only a single predomi-
nant MR jet is present, the VC height can be a valuable and
relatively easy-to-obtain linear measure of regurgitation
severity that does not vary significantly with hemodynamic
loading conditions. Details of accurate VC imaging tech-
niques have been described9 and are shown in Figures 21.33
and 21.36. Accurate measurement requires optimized
zoomed views of the jet origin (PFC zone, anatomic orifice,
and VC region), without regard to the appearance of the distal
expanding jet lesion. Measurement is made ideally in the
parasternal long axis view to take advantage of the relatively
high axial resolution of color Doppler. The VC width is a
direct linear measurement, and any error is not propagated
due to squaring. The pitfalls are as follows: The VC may not
be visible because of leaflet calcification. The method is not
valid for multiple jets. The VC width may be overestimated
in apical views because of lower color Doppler lateral resolu-
tion relative to axial resolution.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 5 21

A B

C D
FIGURE 21.35. Mitral regurgitation by CW Doppler, surface echo, dense signal intensity. (D) Severe MR. Mitral inflow (above baseline)
four-chamber view. (A) Trivial or trace MR with faint, incomplete can be used as a reference for signal intensity. Note: Signal profiles
signal. (B) Mild MR with faint but complete spectral Doppler enve- and intensity can be markedly diminished with eccentric jets, shad-
lope. (C) Moderate MR with complete envelope and moderately owing artifacts or with poor interrogating beam alignment.

PROXIMAL ISOVELOCITY SURFACE A REA M ETHOD FOR
EFFECTIVE R EGURGITANT ORIFICE A REA AND
R IGHT VENTRICLE13,92,93
This method works best for central jets and may be particu-
larly useful for demonstrating central jets that appear severe
by color Doppler jet area alone. The concepts of proximal
flow convergence and PISA were discussed earlier. In TTE,
images are obtained in apical views in zoomed mode (Fig.
21.36E). In TEE (Fig. 21.37), the best coaxially aligned views
are used. Whether by TTE or TEE, a standard practice is to
shift the color Doppler baseline toward the direction of the
regurgitant jet, so that the lower Nyquist limit (Va) is reduced
to approximately 40 cm/s or lower. This produces a homoge-
neous PFC zone color appearance within the PISA border. Va

TABLE 21.8. Mitral regurgitation Doppler and quantitative parameters

Mild Moderate Moderate-to-Severe Severe

Jet area† (color Doppler) Small, central jet(<4 cm or <20%

2
Variable Large, central jet (>10 cm2
LA area) Variable or >40% LA area)
Mitral inflow (PW) A-dominant* E-dominant, >1.2 cm/s*
MR jet density (CW) Faint/incomplete Dense Dense
MR jet contour (CW) Parabolic Parabolic Early-peaking or V-wave
cut-off (triangular)
VC width (cm) <0.3 0.3–0.69 ≥0.7
RV (mL/beat) <30 ≥60
RF (%) <30 ≥50
EROA (cm2) <0.20 0.20–0.29 0.30–0.39 ≥0.40
PW, pulsed-wave Doppler; CW, continuous-wave Doppler; VC, vena contracta; RV, regurgitant volume; RF, regurgitant fraction; EROA, effective regurgitant
orifice area.
* In the absence of other causes of increased LA pressures, individuals >50 yrs.
† Jet area for eccentric jets is not predictable by color Doppler.
522 chapter 21

A B

C D

E F

G H

I
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e
FIGURE 21.36. MR quantitation using three methods in the same
patient in a routine exam. (A) LVOT diameter measurement. (B)
Zoom mode, for vena contracta (VC) measurement. (C) MV short
axis with color Doppler confirms single MR orifice. (D) Moderately
large central jet, apical four-chamber view (color Nyquist limit >50
and <60). (E) “Zoomed” view of proximal flow convergence; reduc-
tion of color Doppler Nyquist limit in direction of the jet lesion;
PISA radius measurement (r). (F) Mid-diastolic mitral annulus diam-
eter measurement. (G) Pulsed Doppler at the mitral annulus level;
MV annulus VTI measurement. (H) VTI and peak velocity of MR
can be adjusted to produce a hemispheric shape. The mitral
regurgitation peak velocity (Vpk) is obtained from the CW
Doppler signal when there is good coaxial alignment of the
beam:
EROA = 6.28r 2 × Va/Vpk
The EROA can be a useful indicator of severity94 (see Table
21.8). The regurgitant volume is derived using the following
equation:
RV = EROA × VTI MR
or
EROA = RV × VTI MR
A B
VMR = 654 cm/s
VTIMR = 224 cm
C
FIGURE 21.37. PISA method for MR quantitation by TEE. A nearly
perfectly hemispheric PISA is formed by a punctate fenestration
(arrow) in the mitral anterior leaflet base (A, simultaneous 2D and
color Doppler image). The radius is easily measured in zoom mode
(B). Aliasing velocity (Va) is reduced in direction of jet lesion. (C) CW
523
jet by CW Doppler. (I) Pulsed Doppler for VTI of the LVOT. See
images for variables.
VC method: VC = 0.5 cm (simple, direct linear measurement).
PISA method: EROA = 6.28 r 2 × Va/Vpk = 0.22 cm2; RV = EROA ×
VTI MR = 41.6 mL; SV = 6.28 (r 2) × Va = 118 mL; RF = RV/SV = 0.35
(moderate MR, see Table 21.8). Doppler flow method: SV LVOT = 0.785
× D LVOT2 × VTI LVOT = 37.7 mL; SVMVann = 0.785 × D MVann2 × VTI MVann =
73.2 mL; RV = SVMVann − SV LVOT = 35.5 mL; RF = RV/SVMVann = 0.48.
All methods are in rough agreement for a diagnosis of moderate MR
(see text for formulas and Table 21.8 for reference values).
The regurgitant volume (with preserved overall LV systolic
function) is an additional severity indicator (see Table 21.8).
The mitral valve VTI (VTI MR) is obtained automatically by
outlining the CW Doppler MR signal.
Proximal Isovelocity Surface Area Pitfalls.93,95 The
method is valid only when a single dominant jet is present,
and not if two or more (multiple jets) are identified (Fig. 21.38).
The method may be less reliable when the jet origin is
complex (curvilinear by short axis view) or restrained
by adjacent prolapsing leaflets or ventricular myocar-
dium (eccentric jets). In addition, the CW Doppler is diffi-
cult to align in eccentric jets, leading to a low Vpk and an
Doppler of the MR jet. Calculations: see images for variables. EROA
= 6.28 r 2 × Va/Vpk = 0.22 cm2 = 0.07 cm2; RV = EROA × VTI MR =
15.7 mL; SV = 6.28 (r 2) × Va = 114.5 ml; RF = RV/SV = 0.13. All con-
sistent with mild MR (see Table 21.8).
524
FIGURE 21.38. TEE shows three separate MR jets (arrows); there-
fore, we cannot use the PISA or vena contracta methods. LV, left
ventricle; LA, left atrium.
overestimated EROA. Despite these limitations, the presence
of one or more areas of prominent proximal flow convergence
(at standard color Doppler Nyquist settings) is a sign of pos-
sibly significant MR that warrants further investigation.
Therefore, PFC (PISA) imaging attempts are never wasted.
M ITRAL A NNULAR FLOW AND R IGHT VENTRICLE BY
PULSED DOPPLER 50,51
The standard exam includes pulsed Doppler within the
mitral annulus. The mitral annular diameter can be mea-
sured, and mitral annular stroke volume determined (SV =
CSA × VTI) (see example calculation in Figure 21.36). When
mitral regurgitation is present, the forward diastolic mitral
flow includes the useful forward stroke volume in addition
to the added “wasted” RV. The mitral valve RV can be deter-
mined by subtracting the stroke volume obtained at a com-
petent reference valve (LVOT or RVOT) from the increased
mitral annular total SV:
Total SVMVannulus = SVreference valve − RVMV
See Table 21.8 for clinically useful RV values. When the
overall forward stroke volume is reduced (cardiomyopathy),
the regurgitant volume may be misleadingly low, and the
regurgitant fraction (RF) should be used instead (see Table
21.8 for reference values):
RFMV = RV/SVMV
Pitfalls. The method is difficult to apply in irregular
rhythms (e.g., atrial fibrillation) because of variable stroke
volumes beat to beat. Because annular diameters are squared,
measurement errors are compounded. Significant reference
valve regurgitation invalidates the method. Accurate mitral
annular measurement can be difficult or impossible with
severe mitral annular calcification (Fig. 21.22) or other mor-
phologic deformity.
M ITRAL R EGURGITATION ASSESSMENT BY
T RANSESOPHAGEAL ECHOCARDIOGRAPHY
Transesophageal echocardiography can be an ideal modality
for assessing mitral leaflet morphology and MR severity. The
chapter 21
left atrial blood pool provides an excellent acoustic medium
for imaging, usually with no interposed structures that could
cause signal attenuation. Transesophageal echocardiography
is very useful when surface echocardiography is technically
difficult for any reason, particularly when there is left atrial
shadowing from calcification or a mitral valve prosthesis.
Any of the above-mentioned quantitative measures or indica-
tors can be applied to TEE, potentially with improved accu-
racy in some cases. Many times, surface echocardiography
excels at gathering spectral Doppler data because of an
increased number of potential imaging windows necessary
for obtaining coaxial jet alignment. Transesophageal echo-
cardiography generally excels at providing a higher resolu-
tion detailed look at leaflet anatomy. One must bear in mind
that mild MR to moderate-range jets will appear more
impressive by TEE than by TTE because of improved image
clarity and decreased imaging depths. Therefore, the other
factors regarding jet severity (jet density by CW Doppler, VC,
PISA analysis, etc.) must be kept in mind to avoid overcalling
MR severity. Transesophageal echocardiography is ideally
used as a complementary imaging modality when the surface
exam is inconclusive or when surgery is being considered
(endocarditis with potential abscess, possible mitral valve
repair, prosthetic valve dysfunction).
Acute Severe Mitral Regurgitation
Acute severe MR should be considered in the differential
diagnosis of patients with cardiogenic shock. Acute severe
MR can be inadvertently missed on review of a surface echo-
cardiogram without a high index of suspicion. As mentioned
above, the CW and color Doppler signals may be inconspicu-
ous in torrential MR (e.g., acute chordal or papillary muscle
rupture) because of systemic hypotension and high left atrial
pressure (low LV-to-LA pressure gradient) due to almost
unobstructed (nonturbulent) regurgitant flow. Color Doppler
signs for low-velocity acute severe MR may also be lacking
in this situation due to tachycardia with relatively slow color
Doppler sample rate. The MR “V-wave cut-off” sign by CW
Doppler (Fig. 21.39) is usually present, however. Other clues
FIGURE 21.39. Typical appearance of CW spectral Doppler in acute
severe MR with cardiogenic shock. Low velocity (3.8 m/s), triangu-
lar shaped with “v-wave cut-off” (arrows). This patient had papillary
muscle rupture after myocardial infarction.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 525
to the diagnosis include normal or hyperdynamic LV contrac-
tility with a reduced LVOT stroke volume by LVOT PW
Doppler. Acute severe MR is a potential surgical emergency.
Confirmatory TEE for both severity and mechanism assess-
ment should be performed expeditiously when the diagnosis
is suspected.

Tricuspid Valve Disease

Tricuspid Stenosis

Two-Dimensional Imaging and

Differential Diagnosis
Tricuspid stenosis (TS) is an uncommon diagnosis that is
suspected in the clinical setting of systemic venous hyper-
tension with a prolonged y-descent as observed in the jugular
vein, visually; by RA pressure tracing; or by hepatic vein
pulsed Doppler. Rheumatic TS, carcinoid heart disease,
tumor obstruction, and obstructed tricuspid valve (TV) pros-
FIGURE 21.40. Carcinoid heart disease. The patient had torrential
thesis are all important but uncommon conditions that can tricuspid regurgitation (TR) and mild tricuspid stenosis (TS) due to
be recognized by echocardiography. thickened TV leaflets “frozen” in the semiopen position (arrows).

R HEUMATIC T RICUSPID STENOSIS

Rheumatic TV changes that are evident by echocardiography
mirror those seen in rheumatic mitral valve disease: leaflet
leading edge thickening, with reduced mobility; commis-
sural fusion; and leaflet doming and leaflet tethering from
chordal shortening and fusion. Rheumatic TS rarely if ever
occurs in the absence of rheumatic MV disease. Associated
TR is common.
CARCINOID HEART DISEASE
Carcinoid heart disease is suspected by 2D echocardiography
when the TV leaflets and submitral apparatus appear mark-
edly thickened and fully or partially frozen in a semiopen
position with marked systolic leaflet malcoaptation (Fig.
21.40). Tricuspid stenosis is usually in the mild to moderate
range with associated torrential TR. Associated pulmonary
stenosis (PS) and PR (due to similar leaflet deformity) are the
rule in carcinoid heart disease, whereas rheumatic PV disease
is a rare diagnosis, particularly in Western countries.
Tricuspid stenosis rarely occurs with obstructive atypical
right atrial myxomas or other, usually malignant, tumors. A
prosthetic TV (either biologic or mechanical) can develop
forward flow obstruction (Fig. 21.41).
Tricuspid Stenosis Assessment by Doppler
Pulse-wave Doppler of the hepatic vein inflow demonstrates
a prolonged y-descent due to delayed diastolic RA emptying.
Because complicating TS can be easily overlooked in the
setting of dramatic associated TR (rheumatic or carcinoid TV
disease), the diastolic tricuspid inflow velocities should
always be carefully observed by CW Doppler. Values for
pathologic TV gradients are much lower than for MS, since
systemic venous hypertension is very poorly tolerated. Clini-
cally apparent TS (lower extremity edema, ascites, early
satiety, etc.) can occur whenever the mean resting TV gradi-
ent is >5 mm Hg. After TV repair, intraoperative TEE is useful
for evaluating successful treatment of TR and also for ensur-
ing that excessive annular reduction has not created TS.

FIGURE 21.41. (A) Tricuspid valve mechanical prosthesis thrombosis with severe obstruction gradient by CW Doppler. (B) Normalized TV
prosthesis gradient after thrombolytic therapy.
526 chapter
Tricuspid Regurgitation
Two-Dimensional Examination and
Differential Diagnosis
Hemodynamically significant TR is commonly seen in adult
echocardiography laboratories. Moderate and even severe-
range TR is often tolerated without clinical symptoms for
long periods, as long as the pulmonary artery pressure
(forward flow resistance) remains normal (low) and right ven-
tricle systolic function is normal. Echocardiography is impor-
tant not only for diagnosis of TR but also for detecting signs
of eventual right ventricle failure due to volume overload.
T RICUSPID VALVE PROLAPSE
Tricuspid valve prolapse, often associated with myxomatous
degeneration of the mitral valve, is recognizable by 2D
imaging, though obtaining views that are in true long or
short axis alignment with the TV annulus can be difficult.
In any of a number of views, one or both leaflets may be seen
underriding the opposing leaflet or appearing to cross that
annular plane. Flail leaflet segments and severe TR can
result from chordal rupture, related to myxomatous degen-
eration, endocarditis (Fig. 21.42), endomyocardial biopsy,96,97
or deceleration injury.
A B
C D
FIGURE 21.42. Signs of severe “unobstructed TR” from TV endo-
carditis. (A) Flail leaflets (arrows) with unimpressive color Doppler
jet lesion (potentially overlooked laminar flow). (B) Low-velocity TR
jet by CW Doppler with “v-wave cut-off” (double arrows) with
21
POSTTRAUMATIC T RICUSPID R EGURGITATION
Deceleration injuries (e.g., fall from a ladder, car crashes)
can result in chordal rupture or anterior leaflet tear, most
commonly. The anatomic clue for leaflet tear may be the lack
of other valve pathology and an odd appearance to the jet
origin (e.g., a basal leaflet jet origin) with the trauma even
sometimes having occurred years or decades before
diagnosis.
R HEUMATIC T RICUSPID R EGURGITATION
The association with rheumatic MV disease is high, with
clinically significant rheumatic TR being much more
common than TR. The degree of rheumatic TR should be
routinely excluded prior to MV surgical repair, since postop-
erative severe TR is often not well tolerated, particularly in
older patients. Recognizable TV leaflet malcoaptation due to
leaflet overtethering from chordal thickening, and shorten-
ing and secondary annular dilatation are usually apparent
echocardiographically due to increased leaflet and subvalvu-
lar echogenicity.
FUNCTIONAL T RICUSPID R EGURGITATION
When the right ventricle is chronically exposed to volume or
pressure overload, for whatever reason, annular dilatation
increased TV inflow velocity (>1 cm/s, single arrow). (C) Large
hepatic vein systolic wave by pulsed Doppler. (D) Paradoxical septal
motion by M-mode, parasternal long axis view with inferolateral
and septal walls moving in unison.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 527

FIGURE 21.43. Paradoxical septal motion as seen by 2D parasternal short axis view. This finding may be seen in right ventricle volume
overload from severe TR, severe pulmonary regurgitation (PR), large atrial septal defect, or any combination of these lesions.

and possibly papillary muscle displacement can cause severe
leaflet malcoaptation. Acute pressure overload (acute pulmo-
nary embolus) can also cause acute functional TR, as can
acute right ventricle dilatation and right ventricle dysfunc-
tion from right ventricle infarction. The TV annulus is less
fibromuscular than the MV annulus. The looser TV annulus,
therefore, is particularly subject to functional TR that is
frequently at least partially reversible with medical or other
treatment of the underlying cause of right ventricle pressure
and or volume overload. However, chronic severe right ven-
tricle volume overload from any cause (PR, atrial septal
defect, and TR itself) begets more functional TR and eventu-
ally leads to right ventricle failure. This process can be accel-
erated by pulmonary hypertension. Paradoxical septal
motion by M-mode (Fig. 21.42A) or 2D inspection (Fig. 21.43)
is a sign of right ventricle volume overload that should
prompt a search of significant TR, PR, and ASD—if not all
three—in some cases. Paradoxical septal motion occurs
because of equalized right ventricle and LV diastolic pres-
sure, causing the septum paradoxically to move toward the
LV central axis during diastole.
Doppler Evaluation of Tricuspid
Regurgitation Severity
COLOR DOPPLER
Severe TR can be missed by color Doppler when there is
nearly unobstructed and nonturbulent regurgitant flow (Fig.
21.42), particularly when associated with low pulmonary
artery pressure (low right ventricle to right atrium peak pres-
sure difference). With unobstructed TR, a turbulent color
Doppler jet lesion may not be present at all (Fig. 21.42A). On
the other hand, when the leaflets are reasonably intact, a
color Doppler jet lesion can be very prominent (Fig. 21.44A),

VTR = 3.5 m/s

A B
FIGURE 21.44. Severe TR with obstructive regurgitant orifice (compare with Fig. 21.42). (A) Larger TR color Doppler area, filling the right
atrium (RA) with a PFC zone. (B) Dense CW Doppler jet with inflow velocity >1 cm/s.
528 chapter 21

and the area of the color Doppler jet as a percentage of the

right atrium (RA) can be a helpful qualitative measure when
the TR. The TR jets under high pressure (pulmonary hyper-
tension or with RVOT obstruction) that are only mild to
moderate may deceptively appear “severe” by color Doppler
jet area because of significant entrained blood flow. A promi-
nent proximal flow convergence zone98 and “wide” vena con-
tracta99 usually signify clinically significant TR. Eccentric
TR jets may be underestimated by color jet area. Because the
TV leaflets are not always clearly visualized by TTE, and
color Doppler alone can be misleading in severe TR, other
Doppler criteria are needed.

SPECTRAL DOPPLER
As with MR, the TR CW Doppler signal density can be
helpful for separating trace or mild TR from moderate- to
severe-range TR. The V-wave cut-off sign indicates rapid
equalization of the right ventricle-RA pressure difference FIGURE 21.45. Severe stenosis of a pulmonary valve homograft
prosthesis (horizontal arrow) with moderate PR (downward arrow)
and is a sign of severe TR (Fig. 21.42C). Because of the larger
with relatively steep deceleration slope.
TV area, the normal TV inflow velocity is lower than that
of the mitral valve. In the absence of TS, a TV inflow velocity
of ≥1 cm/s can be a supportive sign of potentially severe TR
(Figs. 21.42B and 21.44B). The TR velocity by CW Doppler
and residual or very slowly progressive obstruction of previ-
can be used to estimate systolic PA pressure (see Chapter 5),
ously ballooned congenital PS can be seen in adult echocar-
which may influence interpretation of the color Doppler jet
diography laboratories. As previously mentioned, carcinoid
size. Important note: Systolic PA pressure assessment by CW
heart disease (also unusual) is characterized by mixed PS and
Doppler may be unreliable in torrential TR because the
PR, the stenosis component of which is usually mild to
regurgitant flow is relatively unobstructed, in which case the
moderate in severity. An important feature of severe RVOT
modified Bernoulli equation does not apply.
obstruction (PS) is that the right ventricle can produce sys-
temic-level systolic pressures when the pressure rise has
PULSED DOPPLER OF THE HEPATIC VEIN, SUBCOSTAL VIEW
been gradual. A sign of this is a D-shaped ventricular septum
A large hepatic vein systolic wave by pulsed Doppler (Fig.
in the parasternal short axis view of the left ventricle. This
21.42C) can be an important sign of severe TR, particularly
is different from the paradoxical septal motion of right ven-
when the TV is not well visualized either by 2D exam or by
tricle volume overload (see above) in that the septum remains
color Doppler and when correlated with an enlarged right
“flattened” during diastole and systole because the high right
ventricle with paradoxical septal motion. The hepatic vein
ventricle pressure no longer allows the left ventricle systemic
systolic wave, however, may become less prominent with
pressure to determine systolic septal curvature. Interven-
severe right ventricle failure and decreased overall right ven-
tricular septal flattening, however, is a nonspecific finding
tricle stroke volume.
since it will also occur in other conditions leading to right
ventricle pressure overload (pulmonary hypertension from
any cause).
Pulmonary Valve Disease
Doppler Evaluation
Pulmonary Stenosis
Although the pulmonary valve may be difficult to fully visu-
alize by 2D imaging, it is often well aligned for Doppler
Two-Dimensional Evaluation and
evaluation. A routine component of the TTE is CW Doppler
Differential Diagnosis
of the right ventricle outflow tract/pulmonary valve. This
Due to a relatively anterior and immediately retrosternal generally detects either valvular or subvalvular obstruction
position and a posteriorly directed orientation, the pulmo- as in the case of the failed pulmonary homograft prosthesis
nary valve can be difficult to visualize by both surface and in Figure 21.45. Dynamic infundibular RVOT obstructive
transesophageal echocardiography. The normal, thin semilu- gradients are usually late-peaking and can be superimposed
nar cusps are almost identical in morphology to the normal upon the fixed valve lesion. This phenomenon is not uncom-
aortic valve cusps, making them frequently difficult to fully mon in congenital forms of PS.
visualize under normal circumstances. Acquired native
valve PS is distinctly uncommon, with rheumatic heart
Pulmonary Regurgitation
disease only rarely involving this valve. Calcific PS of a
native congenitally normal trileaflet valve is essentially not A trivial to mild degree of PR is present in most normal
a described entity, although calcification and stenosis of a subjects. This is usually detectable by color Doppler on
pulmonary valve biologic prosthesis can occur (Fig. 21.45), routine exam since the valve lies very close to the transducer
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e
A B
C D
FIGURE 21.46. Mild PR in a normal individual shown by color (A)
and CW (B) Doppler. Low velocity with relatively flat deceleration
slope. (C,D) Severe “free” PR in a tetralogy of Fallot patient status
post–pulmonary valvotomy. (C) PR color Doppler jet appears
in the parasternal short axis view, and the PR jet is usually
ideally aligned for detection by Doppler. Even mild PR
lesions, therefore, can appear somewhat prominent by CW
Doppler, as in Figure 21.46A,B. With small PR regurgitant
volumes, the deceleration time of the PR jet is long, and some
degree of persistent PV end-diastolic pressure differential
exists, which is even more evident in the setting of pulmo-
nary hypertension (increased PR velocity throughout dias-
tole by CW Doppler). Severe PR, on the other hand, produces
a dense but steep deceleration time by CW Doppler with no
significant residual end diastolic pressure difference (Fig.
21.46. Unobstructed PR can be due to endocarditis, congeni-
tal or surgical absence of the valve leaflets, failed prosthesis,
or carcinoid heart disease. Endocarditis is the least likely of
these to produce mixed PS and PR. In “free” PR, the brief,
low-velocity, severe PR jet can be easily missed by color
Doppler. So careful attention to other signs of right ventricu-
lar volume overload can be important clues for the diagnosis
[paradoxical septum, right ventricle enlargement, functional
TR, high forward RVOT VTI by pulsed Doppler and the
typical CW Doppler profile (Fig. 21.46D)].
529
“laminar” due to unobstructed regurgitant flow. (D) The PR dias-
tolic deceleration slope is steep (double arrows) with mild associated
PS (peak velocity = 3 m/s).
Prosthetic Valve Dysfunction
Prosthetic valves may be placed in any of the four valve posi-
tions. In addition, the mitral, tricuspid, and pulmonary
valves can be repaired in favorable circumstances. A clinical
history of prosthetic valve surgery may not be available for
the sonographer or interpreting physician, although 2D and
Doppler signs of prosthetic valves can be recognized.
Mechanical Prostheses: Recognition by
Two-Dimensional Imaging
Although many old-generation prosthetic valve types remain
in the population, they are now much less commonly encoun-
tered in echocardiography laboratories. The most common
type of new-generation mechanical valve prosthesis (in usage
for >20 years) consists of two symmetrical durable pyrolytic
carbon tilting disks, suspended within a rigid ring. The
mechanical valve ring typically produces a small shadowing
artifact in the far field. The disks, particularly in the closed
530 chapter
A B
C
FIGURE 21.47. Bileaflet mechanical valve prosthesis, mitral posi-
tion. (A) TTE, four-chamber view. Prosthetic valve reverberation
artifacts obscure the left atrium (LA). (B) TEE, four-chamber view.
Prosthetic valve reverberation artifacts obscure the left ventricle
(LV). (C) TEE shows normal degree of central bileaflet mechanical
position, produce a prominent and usually easily recogniz-
able reverberation artifact. Reverberation consists of addi-
tional artifactual echo reflections in the far field,
distinguishing it from shadowing, which is the lack of echoes
in the far field. These imaging artifacts aid in recognition of
mechanical prosthetic valves, but they also make obstructive
or insufficiency lesions and their mechanisms difficult to
identify (Fig. 21.47).
Biologic Valves: Recognition by
Two-Dimensional Imaging
Modern biologic valves can be divided into three subtypes
that can be recognized echocardiographically: (1) “Stented”
valves (used in any position) consist of trileaflet semilunar
cusps constructed from pericardium or from porcine aortic
valve zenograft origin, suspended with three rigid supporting
“struts.” (2) “Stentless” valves (used in the aortic position)
are porcine aortic valve zenografts supported by a fabric
backing instead of struts. (3) Pulmonary autografts or homo-
grafts (used in the aortic or pulmonary positions) consist of
the intact pulmonary annular and leaflet structures. Stent-
less valves and pulmonary homografts or autografts can be
difficult to differentiate echocardiographically from a native
21
prosthetic MR. Jets typically originate from the central margin of
the sewing ring as shown. Sewing ring shadowing artifact (absent
far field echos, double arrow, left side); reverberation artifact (addi-
tional far field echos, double arrows, right side).
valve, although on detailed inspection annular thickening is
seen, and for stentless valves the backing material can often
be distinguished by careful inspection. The stented biologic
valve, on the other hand, is easily recognized because of the
protruding echogenic struts (Fig. 21.48). The biologic leaflets
should exhibit opening and closure characteristics typical of
any normal aortic valve. Over time, however, reduced leaflet
motion, calcification and even cusp prolapse or flail seg-
ments can sometimes be identified by surface imaging as
shadowing and reverberation artifacts are less problematic.
Doppler Evaluation
In comparison with normal native valves, normally func-
tioning prosthetic valves (and repaired valves) typically
exhibit mild obstructive gradients at rest. Normal prosthetic
valve flow velocities and gradients vary among patients
according to valve type, patient size, and other hemody-
namic variables. Therefore, it is important to conduct a base-
line echocardiography examination, usually within 6 to 8
weeks after valve implantation surgery for future reference.
For questionable valves and when baseline data are not avail-
able, reference tables may be consulted for normal valve
velocities and gradients.100
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e
A B
C
FIGURE 21.48. Stented biologic prosthesis in the mitral position.
(A) Parasternal long axis view and apical two-chamber view. The
valve “struts” (arrow) protrude into the LV. (C) TEE image demon-
Many of the same principles that apply for native valve
obstructive lesions can be used for evaluating prosthetic
valve forward flow.6 A mechanical valve can become
obstructed due to pannus (organized thrombus) or recent
thrombus formation within the sewing ring. Unfortunately,
thrombus and pannus formation can be difficult to visualize,
although TEE may be of significant incremental benefit for
making this diagnosis101 and guiding therapy.102 Perivalvular
leaks can result from technical failure of a suture or from
inadequacy of the underlying anchoring connective tissue
(degenerative changes or destruction from endocarditis).
Prosthetic valves can become dysfunctional due to obstruc-
tive lesions or regurgitation. As already alluded to, biologic
valves undergo degeneration over time, which can produce
obstructive, insufficiency, or mixed lesions.
The CW Doppler signal is usually diagnostic for a bileaf-
let mechanical valve because of the prominent opening and
closure ultrasound artifacts produced by the disks (Fig. 21.49).
Prosthetic valve forward flow gradients can increase mark-
edly from either obstructive or regurgitation lesions. When-
ever a prosthetic valve gradient is more than mildly increased,
a thorough Doppler investigation is warranted. Regardless of
valve position, the sonographer should systematically image
5 31
strates biologic leaflets in the closed position (arrow) with sewing
ring partially shadowing the LV, but with no reverberation
artifacts.
all aspects of the valve sewing ring with color Doppler, in an
attempt to identify sites of abnormal proximal flow conver-
gence in the sewing ring, which can be a sign of a perivalvu-
lar leak since the jet lesion (particularly with perivalvular
MR on surface echo) may be hidden by shadowing and rever-
beration artifacts. CW Doppler should “explore” the pros-
thetic ring in case a focal, dense regurgitation jet is
encountered. Mechanical valves always exhibit a normal
amount of central regurgitation that originates inside the
sewing ring and generally extends no more than 1 to 2 cm in
jet length by color Doppler from the valve (Fig. 21.48C). These
small jets are normal in the LV outflow tract with a normally
functioning aortic valve prosthesis. More extensive LVOT
jets may require further investigation. Although there is no
normal amount of central leak for a biologic prosthesis, mild
central regurgitation is sometimes seen even immediately
after implantation. Baseline documentation and routine
follow-up by surface echocardiography are all that is indi-
cated if the forward flow characteristics and leaflet motion
are otherwise normal.
A high peak forward flow gradient across the mitral103 or
tricuspid valve prosthesis and a relatively steep (short) decel-
eration time suggest prosthetic valve regurgitation.104 A high
532 chapter 21

A B
FIGURE 21.49. Normal forward flow velocities by CW Doppler of (IC) and isovolumic relaxation (IR) periods are clearly demarcated
a mechanical aortic valve prosthesis (A) and mechanical mitral by the characteristic mechanical leaflet opening and closure arti-
valve prosthesis (B) in the same patient. The isovolumic contraction facts in this patient with “double” mechanical prosthetic valves.

peak and mean gradient and lengthened mitral deceleration comprehensive TTE and TEE are frequently needed in order
time usually suggests prosthetic valve obstruction (Fig. to address the situation.91,102,104 Figures 21.50 and 21.51 show
21.41), although combined obstruction and regurgitation can TEE evaluations of dysfunctional mechanical mitral and
occur. Whenever prosthetic valve dysfunction is suspected, aortic valve prostheses, respectively.

A B

C
FIGURE 21.50. TEE evaluation of severe perivalvular MR in a
patient with prosthetic valve bacterial endocarditis. (A) The pros-
thetic leaflets appear in a typical closed position. Mitral annular
abscess with associated vegetation (arrow). (B) In another imaging
plane, same patient, a localized region of sewing ring dehiscence
(upward arrow) is visible. Sewing ring (downward arrow); linear
reverberations, mechanical disks in open position (arrowhead);
left atrial appendage (LAA). (C) Dolor Doppler shows severe perival-
vular MR (from outside the sewing ring) entering the left atrial
appendage.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e
References
FIGURE 21.51. TEE evaluation of paravalvular AR in a patient with
mechanical aortic valve prosthesis. This en face view of the aortic
valve sewing ring successfully identifies the location of a significant
paravalvular leak (arrow) resulting from failure of at least two
sutures.
Dimensionless Velocity Index
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Figs. 21.11 and 21.12).
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21
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205.
 2 Magnetic Resonance
2 Imaging of
Valvular Disease
Scott D. Flamm and Raja Muthupillai
Magnetic Resonance Imaging Methods. . . . . . . . . . . . . . 538
Clinical Applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
Key Points
• Cardiovascular magnetic resonance (CMR) is an accurate
and complementary method for evaluating ventricular
function and volume analysis.
• Cardiovascular magnetic resonance can readily assess
the morphology of all four cardiac valves and accurately
determine the severity of stenosis and regurgitation.
The rhythmic contraction of the heart muscle propels blood
carrying nutrients to all organs of the body. The blood flow
into and out of the ventricles is well regulated by exquisitely
designed valves, and any abnormality of the valve structure
or function can adversely affect cardiac function. Patient
management can be significantly improved with accurate
knowledge of the type and extent of valve pathology. Clini-
cally, a comprehensive diagnostic evaluation of valves
requires assessment of the following: (1) morphology of the
valve, for example, size, shape, and structure of the valves,
and the adjoining supporting structures; (2) hemodynamics
across the valve, for example, direction, speed, and the
amount of blood flow during the cardiac cycle to define the
extent of regurgitation or stenosis; (3) effect of the valvular
dysfunction on the morphology of the heart, for example,
enlargement of the chambers due to volume overload, or
hypertrophic adaptation of the pumping chambers due to
pressure overload; and (4) effect of valvular pathology on
global left ventricular (LV) function.1 The value of such infor-
mation has long been recognized, and a number of invasive
and noninvasive methods for evaluating blood flow within
the body have been proposed.2–5
Conventional catheter x-ray angiographic methods can
give accurate information about both flow and pressure
across the valves and is unique in this respect. However, x-
ray angiography is invasive, imposes a radiation burden,
requires nephrotoxic contrast media, and carries a small but
not insignificant risk.6,7 Conventional echocardiographic
Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553
methods can visualize the cardiac chambers, valves, and,
when combined with Doppler techniques, can also provide
quantitative information about blood and tissue velocity.8,9
Ultrasound based methods are widely available, and are supe-
rior to other methods for visualizing valve leaflets with high
temporal resolution, and for rapidly providing velocity spectra
at a given location. However, ultrasound techniques require
favorable acoustic windows, ultrasound-based volume esti-
mates often involve geometric assumptions, and the estima-
tion of flow velocity is restricted to the blood moving toward
or away from the ultrasound transducer.
In this respect, cardiovascular magnetic resonance (CMR)
imaging provides a number of tools to assess valvular dys-
function. Conventional spin-echo–based “black-blood” and
gradient-echo “bright-blood” cine magnetic resonance (MR)
imaging can readily provide information about the size and
shape of the chambers and parameters that describe global
LV and right ventricular (RV) function such as stroke volume
and ejection fraction, without the need for geometric assump-
tions or models. Recent advances in CMR hardware and
imaging methodology make it possible to obtain cine frame
rates that are comparable to echo ultrasound and acquire
images within a breath-hold. These gradient-echo–based cine
imaging methods can be modified to reveal qualitative infor-
mation about the presence, extent, and duration of jets caused
by regurgitation or stenosis. With respect to estimating the
blood velocities, MR phase-contrast methods can directly
measure the blood velocity from the phase of the received
MR signal independent of the orientation of the vessel or the
direction of blood flow within the body. As a result, MR can
directly estimate volume flows without geometric assump-
tions, a characteristic lending technical superiority over
Doppler methods. Lastly, CMR techniques provide an array
of contrast mechanisms that may be exploited to visualize
intracardiac thrombus, postsurgical leaks in and around
valve structures, and vegetations.10–14
5 37
538 chapter 22

Magnetic Resonance Imaging Methods After 90-degree

pulse
Before 180-degree
pulse
Resulting
image

Magnetic resonance imaging techniques for assessing valvu- Slow flow

lar heart disease in routine clinical practice may be broadly
divided into three broad categories: black-blood imaging
techniques, bright-blood cine imaging techniques, and phase- A
contrast velocity mapping techniques. The physical princi-
ples behind each of the techniques are described in the Mod. flow
following subsections (Table 22.1).

Black-Blood Morphologic Imaging Techniques B

Simple cardiac gated spin-echo (SE) techniques are sensitive
to blood flow, and this sensitivity can be exploited to provide
flow-dependent contrast. This is best illustrated by consider-
ing the case of an imaging slice oriented orthogonal to a
flowing vessel (Fig. 22.1). In a simple SE method, the initial
90-degree radiofrequency (RF) pulse rotates the entire longi-
tudinal magnetization (M z) into the transverse plane, creat-
ing transverse magnetization (M xy) that is measurable. The
measurable component of magnetization creates a signal
that decays rapidly. This signal decay is composed of an
irreversible signal loss due to spin–spin interactions (referred
to as T2), and a potentially reversible loss of signal due to
local magnetic field inhomogeneities (referred to as the T2’).
In a simple SE implementation, another RF pulse is applied
after time τ from the 90-degree pulse, such that it rotates M xy
by 180 degrees in the transverse plane. This restores the
signal from the reversible component of signal loss by refo-
cusing the transverse magnetization to form the so-called
spin echo at 2τ, a time often referred to as the echo time
(TE). The nonmoving tissue experiences both the excitation
Fast flow
C
FIGURE 22.1. Spin-echo–based black-blood imaging based on time-
of-flight (TOF) phenomenon. Through plane flow through a slice at
different flow rates, slowest on the top panel and the fastest in the
bottom panel. Slow-flowing spins experience both the 90- and the
180-degree pulses, and therefore fully refocus to give a bright signal
(A). On the other hand, if the spin velocity is high enough, none of
the spins experience both the 90- and the 180-degree pulses, and the
resulting image has a signal void (C). If the spin velocity is inter-
mediate, then the resulting image has a signal intensity that is
proportional to the fraction of the spins that experienced both the
90- and the 180-degree radiofrequency (RF) pulses (B). Typically,
the spins near the vessel wall appear brighter as these flow the
slowest.

TABLE 22.1. Magnetic resonance (MR) imaging techniques for assessing valvular heart disease in clinical practice
MR technique Potential information content Clinical applications

Black-blood imaging • Valvular thickening/calcification • Evaluation of stenosis

Cine bright blood imaging
(T1-weighted gradient-echo
and steady-state free
precession sequences)
Phase-contrast imaging
* LV, left ventricle; RV, right ventricle; TFE, turbo field-echo.
• Overall shape and geometry of the heart
• Tissue characterization
• Volumetric information about RV and LV:
• End-diastolic volume (EDV)
• End-systolic volume (ESV)
• Stroke volume (SV)
• Ejection fraction (EF)
• Cardiac mass (LV mass)
• Contraction pattern
• Signal voids due to complex flow
• Adjust by changing TE (primarily for T1-TFE)
• Valve morphology
• Shape, size, number of leaflets, etc.
• Quantitative information on:
• Pixel-by-pixel velocity
• Direction of flow
• Components of velocity vector
• Direct estimation of time gradient from
peak volume flow
• Direct estimation of peak velocity
• Visualize volume flow patterns, e.g.,
pulmonary venous flow patterns
• Effect of valve pathology on heart
• Evaluation of vegetations, perivalvular leaks, or
abscesses
• Assess the effect of valve disease on global cardiac
function
• Assess valve size
• Postsurgical evaluation of valves
• Assess shunts with LV and RV stroke volumes
in simple single valve disease
• Qualitatively assess
regurgitation and stenosis
• Evaluation of regurgitant volumes from volume
flow curves
• Assess shunts
• Evaluation of peak velocity in stenosis
• Estimate the pressure velocity using simplified
Bernoulli equation to grade stenoses
• Visualization of flow patterns can reveal clinically
useful information, e.g., flow reversal in
pulmonary veins due to diastolic dysfunction
• Estimate valve orifice area using velocity time
integral approach
 m a g n e t i c r e s o n a n c e i m a g i n g o f va lv u l a r d i s e a s e
(90-degree), and the refocusing (180-degree) pulses, and as a
result the echo formed has full signal due to contributions
from the entire magnetization within the slice. On the other
hand, for moving tissue (e.g., blood flow) if the velocity is
rapid enough, flowing blood experiences the 90-degree pulse,
but can leave the slice before the 180-degree pulse is applied,
resulting in the “black-blood” appearance. For all velocities
in between the two extremes, the signal intensity in the
resulting image is proportional to the fraction of the hydro-
gen nuclei that experience both the 90- and the 180-degree
pulses. Such simple spin-echo–based techniques can provide
a good anatomic overview of the cardiac chambers, vessels
leading into and out of the heart, and some limited informa-
tion about the valves. Recent methodologic advances permit
black-blood imaging of the cardiac chambers in any
orientation.15
Bright-Blood Imaging Techniques
The bright-blood imaging techniques exploit the presence or
inflow of blood signal within the slice of interest as follows.
Gradient-echo techniques typically rotate only a fraction of
M z into the transverse plane by applying an RF pulse with a
limited flip angle (typically around 20 to 30 degrees). The
transverse magnetization that is created is immediately
measured with a gradient reversal. As a result, the gradient-
echo sampling process may be repeated more quickly, that
539
is, with a shorter repetition time (TR) (without having to wait
for the regrowth of M z from zero via spin-lattice or T1 relax-
ation as is the case for spin-echo techniques).16–18 As a result
of the rapid application of RF pulses, the steady-state signal
of static spins is diminished compared to flowing spins, and
thus generates an in-flow dependent contrast. With cardiac
gating and modern imaging hardware, it is possible to attain
cine images at high frame rates, obtaining information about
global and regional function.
T1-weighted Cine Gradient-Echo Technique
T1-weighted cine gradient-echo methods are useful in a
number of ways to evaluate valve function. The enhance-
ment of blood signal caused by the inflow effect can be used
to visualize valve morphology. For example, an “en-face”
view of the aortic valve can reveal information not only
about the size of the valve, but also about the number of valve
leaflets by highlighting the coherent inflow enhancement
during systole (Fig. 22.2). The size of the valve orifice can
also be determined from direct planimetry.
As blood accelerates through a stenotic valve, a region of
signal loss appears as a jet distal to the stenosis in the gradi-
ent-echo images. The size and shape of the jet depend not
only on the stenosis degree and the hemodynamics across
the valve, but also on several MR acquisition parameters,
such as in-plane and through-plane voxel size,19 type of gradi-
ent-echo sequence used,20 and most importantly, on the TE

A B

FIGURE 22.2. Four frames from a cine gradi-

ent–echo image of the aortic valve demonstrate
the effect of inflow related enhancement char-
acteristic of T1-weighted gradient echo images.
(A) En-face view of the aortic valve at end-dias-
tole shows little signal due to lack of inflow in
contrast to the bright appearance of the infe-
rior vena cava that drains venous blood into the
right atrium. (B,C) Aortic valve opens during
peak and late systole, clearly depicting the
trileaflet configuration, and bright blood signal
across the valve due to inflow enhancement.
(D) Aortic valve closes during early diastole,
and appears dark due to lack of inflow. Such
views readily allow the visualization of the
valve morphology, and direct planimetry can
C D
give information about valve size.
540 chapter
used for data collection.21–24 The longer the TE, the greater
the flow-induced dephasing and the bigger the size of the jet.
As a result, small flow disturbances can be visualized by
choosing a longer TE or obscured by a very short TE.
For the same reasons causing signal loss in stenotic jets
described above, regurgitant jets also result in signal loss,
and can be readily visualized in cine gradient-echo images
with an appropriate TE. While the extent of signal loss can
be used as a qualitative measure to determine the severity
of regurgitation, MR provides better methods for accurately
quantifying regurgitation volume using phase-contrast
methods (described below).25,26 To visualize the size and
duration of the jet, it is necessary to align the imaging slice
along the axis of the core of regurgitation. The ability to
freely align the imaging slice parallel to the axis of the regur-
gitant jet is an intrinsic strength of CMR cine imaging
methods compared to the ultrasound-based methods, partic-
ularly with eccentric regurgitant jets.23
Steady-State Free Precession Methods
With the advent of higher strength gradients, the recently
described steady-state free precession (SSFP) sequences are
gaining wider acceptance [also referred to as balanced fast
field echo (bFFE), true fast imaging with steady-state preces-
sion (TrueFISP), or fast imaging employing steady-state
acquisition (FIESTA)] for evaluating LV function.27 The SSFP
sequence is preferred because of improved temporal resolu-
tion, better blood-to-myocardium contrast, and higher signal
over conventional T1-weighted cine gradient-echo sequences,
making it a sequence of choice for routine LV function
evaluation.28–30
However, there is a significant difference between the T1
cine gradient-echo technique and the SSFP cine gradient-
echo technique with respect to visualizing the regurgitant
jets. In the case of the T1 cine gradient echo, the sensitivity
to regurgitation (or stenosis) can be readily adjusted by
changing the TE. However, SSFP sequences are very sensi-
tive to magnetic field inhomogeneities, and, to prevent arti-
facts, the shortest possible TEs (<2 ms) are used. In addition,
the balanced gradient structure of the SSFP sequences also
makes it relatively insensitive to spin velocity. Because of
these two factors, from a clinical imaging perspective, the
jet size in the SSFP sequences qualitatively appears less sig-
nificant for the same degree of gradient.31
Phase-Contrast Velocity Mapping
Principle of Phase-Contrast Velocity Mapping
The measured MR signal, the transverse magnetization
(M xy), is a vector quantity that has both amplitude and direc-
tion. The amplitude of the signal depends on the interplay
among the tissue relaxation parameters (T1, T2, PD [proton
density], etc.), and the conditions (sequences, TR/TE, etc.)
under which the MR data acquisition is conducted. The
direction of the signal often referred to as the phase, can also
be manipulated to yield a variety of information such as the
local susceptibility and spin velocity. In MR phase-contrast
velocity mapping (PVM), the phase of the MR signal is
manipulated to yield information about spin velocity.
22
All spins precess at a characteristic frequency (f) in the
presence of a homogeneous main magnetic field (B). The
frequency of precession is proportional to the strength of the
field experienced by the spins and is often referred to as the
resonant or Larmor frequency. The proportionality constant,
γ, is characteristic for each nuclei. The addition of an appro-
priate gradient waveform within the imaging sequence, for
example, bipolar gradient, allows a spin moving in the direc-
tion of the magnetic field gradient to accumulate a net phase
shift compared to a static spin. This phase shift can be
directly related to the velocity (ν) of the spin using the fol-
lowing relationship25:
f = γ M1 ν,
where γ is a constant specific to a given nuclei, and for protons
the value of γ is 42.57 MHz/tesla (gyromagnetic ratio), and
M1 is the first temporal moment, an operator controlled
variable that is a function of the strength, shape, duration,
and the temporal position of the gradient waveform within
the imaging sequence (referred to as the first temporal
TE
moment of the gradient waveform: M1 = ∫ t ⋅ G(t)dt ).
0
In routine clinical imaging, a bipolar gradient waveform
is used to introduce motion sensitivity to an imaging
sequence, and the strength of the bipolar gradient is altered
to adjust the first temporal moment of the gradient, which
scales linearly with the induced phase shift, for any given
velocity. It is also important to note that the induced phase
shift is proportional only to the component of velocity along
the direction of the magnetic field gradient, and phase is
sensitive to direction of flow along the gradient waveform
(Fig. 22.3). Therefore, to measure the true velocity, it is nec-
essary to either align the velocity-encoding direction in the
direction of flow or measure all three components of the
velocity vector by superimposing gradients along all three
orthogonal directions. In this respect, unlike Doppler
methods, which can only measure velocity of blood particles
moving away or toward the transducer, MR can measure
flow along any direction.
Technical Considerations
While MR phase-contrast velocity mapping is a powerful
tool for noninvasively measuring flow velocities within the
human body, the choice of imaging parameters has a pro-
found influence on the accuracy and precision of velocity
measurements, the practical aspects of which will be dis-
cussed in the following subsections.
Strength of Velocity Encoding
As discussed above, the motion-induced phase shift is pro-
portional both to the spin velocity ν, as well as dM1 used in
the pulse sequence. By adjusting the strength of velocity
encoding, that is, dM1, it is possible to induce a very large or
a very small phase change in the signal, for a given spin
velocity. When encoding through plane flow within an
imaging slice that comprises both the ascending and descend-
ing aorta, for example, the flow toward the head in the
ascending aorta is represented by a positive value, and the
 m a g n e t i c r e s o n a n c e i m a g i n g o f va lv u l a r d i s e a s e
DB
G G
–x3 x3 x t0 t1 t2
t
f f
t0 t1 t2 t t0
A B
FIGURE 22.3. (A) Effect of bipolar gradient on static spins. On the
left, the field variation imposed by the bipolar gradient is shown
schematically. The solid blue line indicates the field gradient between
time points to and t1, and the dotted blue line indicates the field gradi-
ent between time points t1 and t2. The bipolar gradient waveform is
shown on the right, and the corresponding phase evolution diagram
during the course of the gradient is shown below. A spin located at
the isocenter (cyan color) experiences no net additional field and as a
result accumulates no phase shift. Let us consider the case of a spin
at location xs (red color). This spin experiences a slightly higher mag-
netic field during the positive lobe of the bipolar gradient between
time points t 0 and t1 and during this time accumulates a net positive
phase shift (with respect to a spin at the isocenter). When the gradi-
ent polarity is reversed during time interval t1 and t2, the same spin
experiences a slightly lower magnetic field strength and starts to
accumulate a negative phase shift. At the end of the bipolar gradient
lobe, the spin at location xs accumulates no net phase shift. By the
same argument, it is easy to see that static spins do not accumulate
a net phase shift independent of their location along the x-axis. (B)
Effect of bipolar gradient on moving spins. Let us consider a spin at
flow toward the feet in the descending aorta is represented
by a negative value or vice versa. The phase-contrast velocity
measurements are chosen such that the maximum velocity
within the slice of interest induces a phase shift less than
180 degrees. This limiting value of the strength of the veloc-
ity encoding is often referred to as the Venc value. Any veloci-
ties greater than the Venc value within the slice of interest
appear with artificially lower velocities flowing in the other
direction—a phenomenon referred to as aliasing. Because the
standard deviation of the measured velocity is proportional
to the Venc value, the Venc value should be chosen just high
enough to avoid velocity aliasing in the vessel of interest.32
Strategies for Velocity Encoding Directions
As discussed above, to measure a single component of the vel-
ocity vector using the PC method, two complete sets of mea-
surements are sufficient, yet to measure all three components
of an arbitrary or unknown velocity vector, it is necessary to
have multiple measurements.32,33 The simplest approach to
completely measure all three components of an arbitrary
velocity vector is a direct extension of the simple two-point
method, by using three pairs of measurements to measure
each component of velocity vector; however, the imaging time
is tripled compared to the simple two-point method.
Instead of tripling the acquisition time using the six-
point method to encode for all three components of the
velocity vector, more efficient ways for encoding velocities
5 41
DB
x0 x1 x2 x t0 t1 t2
t
t1 t2 t
location x0 at time point t 0 that moves at a constant velocity. Between
time points t 0 and t1, the moving spin traverses through an ever-
increasing magnetic field strength as shown on the left. Compared
to a static spin at location x0, by virtue of its motion from location x0
to x1 in the presence of the positive lobe of the bipolar gradient ori-
ented along the x-axis, the spin accumulates a slightly higher phase
at time point t1. As the gradient polarity is reversed at time point t1,
the spin starts to accumulate a negative phase shift. As the spin
continues to move from x1 to x 2 under the influence of the negative
lobe of the bipolar gradient, the rate of phase accumulation is even
greater, as the spin experiences a much higher negative magnetic
field strength. At the end of time point t2, unlike a static spin, the
moving spin accumulates a net negative phase shift. By the same
argument, it is easy to show that spins moving in the opposite direc-
tion at the same rate would accumulate a net positive phase shift
under the influence of the same bipolar gradient. Thus, moving spins
accumulate a phase shift that gives information both about the rate
of displacement, as well as the direction of motion. This phase accu-
mulation forms the basis of phase contrast measurements in mag-
netic resonance imaging.
have been developed.32,33 A common approach is to use one
reference acquisition and three velocity-encoded acquisi-
tions. This requires a total of four acquisitions, and therefore
the scan time is only twice that of the two-point unidirec-
tional method (Fig. 22.4). However, in this case, the same
reference scan is used for all three velocity-encoded images,
and therefore the noise in the images is correlated. 32
In summary, at least two measurements are required for
encoding velocity in one direction, and four measurements
are required for measuring velocity in all three directions.
When clinical conditions warrant the complete resolution of
the velocity vector components, for example, for the estima-
tion of peak velocity of a stenotic jet that does not lie in one
plane, an appropriate choice of encoding scheme may provide
benefits in reducing velocity noise.
Type of Cardiac Gating
Most cardiac studies use some form of gating to acquire
information about temporal variations in velocity (and flow)
over the cardiac cycle.34 There are two prominent types of
cardiac gating used in MR quantitative flow imaging: pro-
spective gating and retrospective gating.35,36 In prospective
gating methods, the MR spectrometer essentially waits for
the electrocardiogram (ECG) trigger (usually identified by
the top of the R wave) and then starts to acquire data for
most of the cardiac cycle (typically about 80% to 90% of the
RR interval). The scanner “waits” for the next trigger and
542 chapter
FIGURE 22.4. Complete evaluation of the velocity vector compo-
nents by superimposing velocity-encoding gradients along each of
the three orthogonal axes. A single frame of the phase contrast
image obtained with velocity-encoding gradients along the right-left
(RL) (red), foot-head (FH) (green), and anteroposterior (AP) (brown)
directions is shown in panels A, B, and C, respectively. Note velocity
aliasing (B) due to velocities in the FH direction exceeding the pre-
collects data, and this process continues for all necessary
views acquired to make an image. As a result of this “dead
time” in the prospective triggering method, data are not
acquired during a portion of the RR interval (typically end-
diastole), which has clinical implications for the evaluation
of valve disease using PVM. For example, much of aortic/pul-
monary regurgitation occurs during diastole, and missing a
portion of diastole can result in substantial underestimation
of the severity of aortic/pulmonary regurgitation.
Retrospective gating eliminates this limitation, by con-
tinuously acquiring data without interruption, and the phase-
encoding step is incremented once during each RR interval,
while retaining the temporal information of when the data
are acquired during the cardiac cycle. After all phase-encod-
ing steps are acquired, the scanner can then retrospectively
reconstruct images that are spread throughout the cardiac
cycle. For clinical quantitative flow imaging, retrospective
gating has been the preferred form of gating, and it is also
common clinical practice to average the data to minimize
errors introduced by other undesired forms of motion. The
main disadvantage of the retrospective gating methods is the
prolonged acquisition time, which is on the order of 2 to 3
minutes per slice per velocity-encoding direction.
Choice of TE
In the context of gradient-echo–based phase-contrast mea-
surements, shorter echo times (TEs) are desirable for many
reasons. The shorter the TE, the lesser the spurious phase
accrual caused by off-resonant effects, the lesser the signal
loss caused by intravoxel dephasing due to fast or irregular
22
scribed Venc value (see text for details). An artificial color scale based
on the phase measurements in the velocity-encoded image (RL
direction) is superimposed on the magnitude image for visualization
purposes (D). The magnitude image that provides anatomic infor-
mation can be readily reconstructed from the phase contrast mea-
surement data (E). The average velocity (V) across the vessel along
the RL, FH, and AP during the cardiac cycle is shown (F).
flow,37 and the lesser the undesirable effect of acceleration
and other higher order effects.38–40 The effect of convective
acceleration is particularly important in the context of mea-
suring rapid flow through a severe narrowing, for example,
valve stenosis. If a peak velocity across the valve of 200 cm/
sec is measured with an imaging sequence with a TE of 15 ms
and a slice thickness of 5 mm, then the spins may travel up
to 30 mm (or six times the slice thickness) between the slice
encoding and the measurement, and the resulting velocity
measurements may be quite erroneous. Recent advances in
gradient hardware and methodologic improvements make it
possible to obtain extremely short echo times on the order
of 1 to 2 ms, which can substantially minimize such errors.
In-Plane Versus Through-Plane Velocity Encoding
Estimation of peak velocities (Vm) of stenotic jets is clinically
important and can be used to estimate the pressure gradient
(ΔP) using the simplified Bernoulli equation: DP = KVm 2
, where
K is the loss constant usually assumed to be 4. For the pur-
poses of visualizing and quantifying peak velocities in ste-
notic jets, it is advantageous to encode for velocities in the
plane of the jet. However, such in-plane velocity encoding is
fraught with several problems and has to be used carefully in
a clinical setting for the following reasons. First, the dimen-
sion of the voxel in the slice direction is about two to three
times longer than in the other directions. Therefore, there
could be a significant amount of partial volume effect within
the voxel, if the jet is very small, and can result in an under-
estimation of the peak velocity. Second, the turbulent jet
may not be in just one plane, and it may be necessary to
 m a g n e t i c r e s o n a n c e i m a g i n g o f va lv u l a r d i s e a s e
encode for velocities in more than one direction. Lastly, in-
plane encoding does not permit the measurement of the
cross-sectional area of the vessel and therefore volume flow
rates. In this regard, phase contrast sequences with a spiral
readout have attractive flow properties, as they result in
substantially lower displacement and blurring artifacts for
in-plane flow.41 Through-plane velocity encoding allows for
simultaneous measurement of velocity as well as the cross-
sectional area and therefore volume flow rate. The disadvan-
tage of through-plane velocity encoding is that it is important
to position the slice across the location of maximum velocity,
and this may be difficult to determine a priori. However,
the peak velocity profile of the jet can extend up to five times
the diameter of the jet within the imaging plane, allowing
some margin for accurate slice placement.42 In general, the
location of the phase contrast imaging slice can have a major
influence on the accuracy of measurements, not only on
peak velocity estimation but also on the estimation of
regurgitation.43,44
Partial Volume Effect
Voxels at the boundary of the vessels contain both static and
moving spins, and this results in systematic errors that
reduce the accuracy of phase contrast measurements.19,45,46
Partial volume errors can also occur in through-plane veloc-
ity encoding measurements if the slice intersects the vessel
of interest nonorthogonally. The extent of error is propor-
tional to the ratio of voxel size to vessel size.19,45 Studies have
shown that it is necessary to have roughly four pixels across
the diameter of the vessel of interest (or around 14 voxels
across the cross section of the lumen) to have errors less than
10%.47–50 The measurement of peak velocity is a bit more
complicated. Estimation of peak velocity from a single pixel
may suffer from poor precision, and averaging adjacent voxels
would introduce partial volume error. Some studies have
suggested that an average of four pixels in the central core of
the jet may be used.24 It should also be remembered that MR
measurements of peak velocities are time-averaged values
and in general are lower than instantaneous measurements
of velocity.
Region of Interest (ROI) Placement
When through-plane velocity encoding is used, MR provides
both the velocity as well as the cross-sectional area of the
vessel of interest, making it simple to compute volume flow.
An ROI prescribed smaller than the vessel size would under-
estimate volume flow, and an ROI that is larger than the
vessel size might introduce spurious phase shifts associated
with low signal-to-noise ratio (SNR) regions outside the
vessel of interest.51 From a theoretical point of view, it is
necessary to use an ROI as small as possible but as large as
necessary to cover the entire vessel.19 From a clinical point
of view, it is common to prescribe the ROI in the high-con-
trast magnitude images and then transfer them over to the
phase difference images, and adjust their size over the cardiac
cycle to account for any vessel motion due to vascular com-
pliance. There have been a number of methods proposed in
the literature to automatically draw the contours to mini-
mize errors due to ROI placement, and such methods have
to be clinically validated.52–55
543
Clinical Applications
Aortic Valve Disease
Cine MR has demonstrated good facility for anatomic evalu-
ation of the aortic valve for at least the last decade and a half.
Valve morphology can be determined with either spin-echo
black-blood imaging or gradient-echo bright-blood imaging.
Typically, such imaging is performed using both techniques;
spin-echo imaging helps determine the static morphology of
the valve, whereas cine imaging provides greater detail
regarding function.
Normal aortic valve morphology is trileaflet, although
bicuspid valves are frequently seen. The typical configura-
tion for a bicuspid valve is fusion of the left and right coro-
nary cusps, along with a prominent noncoronary cusp
resulting in a slit-like or “fish-mouth” opening during ven-
tricular systole. More severe congenital malformations
include unicuspid and quadricuspid valves, although these
are infrequently encountered, except in laboratories with a
large volume of congenital studies.
Static spin-echo imaging can determine the size, shape,
and thickness of the valve cusps, but does a relatively poor
job identifying calcification.56 Alternatively, cine gradient-
echo imaging can evaluate the mobility of the valve cusps
and identify the presence of valvar calcifications, manifested
by regions of signal dropout against the background of bright
moving blood. Calcium typically has little to no mobile
protons and therefore has little to no signal intensity on cine
imaging.
Additional information that may be determined with
either spin-echo or gradient-echo imaging includes the size
of the aortic annulus, the shape and size of the sinus of Val-
salva, the presence of a distinct sinotubular junction (or
effacement thereof), and the caliber of the proximal tubular
portion of the ascending aorta. These features can be critical
differentiators of aortic valvular disease etiology, as in
patients with Marfan syndrome where aneurysmal enlarge-
ment is centered in the aortic root and typically results in
complete effacement of the sinotubular junction.
Aortic Stenosis
In the evaluation of patients with aortic stenosis, a complete
evaluation should include qualitative and quantitative deter-
mination of stenosis degree, evaluation of left ventricular
function, and quantification of left ventricular volumes and
mass. These are all parameters for which CMR is now well
positioned to acquire in an accurate and reproducible
fashion.
Initial evaluation of suspected aortic stenosis begins with
morphologic assessment of the aortic valve, which in normal
adults has a valve orifice of 3 to 4 cm2. An aortic valve orifice
greater than 1.5 cm2 is considered mild stenosis, greater than
1.0 to 1.5 cm2 is considered moderate stenosis, and less than
1.0 cm2 is considered severe stenosis.57 Morphologic assess-
ment may be performed with spin-echo images, although the
valve orifice may be overestimated as a result of misposition-
ing of the acquired imaging slices, or volume averaging from
imaging slices that are too thick for accurate determination56
(Fig. 22.5; and Video 22.1 on the DVD).
544
Area = 0.8 cm2
FIGURE 22.5. A cine gradient-echo sequence was performed across
the face of the aortic valve. This image, acquired during peak systole,
reveals calcific fusion of the commissures between the left and
right, and the right and noncoronary cusps. A small, slit-like orifice
remains with a planimetered cross-sectional area of 0.8 cm 2.
In the past, cine imaging was performed with slices
acquired parallel to the aortic annulus and across the face of
the valve to assess valve orifice size. The relationship was a
reasonable one, although in general less accurate than echo-
cardiography as a result of the previously more limited spatial
and temporal resolution afforded by CMR techniques.58
Current techniques using steady-state free-precession
imaging has both high spatial and temporal resolution and
excellent signal to noise and contrast to noise ratios, result-
ing in high-quality morphologic visualization. This tech-
nique can now determine valve orifice areas with accuracy
comparable to that of echocardiography, although with the
same limitations as echocardiography,59,60 namely, that the
imaging plane must be precisely at the valve orifice and not
slightly proximal or distal to the coaptation zone, which will
result in overestimation of the orifice.
Qualitative Evaluation
Qualitative assessment of aortic stenosis severity may be
performed with flow-sensitive cine imaging performed paral-
lel to the turbulent jet of stenotic blood. Typically, these flow
sensitive sequences have longer TEs (in the range of 6 to 8 ms
for clinical use), resulting in sufficient phase dispersion to
identify turbulent jets as signal voids within the surrounding
bright blood having more laminar flow.61 Mild aortic stenosis
results in a relatively narrow jet of turbulence that extends
only to the proximal portion of the ascending aorta. More
severe aortic stenosis results in a border jet of signal void that
may extend clear to the distal ascending aorta. In addition,
more severe aortic stenosis may be associated with aneurys-
mal dilation of the ascending aorta, which may be imaged
simultaneously.
chapter 22
Quantitative Evaluation
While qualitative approaches are sufficient for screening of
valvular disease, the accurate initial determination and
follow-up of patients with aortic valvular disease require
quantification of the degree of stenosis. Similar to echocar-
diography, CMR using flow quantification sequences can
determine the transvalvular gradient by determining the
peak velocity of blood flow through the stenotic orifice.62
Once the peak velocity through the stenotic orifice is deter-
mined, the modified Bernoulli equation allows determina-
tion of both peak and mean transvalvular gradients (Fig. 22.6;
and Video 22.1 on the DVD). Multiple studies have demon-
strated close agreement between gradients determined by
CMR and echocardiography. Similar to echocardiographic
measurements, CMR measurements may underestimate
500 cm/s
333
167
0
–167
–333
–500 cm/s
PCA/P
SI 1
500
400
Peak velocity = 4.9 m/sec
Velocity (cm/sec)
Peak gradient = 96 mm Hg
300
200
100
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
–100
Cardiac phases
FIGURE 22.6. The upper half of the image demonstrates a phase-
contrast velocity-encoded image with superimposed color corre-
sponding to the velocity of blood flow. The patient has severe aortic
stenosis, and a high-velocity jet is seen immediately distal to the
restricted coaptation point of the aortic valve. The graph (lower half)
represents the velocity profile of the oval region of interest placed
within the velocity jet. A peak velocity of 4.9 m/sec was recorded,
corresponding to a peak gradient of 96 mm Hg.
 m a g n e t i c r e s o n a n c e i m a g i n g o f va lv u l a r d i s e a s e
those found in the catheterization laboratory as a result of
the patient being in a more relaxed state during a CMR
examination. Lower cardiac outputs, and therefore lower
stroke volumes, lead to lower transvalvular gradient deter-
minations. For similar reasons, patients with depressed
cardiac function may also give artifactually low transvalvu-
lar gradients despite the presence of more severe degrees of
stenosis.
Another approach to quantitative aortic stenosis assess-
ment is the use of time-velocity integrals (TVIs). This
approach is based on the continuity equation in which all
flow through the left ventricular outflow tract is assumed to
move through the stenotic aortic valve. As such, the flow can
be based on the simple product of cross-sectional area and
mean velocity, with the valve area easily calculated. Echo-
cardiography has shown good results compared to the inva-
sively determined Gorlin formula, despite the assumption
that the LV outflow tract (LVOT) is round. The TVI approach
has not routinely been performed using CMR, yet a recent
report by Caruthers et al.63 has confirmed the excellent
utility of this approach. These investigators acquired two
flow quantification sequences, one in the LVOT, immedi-
ately subvalvar, and the second in the immediately supraval-
var position. In this study the authors noted a close correlation
between CMR and echocardiographically derived values for
peak velocities between 1 and 4 m/sec. Velocities greater
than 4 m/sec were slightly underestimated by CMR, although
there was no change in the clinical categorization of aortic
stenosis severity.
Left Ventricular Function and Mass
In addition to the qualitative and quantitative approaches to
aortic valve stenosis severity, CMR can also determine left
ventricular function, volumes, and mass, all parameters
critical in the global assessment of the patient with aortic
stenosis. In the early stages of significant aortic stenosis,
patients may maintain left ventricular function even in the
545
face of left ventricular hypertrophy. Despite the presence of
a significant gradient (greater than 50 mm Hg mean value),
the patient may remain asymptomatic. Nonetheless, once a
patient with severe aortic stenosis becomes symptomatic,
valve replacement surgery is the generally accepted therapeu-
tic option. Alternatively, patients with severe aortic stenosis
who are symptomatic should have valve surgery considered
when there is left ventricular dysfunction or left ventricular
hypertrophy.
While valvular aortic stenosis has been the focus of this
section, concomitant or mimic lesions can also be found
with CMR. Specifically, subvalvular membranes or masses
resulting in LVOT obstruction, turbulence, and gradients can
be evaluated using a combination of spin-echo and cine
imaging, along with phase-contrast velocity imaging for gra-
dient evaluation. Similarly, supravalvular stenosis, usually
either congenital or postsurgical in nature, can be evaluated
in comparable fashion.
Concurrent Valvular Lesions
When significant aortic insufficiency is also present, the
qualitative assessment of aortic stenosis may be overesti-
mated as a result of the increase in stroke volume and cardiac
output (Fig. 22.7; and Video 22.1 on the DVD). These factors
also complicate calculations by the Gorlin formula. In these
cases, the TVI calculation is the preferred approach as it is
not dependent on isolated disease and continues to provide
an accurate measurement of aortic valve area despite the
presence of aortic insufficiency.
Aortic Insufficiency
Aortic insufficiency typically has a broader list of etiologies
than aortic stenosis and includes congenital anomalies, such
as bicuspid valves; rheumatic heart disease; endocarditis; and
the range of cystic medial necrosis, including Marfan syn-
drome. Further, aortic insufficiency may occur secondary to

FIGURE 22.7. Severe calcific aortic stenosis as

seen using a flow-sensitive cine sequence in an
oblique coronal orientation. The left panel
demonstrates a prominent, broad jet of turbu-
lence extending to the mid-ascending aorta
(arrow), and the valve leaflets are nearly immo-
bile. The right panel is from mid-diastole and
demonstrates moderate aortic insufficiency
with a jet of turbulence directed into the basilar
left ventricular cavity (arrowhead). Note the
extensive black areas on the aortic valve cusps
compatible with calcification.
546 chapter 22

aortic dissection, or as a postsurgical consequence. Natu- throughout the cardiac cycle with the change in caliber from
rally, treatment varies depending on the underlying anatomy, systole to diastole. Mean velocities are determined at each
and importantly, on the associated aortic root and proximal phase of the cardiac cycle and then multiplied by the cross-
ascending aortic anatomy. Spin-echo, static images are sectional area of the region of interest to determine instan-
routine in evaluation of aortic valve morphology, and likely taneous flow at each phasic time point.54 These data points
most beneficial for analysis of the aortic root and proximal can be graphed rapidly, and determination of both forward
ascending aorta. and reverse blood flow volumes calculated64 (Fig. 22.8).
The regurgitant fraction is determined by dividing the
Qualitative Evaluation regurgitant volume of blood seen in diastole by the forward
blood flow volume seen during systole (Fig. 22.9; and Video
Cine imaging provides the starting point for evaluation of
22.1 on the DVD). Normal values of aortic regurgitant
aortic sufficiency. Functional imaging across the face of the
fraction range up to 7%, as a result of runoff into the
valve helps determine the valvular morphology, as well as
coronary arteries, as well as compliance of the aortic root
the size of the orifice that fails to coapt during valve closure.
and proximal ascending aorta, and the slight reflux associ-
On cine gradient-echo imaging this lack of coaptation point
ated with aortic valve closure. Variations in measurements
appears as bright white in the center of the valve cusps when
will occur based on the patient’s loading conditions, and
using standard cine gradient-echo imaging with short TEs
for serial studies similar hemodynamic patient states are
that rely on inflow of fresh spins through the valve plane.
necessary.65
Alternatively, flow-sensitive cine imaging (with longer TEs
The phase-contrast velocity encoded MR techniques have
resulting in sufficient phase dispersion and a resultant signal
an additional technical limitation in that the imaging plane
void in areas of turbulence) is used in projections parallel to
within the chest is static. In younger patients or in those
the long axis of the valvular jet. Typically these orientations
with significant aortic insufficiency, there may be a substan-
include a short axis at the base of the left ventricle through
tial degree of excursion of the aortic valve plane through the
the aortic root, as well as a parasternal long axis orientation.
cardiac cycle,66,67 and the valve orifice may alter dynamically
The length and breadth of the signal void related to a turbu-
throughout the cardiac cycle.68 As such, flow measurements
lent jet of insufficiency is used to assess the severity of aortic
may have small variations. Recently, a technique has been
regurgitation. Similar to echocardiography, if the regurgitant
developed to determine and compensate for the valvular
jet is relatively narrow and extends only partially into the
motion during the velocity-encoded acquisition. Taking into
left ventricular cavity, it is considered mild, whereas severe
account the through-plane motion of the aortic valve, correc-
insufficiency is characterized by a broader jet of turbulence
tions are made to the data, which minimizes the underesti-
that extends deep into the left ventricular cavity toward the
mation of aortic regurgitant volume.69
inferolateral wall.
Qualitative determination of eccentric aortic insuffi-
ciency is more complicated and requires placement of mul-
tiple imaging planes parallel to the jet of insufficiency.
Because of the greater complexity in ensuring proper slice
orientation, the degree of severity may be underestimated.
Fortunately, quantitative approaches overcome these
limitations.
Aortic regurgitation
Quantitative Assessment of Aortic Regurgitation 500
Phase-contrast velocity-encoded CMR can assess the sever-
ity of aortic insufficiency in a manner similar to echocar- 400
Forward flow = 223 cc
diography. These techniques include calculation of the
300 Reverse flow = 48 cc
regurgitant volume from the proximal isovelocity surface Regurgitant fraction = 21%
area or evaluation of the spectral profile of the insufficiency
Flux (mL/s)

jet and evaluation of the pressure half-time. However, as in 200

echocardiography, the latter assessment technique is depen-
dent on the presence of isolated aortic insufficiency and pre-
served left ventricular function. These approaches are also
somewhat more complicated in CMR than in echocardiog-
raphy, and, as a result, straightforward volumetric approaches
are the most consistently applied in CMR evaluations. To
quantitatively determine the aortic insufficiency volume
and regurgitant fraction, a phase-contrast velocity-encoded
sequence is applied through the proximal ascending aorta
perpendicular to the directional flow within the aorta. The
phase-contrast technique measures velocities within each
pixel of the cross-sectional area at each phase throughout the
cardiac cycle. A region of interest is applied circumscribing
the aortic wall, which is then varied in size iteratively
100
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
–100
–200
Cardiac phases
FIGURE 22.8. This graph denotes blood flow obtained using a
phase-contrast velocity-encoded sequence acquired in the proximal
ascending aorta in a patient with mild aortic insufficiency. The
systolic forward flow is color coded red (223 cc/beat), whereas reverse
flow, below the baseline, is color coded blue (48 cc). The resultant
regurgitant fraction is 21%.
 m a g n e t i c r e s o n a n c e i m a g i n g o f va lv u l a r d i s e a s e 5 47

FIGURE 22.9. A cine phase-contrast

velocity-encoded sequence is shown in a
patient with mild aortic insufficiency.
The left panels are images from peak
systole, and the right panels are images
from mid-diastole. The bottom row cor-
responds to the magnitude image from
the phase-contrast velocity-encoded
sequence. In the middle row are phase
images containing the velocity informa-
tion, as shown in the standard gray-scale
format. The systolic image has white
signal intensity in the ascending aorta
corresponding to forward flow, whereas
the diastolic image has areas of gray
(minimal flow) and black (reverse flow)
corresponding to aortic insufficiency. In
the top row are also phase images, but
they have been colored using a look-up
table, similar to color flow imaging in
echocardiography. The red and yellow
colors in systole correspond to higher
velocity flows in the foot-to-head direc-
tion, whereas in diastole blue denotes
reverse flow in the head-to-foot
direction.

Concurrent Assessment of Left
Ventricular Function
The comprehensive assessment of aortic regurgitation,
similar to aortic stenosis, should include quantification of
the regurgitant volume and regurgitant fraction, quantitative
assessment of global left ventricular function, and quantifi-
cation of left ventricular volumes and mass. These assess-
ments are essential, as the decision to proceed to surgical
replacement of the aortic valve is based on both the sever-
ity of the regurgitant jet and left ventricular size and
function.57
Patients with significant aortic regurgitation will slowly
dilate their left ventricular end-diastolic and end-systolic
volumes, though preserving left ventricular ejection fraction
and will remain asymptomatic despite increases in preload.
However, as the severity of aortic regurgitation increases and
left ventricular dilation proceeds, left ventricular systolic
function will eventually decline, and the necessity for aortic
valve replacement will become clearer.70 Unfortunately, up
to 25% of patients with severe aortic regurgitation remain
asymptomatic (despite developing severe left ventricular dys-
function) until death. While symptoms of dyspnea, from
elevated left ventricular pressures, or angina pectoris, from
compromised coronary flow reserve, will herald the neces-
sity for aortic valve replacement, routine monitoring with
noninvasive imaging helps identify those patients at greatest
risk. Regrettably, patients with greater left ventricular dila-
tion and worse systolic function are less likely to have symp-
tomatic relief or recover left ventricular function following
valve replacement.
Mitral Valve Disease
In the adult population mitral stenosis is almost exclusively
secondary to rheumatic heart disease, whereas mitral regur-
gitation has a wider range of etiologies including left ven-
tricular ischemic disease resulting in left ventricular and
mitral annular dilation, endocarditis, rupture of the papil-
lary muscle and/or chordae tendineae, myxomatous changes,
and prolapse, to name the most common.
Spin-echo imaging probably has a role only in mitral ste-
nosis, where visualization of thickened leaflets can be identi-
fied. Cine imaging with SSFP techniques is now the state of
the art for anatomic leaflet visualization and qualitative
functional analysis.
The mitral valve consists of two leaflets. The anterior
leaflet is relatively flap-shaped, is longer, and has more
548 chapter
surface area than the posterior leaflet, whereas the posterior
leaflet is broader based and crescentic in shape. In addition,
there are multiple chordae tendineae that extend from the
anterior and posterior papillary muscles providing structural
support for both mitral leaflets. With current SSFP cine
imaging techniques, the valve leaflets, mitral annulus, and
papillary muscles are well seen. With delayed-enhancement
techniques, additional tissue characterization (specifically
myocardial necrosis and infarction) can be identified provid-
ing additional information, influencing the potential success
of mitral valvular repair. While the chordae tendineae may
be seen with SSFP cine imaging, it is not a consistent feature,
and echocardiography remains the primary tool for their
evaluation.
Mitral Stenosis
As noted, mitral stenosis occurs almost exclusively as a
result of rheumatic heart disease. Nonetheless, rarely, adults
may be seen with congenital mitral stenosis. In addition,
other functional equivalents of mitral stenosis, such as left
atrial myxoma, left atrial thrombus, or subvalvular mem-
branes may be identified with CMR.
Valvular mitral stenosis is classically identified as fibro-
sis and thickening of the mitral valve leaflets and particu-
larly of the mitral valve tips, along with involvement of the
chordae tendineae. This thickening results in lack of opening
of the valve leaflets and a reduction in the mitral valve
orifice. “Doming” may be seen earlier in the disease process,
whereas calcification is more frequently seen later in the
disease (Fig. 22.10; and Video 22.1 on the DVD). Long-stand-
ing mitral stenosis can result in elevation of left atrial pres-
sure, dilation of the left atrium, backup of flow through the
pulmonary system, and eventually result in pulmonary
hypertension. Complications include thrombus formation
and atrial fibrillation.13,14
The severity of mitral valve stenosis can be determined
either by direct measurement of the valve orifice or by deter-
mining the gradient across the valve during maximal flow.71
Direct assessment of the valve orifice may be performed
FIGURE 22.10. Three static images are represented from a cine
flow-sensitive sequence performed in the parasternal long axis ori-
entation. The left image is from peak systole demonstrating a black
jet of turbulent blood in the proximal ascending aorta (asterisk) from
significant aortic stenosis. The arrowhead denotes focal calcifica-
tion on the anterior leaflet of the mitral valve. The middle image
22
using either spin-echo or cine imaging, though it is typically
performed more consistently and easily with the latter. Mul-
tiple short axis cine imaging planes using thin slices are
performed from the mitral annulus through the base of the
left ventricle. The image plane with the smallest valve orifice
during ventricular diastole is chosen and the orifice planim-
etered by manual tracing of the leaflet tips, with close cor-
relation of valve areas as compared to Gorlin derived areas.
Similar to aortic stenosis, velocity spectra can be deter-
mined from the mitral valve jet by placing a phase-contrast
velocity-encoded sequence parallel to the long axis of the
mitral valve jet. A small region of interest is placed at the
center of greatest turbulence, denoted by signal void on
the magnitude images, and the velocity waveforms
recorded. From this, both peak and mean gradients can be
calculated.
While the continuity equation has been employed in
echocardiography for mitral stenosis determination, this has
not gained routine utility in CMR. However, recent work by
Lin et al.72 has indicated robust determination of mitral valve
orifice using the pressure half-time approach.
Mitral Regurgitation
Mitral regurgitation occurs as a failure of complete coapta-
tion of the anterior and posterior leaflets of the mitral valve.
Morphologically, features to be evaluated include vegetation
with partial destruction of the valve leaflets, myxomatous
changes or thickening of the valve leaflets, abnormal motion
of the leaflets including prolapse and flail, and necrosis and
acute infarction of the papillary muscles.
Qualitative assessment of mitral regurgitation is per-
formed using cine SSFP imaging, as well as more flow-sensi-
tive cine imaging (using longer TEs) to best visualize the jet
of retrogradely directed blood flow. In the four-chamber or
parasternal long axis projections, an imaging plane that
shows the turbulent jet to best advantage is obtained with
flow sensitive cine imaging. Signal voids encompassing less
than 20% of the left atrial cross-sectional area may be con-
sidered mild. These jets are typically relatively thin and
from early diastole demonstrates aortic regurgitant flow buffeting
against the anterior leaflet of the mitral valve (arrow). The right
image from middle to late diastole demonstrates a black jet of tur-
bulent flow emanating from the coaptation point of the stenotic
mitral valve (double arrowheads).
 m a g n e t i c r e s o n a n c e i m a g i n g o f va lv u l a r d i s e a s e
FIGURE 22.11. In this patient with severe mitral regurgitation a
steady-state free precession (SSFP) cine sequence has been acquired
in the four-chamber orientation. The mitral regurgitant jet is
denoted by the arrow. The relative lack of flow sensitivity from SSFP
imaging makes the regurgitant jet less conspicuous than if the
sequence had been acquired using a more flow-sensitive sequence
(having a longer TE). Note the enlargement of the left atrium and
marked thinning of the proximal two thirds of the entire lateral
wall from prior myocardial infarction.
extend only partway back through the left atrium. Alterna-
tively, broad jets that extend to the back of the left atrium
and encompass larger percentages of left atrial cross-sec-
tional area are consistent with more severe regurgitation
(Fig. 22.11; and Video 22.1 on the DVD).
In addition to measuring mitral regurgitant volumes and
regurgitant fraction, attention must be paid to left ventricu-
lar function and size when evaluating patients with mitral
regurgitation. The success of mitral valve repair decreases as
left ventricular size increases and function decreases.73
Greater success is obtained in patients who remain asymp-
tomatic or are only mildly symptomatic.
Quantitative Assessment of Mitral Regurgitation
While the qualitative assessments of mitral regurgitation
severity provide a useful guide in valve with central jets of
insufficiency, they are less reliable in the face of eccentric
jets or severely prolapsing or flail leaflets. Also, in eccentric
jets, particularly those that course along the posterior aspect
of a valve leaflet or along the wall of the left atrium, the
Coanda effect reduces the perceived volume of regurgitant
blood.74 Fortunately, CMR circumvents these limitations by
direct measurements of mitral regurgitant volumes, which
have shown good correlation with echocardiographic assess-
ments and invasive angiography.75
One approach used when there is isolated mitral valve
insufficiency is to measure the left and right ventricular
stroke volumes using short axis cine imaging. As cardiac
549
output should be virtually equivalent through the systemic
and pulmonary systems (save for the slight volume of blood
through the bronchial arterial circulation), in the presence
of mitral valve regurgitation the difference between left and
right ventricular stroke volumes is the mitral regurgitant
volume. The mitral regurgitant fraction can be calculated
as the difference between left and right ventricular stroke
volumes divided by left ventricular stroke volume.75,76
The second approach incorporates left ventricular stroke
volume and forward flow through the ascending aorta. Left
ventricular stroke volume is measured by the disk summa-
tion method from a stack of short axis cine images through
the left ventricle. Next, the volume of forward flow through
the aortic valve is calculated using a phase-contrast velocity-
encoded technique placed at the proximal ascending aorta.
The difference between the left ventricular stroke volume
and the forward flow during systole through the ascending
aorta is the mitral regurgitant volume. The mitral regurgi-
tant volume can be divided by the left ventricular stroke
volume to determine mitral regurgitant fraction (Fig. 22.12;
and Video 22.1 on the DVD). The advantage of this approach
is that mitral regurgitation can be determined accurately
despite the presence of multivalvular disease, and without
regard to the eccentricity or multiplicity of regurgitant jets77,78
(Fig. 22.13; and Video 22.1 on the DVD).
Finally, it is possible to place a phase-contrast flow quan-
tification sequence across the face of the mitral annulus and
directly measure forward flow through the valve during dias-
tole and retrograde flow during systole, and therefore directly
calculate the regurgitant volume.79 The difficulty with this
approach is the significant through-plane motion of the
mitral annulus and valve throughout the cardiac cycle, and
with respect to the static imaging plane. During both systole
and diastole, mitral valve and annular motion are opposite
the direction of blood flow, and thus measurements in either
portion of the cardiac cycle may be underestimated.80 Kozerke
et al.81 have applied a tagging-based motion-adapted flow
measurement to circumvent this limitation, yet this approach
is not yet widely adapted and therefore may not yet be suit-
able for routine use.
Accessory Findings
The severity of mitral regurgitation may be supported by
ancillary findings. Specifically, evaluation of pulmonary
blood flow may yield additional, corroborative information.
Normal blood flow pattern in the pulmonary veins demon-
strates dominance of inflow during systole and lesser volume
during diastole. Elevations in left atrial pressure are charac-
terized by the reversal of these patterns, such that pulmo-
nary vein inflow is maximal during diastole. This pattern
may be seen with mild to moderate degrees of mitral regur-
gitation. Severe mitral regurgitation, however, can result in
reversal of blood flow within the pulmonary veins during
systole (Fig. 22.14). These patterns of blood flow are easily
seen with CMR phase-contrast velocity-encoded techniques
measuring blood flow and velocity through the right upper
lobe pulmonary vein in a manner analogous to that used in
echocardiography.82
The papillary muscles are critical structures in mitral
valve function, and rupture or infarction will usually neces-
550 chapter 22

Aortic flow

300

Instantaneous flow (cc/sec)

Left ventricular function: 250
EDV = 390 cc, ESV = 310 cc 200
SV = 80 cc, LVEF = 20% 150
Forward flow = 31 cc/beat
100

Mitral regurgitant volume: 50

LV SV (80 cc) - Ao FF (31 cc) = 49 cc 0
1 2 3 4 5 6 7 8 9 101112131415161718192021 222324252627282930
–50
–100
Mitral regurgitant fr. (49/80) = 61%
Cardiac phases

FIGURE 22.12. This composite set of images details the quantita-
tive calculation of mitral regurgitant volume and mitral regurgitant
fraction (fr.) using the combination of the disk-summation method
for left ventricular stroke volume and phase-contrast velocity-
encoded sequence to calculate forward flow through the ascending
aorta. The left upper quadrant is a flow-sensitive cine sequence
acquired in the four-chamber orientation demonstrating eccentric
severe mitral regurgitation and mild tricuspid regurgitation. The
right upper quadrant highlights end-diastolic and end-systolic short
axis images from the mid-ventricular level of the same patient. The
volumetric and functional values are shown in the left lower quad-
rant. The patient has a markedly dilated and severely dysfunctional
left ventricle. The right lower quadrant demonstrates the flow data
acquired in the mid-ascending aorta demonstrating a calculated
forward flow of 31 cc/beat. The mitral regurgitant volume is calcu-
lated by subtracting the aortic forward flow from the left ventricular
stroke volume, resulting in a mitral regurgitant volume of 49 cc/
beat. Accordingly, the mitral regurgitant fraction is 61%.

Severe mitral regurgitation

500

400
Aorta
Instantaneous flow (cc/sec)

Right superior PV
300

200

100

0
10

13

16

19

22

25

28
1

FIGURE 22.13. A flow-sensitive cine sequence was acquired in the
four-chamber orientation in a patient with mitral valve prolapse and
severe mitral regurgitation. The arrowhead denotes the prolapse of
the posterior leaflet of the mitral valve, and the arrow denotes the
jet of insufficiency coursing along the posterior aspect of the ante-
rior leaflet of the mitral valve and then to the interatrial septum.
This form of eccentric mitral insufficiency results in a visual under-
estimation of the severity of mitral regurgitation in what is known
as the Coanda effect.
–100
Cardiac phases
FIGURE 22.14. Flow curves are depicted from blood flow in the
ascending aorta and right superior pulmonary vein demonstrating
reversal of blood flow in the right superior pulmonary vein during
ventricular systole (note the portion of the blue curve below the
baseline denoting reversal of flow). There is prominent flow from
the right superior pulmonary vein into the left atrium during
diastole.
 m a g n e t i c r e s o n a n c e i m a g i n g o f va lv u l a r d i s e a s e 5 51
blood flow. The length and breadth of signal void emanating
from the tricuspid valve leaflets correlates with the severity
of tricuspid stenosis. Quantitative assessment can be per-
formed with phase-contrast velocity-encoded sequences also
performed parallel to the long axis of the turbulent jet. The
spectral velocities are analyzed in similar fashion to those
performed for the mitral valve, and the peak and mean gra-
dients are determined.

Tricuspid Regurgitation
Disease entities such as coronary artery disease and intrinsic
cardiomyopathies, as well as pulmonary hypertension, may
result in right ventricular dilation and progressive stretching
of the tricuspid annulus, resulting in tricuspid regurgitation
(Fig. 22.16; and Video 22.1 on the DVD). Isolated tricuspid
regurgitation is relatively rare, but when present the tricus-
pid regurgitant volume and regurgitant fraction can be cal-
culated directly from the difference in left ventricular and

FIGURE 22.15. This is a short axis image from the same patient in
Figure 22.11. The technique used is the delayed-enhancement
sequence performed after gadolinium administration, which high-
lights infarcted tissue as bright white, and normal myocardium
appears black. Note the marked thinning and bright signal intensity
of the entire lateral wall from prior myocardial infarction involving
the left circumflex coronary artery territory. The arrowheads denote
infarction of both the anterior and posterior papillary muscles,
resulting in the severe mitral regurgitation noted in the cine image
of Figure 22.11.

sitate alteration of mitral repair approach. Delayed-enhance-

ment CMR can now directly determine acutely necrotic or
infarcted papillary muscles necessitating mitral valve
replacement instead of repair (Fig. 22.15). The delayed-
enhancement CMR technique uses a T1-weighted, gradient-
echo sequence prepared with an inversion preparation pulse
following the intravenous administration of a gadolinium
contrast material. After optimizing the inversion delay time,
normal myocardium becomes “nulled” (turns black), whereas
acutely necrotic or infarcted myocardium turns bright
white.83 This technique has been validated extensively in
both animal models and human studies.84–87 Improved knowl-
edge of papillary muscle status may well improve surgical
planning and therefore results, though prospective studies
have yet to be performed.

Tricuspid Valve Disease

The tricuspid valve is normally trileaflet and can be evalu-
ated from a morphologic standpoint with both spin-echo and
cine gradient-echo imaging. Tricuspid stenosis is infrequently
seen, but when present almost invariably occurs as a result
of rheumatic heart disease, although it typically occurs in
concert with mitral and aortic valve involvement.
Qualitative evaluation of tricuspid stenosis severity is
performed similarly to the mitral valve. A flow-sensitive cine FIGURE 22.16. End-diastolic (top) and peak systolic (bottom)
gradient-echo sequence is performed in long axis orienta- images from a flow-sensitive cine sequence demonstrate highly
tions to maximize conspicuity of the stenotic jet of turbulent eccentric, medially directed tricuspid regurgitation (arrows).
552 chapter 22

right ventricular stroke volumes as described previously for Pulmonary Regurgitation

mitral regurgitation. Alternatively, the flow profiles can be
determined using a phase-contrast velocity-encoded sequence
applied parallel to and at the level of the tricuspid annulus
directly measuring forward flow during diastole and regur-
gitant flow during systole.88,89 As with the mitral valve plane,
the tricuspid valve plane too has substantial motion through-
out the cardiac cycle, and flow measurements preferably
should be corrected for this motion.
Finally, the magnitude of tricuspid regurgitation can be
measured using right ventricular stroke volume obtained
using the disk summation method from cine images obtained
through the entire right ventricle and integrating phase-con-
trast velocity-encoded flow measurements from the main
pulmonary artery. The tricuspid regurgitant volume is deter-
mined by subtracting pulmonary artery forward flow during
systole from the right ventricular stroke volume, and the
regurgitant fraction is calculated by dividing tricuspid regur-
gitant volume by right ventricular stroke volume.89–91
Peak systolic right ventricular pressures may also be
determined and are an important component in assessment
of tricuspid valve disease. The tricuspid regurgitant jet peak
velocity can be incorporated into the modified Bernoulli
equation and the gradient across the tricuspid valve deter-
mined. This value can be incorporated with the estimated
right atrial pressure to calculate estimated right ventricular
systolic pressure. While this calculation is routinely used in
echocardiography, it has yet to see routine clinical use in
CMR.
Pulmonary Valve Disease
Diseases of the pulmonary valve, and particularly pulmonic
stenosis, are more frequently encountered in pediatric and
congenital populations (Fig. 22.17; and Video 22.1 on the
DVD). Nonetheless, with the increasing numbers of adults
with congenital heart disease, discrete examination of the
pulmonic valve and surrounding apparatus will likely
become more frequent.
Insufficiency of the pulmonary valve, when mild, usually
has limited consequences for the low-pressure right ventri-
cle. However, as the severity of pulmonic regurgitation
increases, progressive dilation of the right ventricle occurs
with subsequent involvement of the tricuspid valve and tri-
cuspid regurgitation. In severe cases, right ventricular failure
ensues.92 Pulmonic regurgitation is easily assessed with a
phase-contrast velocity-encoded flow sequence performed
perpendicular to the long axis of the main pulmonary artery
similar to that used to calculate aortic regurgitation.93,94 Both
forward flow during systole and reverse flow during diastole
can be directly calculated using the velocity information on
a pixel-by-pixel basis found within the adapted region of
interest encompassing the main pulmonary artery. Forward
and regurgitant volumes and pulmonary regurgitant frac-
tions are calculated the same as with the aortic valve.95
Concurrent Disease
Central or peripheral pulmonary stenosis may contribute to
both pulmonic and tricuspid valve disease. These may be
difficult to assess with echocardiography, except in younger
pediatric populations. In adults, contrast-enhanced pulmo-
nary MR angiography can easily and quickly assess the
majority of the pulmonary arterial tree. These sequences are
typically performed in a breath-hold providing a luminogram
of the pulmonary arterial tree and easily identifying the
presence of stenoses, web-like bands, aneurysms, and arte-
riovenous communications or malformations.
Endocarditis
Vegetations of the valves have been the province of trans-
esophageal echocardiography for many years. Vegetations are
usually focal, mobile, and located along the lower pressure
side of the valve leaflet. Identification of such vegetations is
critical in the treatment of patients with suspected infective
endocarditis. In the past, the spatial and temporal resolution

FIGURE 22.17. Steady-state free pre-

cession (SSFP) cine imaging from a
patient with valvar pulmonic stenosis.
The left panel is a right ventricular
outflow tract projection, and demon-
strates thin, doming pulmonic valve
leaflets and a jet of turbulent flow
extending into the main pulmonary
artery (arrow). The right panel is also a
cine SSFP sequence obtained in the
short axis projection at the mid-ven-
tricular level. This image demonstrates
marked hypertrophy of the right ven-
tricle, as well as a leftward shift of the
interventricular septum during systole
compatible with right-sided pressure
overload.
 m a g n e t i c r e s o n a n c e i m a g i n g o f va lv u l a r d i s e a s e
FIGURE 22.18. A perivalvular pseudoaneurysm is identified reflect-
ing partial dehiscence of the suture line of a prosthetic aortic valve.
The black blood spin-echo image (upper panel) reveals an ovoid
signal void between the aortic root and the left atrium (arrowhead).
The lower panel from a cine gradient echo sequence demonstrates
high signal intensity within the same perivalvular pocket (arrow-
head) consistent with free flowing blood. Note the susceptibility
artifact that encompasses the prosthetic aortic valve and extends a
few millimeters beyond the valve edges in all directions.
limitations of CMR cine imaging precluded practical evalu-
ation of this disease entity. Modern, state-of-the-art SSFP
cine sequences now rival the spatial and temporal resolution
of echocardiography, and have improved contrast-to-noise
ratios. These features suggest the potential for CMR to
compete on an equal footing with echocardiography for the
identification of valvular vegetations and therefore commen-
surately confirm the diagnosis of endocarditis.96
Prosthetic Heart Valves
Prosthetic heart valves typically have varying degrees of
metallic components (aside from homografts) and, as a result,
induce susceptibility artifacts that obviate the precise assess-
ment of prosthetic valvar morphology.97 It should be noted
553
that all prosthetic heart valves are currently MR compatible.
In the past, the Starr-Edwards (St. Jude Medical, St Paul, MN)
Pre-6000 series of prosthetic heart valves were felt to be
incompatible with MR imaging as a result of the metallic
ball-and-cage employed. However, a reassessment of mag-
netic effects on the valve structure was performed and the
valves found to be MR compatible.98
As a result of the susceptibility artifacts, flow measure-
ments, either for stenosis or regurgitation, cannot be made
accurately directly through the valve prosthesis. However,
flow quantification using phase-contrast velocity encoded
techniques may be performed with the imaging slices placed
a few millimeters from the valve, avoiding the susceptibility
artifacts.99
Vegetations or pannus on prosthetic heart valves also
cannot be evaluated directly with CMR as a result of the sus-
ceptibility artifacts. However, processes such as perivalvular
leaks or abscesses are easily evaluated with CMR, as the
abnormalities are typically outside of the localized suscepti-
bility artifacts (Fig. 22.18; and Video 22.1 on the DVD). Further,
the degree of regurgitation of perivalvular leaks is easily quan-
tified using the techniques previously described specific for
each valve. This information can assist in the determination
of proper timing for recurrent valve repair or replacement in
patients who remain hemodynamically stable.
Summary
Cine MR evaluation of valvular disease has now become an
accurate and strongly complementary role to its already cur-
rently accepted gold standard status for ventricular function
and volume analysis. It can readily assess the morphology
and function of all four cardiac valves and accurately deter-
mine degrees of stenosis and regurgitation; more importantly,
it has a distinct advantage in quantifying valvular regurgi-
tant volumes and regurgitant fractions. These advantages
may provide further insights into precise timing of repairs
and prediction for valve replacement or repair, as well as
closer monitoring of medical therapies.
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 2 Balloon Dilatation of the
3 Cardiac Valves
Igor F. Palacios and Pedro L. Sánchez
Percutaneous Pulmonic Valvuloplasty . . . . . . . . . . . . . . 557
Percutaneous Mitral Balloon Valvotomy for Patients
with Rheumatic Mitral Stenosis . . . . . . . . . . . . . . . . 558
Key Points
• Percutaneous balloon pulmonary valvuloplasty (PPV) has
become the treatment of choice for patients with isolated
pulmonic valvular stenosis.
• Percutaneous mitral balloon commissurotomy (PMV)
has been successfully used as an alternative to open or
closed surgical mitral commissurotomy in the treatment
of patients with symptomatic rheumatic mitral
stenosis.
• Increase of mitral valve area with PMV is inversely
related to the presence of atrial fibrillation.
• The presence and severity of MR before PMV is an inde-
pendent predictor of unfavorable outcome of PMV.
• Following PMV, the majority of patients have marked
clinical improvement and become New York Heart Asso-
ciation (NYHA) class I or II in intermediate- and long-
term follow-up.
• Patients with heavily calcified mitral valves under fluo-
roscopy have a poorer immediate outcome with PMV.
• The degree of pulmonary artery hypertension before PMV
is inversely related to immediate and long-term outcome
of PMV.
• The degree of tricuspid regurgitation before PMV is in-
versely related to the immediate and long-term outcome
of PMV.
• Aortic valve replacement is the treatment of choice for
symptomatic patients with severe valvular aortic steno-
sis, but in nonsurgical candidates, because of associated
major medical comorbid conditions, percutaneous aortic
balloon valvuloplasty (PAV) may be considered a short-
term palliative intervention. However, clinical restenosis
occurs, frequently, 6 to 12 months after PAV.
Before 1982, cardiac surgery was the conventional form of
treatment for symptomatic stenotic valvular heart lesions.
Today, percutaneous balloon dilatation of stenotic cardiac
valves is being used in many centers for the treatment of
patients with pulmonic, mitral, aortic and tricuspid
stenosis.
Percutaneous Aortic Balloon Valvuloplasty . . . . . . . . . . 569
Percutaneous Tricuspid Balloon Valvuloplasty. . . . . . . . 575
Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 576
Percutaneous Pulmonic Valvuloplasty
Since its introduction by Kan et al. in 1982, percutaneous
balloon pulmonary valvuloplasty (PPV) has become the
treatment of choice for patients with isolated pulmonic val-
vular stenosis.1–3 In both children and adults with valvular
pulmonic stenosis balloon valvuloplasty produces excellent
immediate and long-term results. Patients with isolated pul-
monic stenosis and a transvalvular gradient greater than
40 mm Hg are candidates for this technique (Table 23.1).3–9
The technique of PPV is relatively simple. It is performed
with the patient under sedation and local anesthesia. Before
performing PPV, accurate measurement of the pulmonary
annulus by two-dimensional (2D) echocardiography and
angiography is fundamental in the appropriate selection of
balloon size. Complete right and left catheterization and
right ventricular cineangiography in both the anteroposte-
rior and lateral projections are performed before PPV to docu-
ment the severity of the stenosis and the presence of
associated lesions.
The stenotic pulmonic valve is crossed with an end-hole
balloon wedge catheter, and the catheter is placed in the left
pulmonary artery. A 0.035- or 0.038-inch exchange guide-
wire is advanced in the distal left pulmonary artery, and the
catheter and venous introducer are removed. When using the
double-balloon technique, a second guidewire could be placed
parallel to the first guidewire with the help of a double-
lumen catheter. In smaller children, double-balloon PPV can
be performed by introducing a dilating balloon through each
of the femoral veins. The balloon or balloons dilating the
catheters are then advanced and placed straddling the pul-
monic valve. A balloon combination that provides a diameter
20% to 30% greater than the pulmonary annulus is used to
provide adequate relief of the stenosis. The valvuloplasty
balloons are then inflated by hand until the waist produced
by the stenotic pulmonic valve disappears. Two to four brief
inflations are performed to minimize the period of hypoten-
sion. The inflation/deflation process takes between 15 and
20 seconds. Double-balloon PPV is tolerated better than
557
558 chapter 23

TABLE 23.1. Recommendations for percutaneous pulmonic pulmonary insufficiency occurs frequently, but it does not
valvuloplasty in patients with isolated pulmonic stenosis have significant clinical or hemodynamic consequences.
Level of Follow-up studies have shown that restenosis is uncom-
Current indication Class evidence mon.10,11 Follow-up cardiac catheterization and Doppler
Patients with exertional dyspnea, I Grade B echocardiography studies have demonstrated that significant
angina, syncope, or presyncope restenosis appears to be uncommon. Recurrent stenosis is
Asymptomatic patients with normal much less likely if the final gradient after PPV is less than
cardiac output 30 mm Hg. The residual gradient measured 6 months after
Transvalvular gradient >50 mm Hg I Grade B PPV has been significantly smaller than the one measured
Transvalvular gradient 40 to 49 mm Hg IIa Grade B
Transvalvular gradient 30 to 39 mm Hg IIb Grade C immediately after the procedure. This finding is probably
Transvalvular gradient <30 mm Hg III Grade C related to improvement in the infundibulum stenosis, which
frequently occurs immediately after PPV.

Percutaneous Mitral Balloon Valvotomy for

single-balloon PPV, resulting in less hypotension and brady- Patients with Rheumatic Mitral Stenosis
cardia during balloon inflations. Following completion of the
dilatations, the deflated catheters are removed and repeat Since its introduction in 1984 by Inoue et al.,12 percutaneous
hemodynamics and right ventricular cineangiography are mitral balloon commissurotomy (PMV) has been used suc-
repeated. At the end of the procedure, the catheters are cessfully as an alternative to open or closed surgical mitral
removed and hemostasis is achieved by local pressure. In commissurotomy in the treatment of patients with symp-
most adults, two balloons are required. Patients are observed tomatic rheumatic mitral stenosis.12–34 It produces good
after the procedure in a general medical ward and discharged immediate hemodynamic outcome, has a low complication
the following day. rate, and results in clinical improvement in the majority of
Percutaneous balloon pulmonary valvuloplasty produces patients with mitral stenosis. It is safe and effective, and
a significant decrease in pulmonic gradient. In general, the provides sustained clinical and hemodynamic improvement
pulmonic gradient decreases by 50% to 80%. The results of in patients with rheumatic mitral stenosis. The immediate
PPV from different centers are shown in Table 23.2. Patients and long-term results appear to be similar to those of surgical
with severe pulmonary dysplasia and with hypoplasia of the mitral commissurotomy.12–34 Today, PMV is the preferred
pulmonic annulus are unlikely to have improvement after form of therapy for relief of mitral stenosis for a selected
PPV. In some patients, a significant gradient could develop group of patients with symptomatic mitral stenosis.
across the infundibulum following relief of the valvular
pulmonic stenosis and may be reduced by the use of beta-
blockers or calcium channel blockers. This infundibular Patient Selection
gradient has no clinical importance and disappears or mark- Selection of patients for PMV should be based on symptoms,
edly decreases at follow-up cardiac catheterization or Doppler physical examination, and 2D and Doppler echocardiographic
echocardiography. findings.35 Percutaneous mitral balloon commissurotomy is
Complications of PPV are rare.1–8 They are more frequent usually performed electively. However, emergency PMV can
in neonates. Perforation of the right ventricular outflow tract be performed as a lifesaving procedure in patients with mitral
has been reported to occur in neonates when attempts have stenosis and severe pulmonary edema refractory to medical
been made to cross the pulmonary valve. Similarly, vessel therapy or to cardiogenic shock. Patients considered for PMV
trauma is more frequent in neonates and infants and can be should be symptomatic [New York Heart Association (NYHA)
diminished by using the double-balloon technique. Mild class II or greater], should have no recent thromboembolic
events, have less than two grades of mitral regur-gitation by
contrast ventriculography (using the Sellers classification),36
and have no evidence of left atrial thrombus on 2D and trans-
TABLE 23.2. Immediate results of percutaneous pulmonic esophageal echocardiography (Table 23.3). Transthoracic and
valvuloplasty
transesophageal echocardiography should be performed rou-
Pulmonary pressure (mm Hg) tinely before PMV. Patients in atrial fibrillation and patients
Author No. of patients Pre-PPV Post-PPV with previous embolic episodes should be anticoagulated
with warfarin with a therapeutic prothrombin time for at
Kan et al. 20 68 ± 27 23 ± 5
least 3 months before PMV. Patients with left atrium throm-
Rao et al. 71 91 ± 41 26 ± 19
bus on 2D-echocardiography should be excluded. However,
VACA registry 784 71 ± 33 28 ± 21
PMV could be performed in these patients if the left atrium
Beekman et al. 90 70 ± 24 30 ± 17 thrombus has resolved after warfarin therapy.
Ali Khan et al. 257 97 ± 30 22 ± 20
Schmaltz et al.* 305 72 ± 32 32 ± 25
Massachusetts
Technique
General Hospital** 39 69 ± 26 17 ± 11 The PMV is performed with the patient in the fasting state
* Multicenter study. and under mild sedation. Antibiotics (dicloxacillin 500 mg
** Adults. p.o. q6h for four doses starting before the procedure, or
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s 559
TABLE 23.3. Recommendations for percutaneous mitral valvuloplasty
Current indication Class Level of evidence

Symptomatic patients (NYHA functional class II, III, or IV), moderate or severe I Grade A
mitral stenosis (area <1.5 cm2), and valve morphology favorable for percutaneous
balloon valvuloplasty in the absence of left atrial thrombus or moderate to
severe mitral regurgitation
Asymptomatic patients with moderate or severe mitral stenosis (area <1.5 cm2) IIa Grade C
and valve morphology favorable for percutaneous balloon valvuloplasty who
have pulmonary hypertension (pulmonary artery systolic pressure >50 mm Hg
at rest or 60 mm Hg with exercise) in the absence of left atrial thrombus or
moderate to severe mitral regurgitation
Patients with NYHA functional class III to IV, moderate or severe mitral stenosis IIa Grade B
(area <1.5 cm2), and a nonpliable calcified valve who are at high risk for surgery
in the absence of left atrial thrombus or moderate to severe mitral regurgitation.
Asymptomatic patients, moderate or severe mitral stenosis (area <1.5 cm2), and valve IIb Grade B
morphology favorable for percutaneous balloon valvuloplasty who have new onset
of atrial fibrillation in the absence of left atrial thrombus or moderate to severe
mitral regurgitation
Patients in NYHA functional class III to IV, moderate or severe mitral stenosis IIb Grade C
(area <1.5 cm2), and a nonpliable calcified valve who are low-risk candidates for
surgery
Patients with mild mitral stenosis III Grade C

cefazolin 1 g i.v. at the time of the procedure) are used.
Patients allergic to penicillin should receive vancomycin 1 g
i.v. at the time of the procedure.
All patients carefully chosen as candidates for mitral
balloon valvuloplasty should undergo diagnostic right and
left and transseptal left heart catheterization. Following
transseptal left heart catheterization, systemic anticoagula-
tion is achieved by the intravenous administration of
100 units/kg of heparin. In patients older than 40 years, coro-
nary arteriography is recommended and should also be
performed.
Hemodynamic measurements, cardiac output, and cine
left ventriculography are performed before and after PMV.
Cardiac output is measured by thermodilution and Fick
method techniques. Mitral valve calcification and angio-
graphic severity of mitral regurgitation (the Sellers classifica-
tion) are graded qualitatively from 0 to 4 as described
elsewhere.36 An oxygen diagnostic run is performed before
and after PMV to determine the presence of left to right
shunt across the atrial septum after PMV.
There is not a unique technique of percutaneous mitral
balloon valvuloplasty. Most of the techniques of PMV require
transseptal left heart catheterization and use of the antegrade
approach.12–22,24–28 Antegrade PMV can be accomplished using
a single- (Fig. 23.1) or a double-balloon technique (Fig. 23.2).
In this latter approach the two balloons could be placed
through a single femoral vein and single transseptal punc-
tures, or through two femoral veins and two separate atrial
septal punctures. In the retrograde technique of PMV, the
balloons dilating the catheters are advanced percutaneously
through the right and left femoral arteries over guidewires
that have been snared from the descending aorta. These
guidewires have been advanced transseptally from the right
femoral vein into the left atrium, the left ventricle, and the
ascending aorta.37 A retrograde nontransseptal technique of
PMV has also been described.38 Recently, a technique of PMV
using a newly designed metallic valvulotome was intro-
duced.24 The device consists of a detachable metallic cylinder
with two articulated bars screwed onto the distal end of a
disposable catheter whose proximal end is connected to an
activating pliers. Squeezing the pliers opens the bars up to a
maximum of 40 mm (Fig. 23.3). The results with this device
are at least comparable to those of the other balloon tech-
niques of PMV,27 and multiple uses after sterilization should
markedly decrease procedural costs.
The Antegrade Double-Balloon Technique
In performing PMV using the antegrade double-balloon tech-
nique (Fig. 23.2), two 0.038-inch, 260 cm long Teflon-coated
exchange wires are placed across the mitral valve into the
left ventricle, through the aortic valve into the ascending and
then the descending aorta.14–16 Care should be taken to main-
tain large and smooth loops of the guidewires in the left
ventricular cavity to allow appropriate placement of the
dilating balloons. If a second guidewire cannot be placed into
the ascending and descending aorta, a 0.038-inch Amplatzer-
type transfer guidewire (AGA Medical Corp., Golden Valley,
MN) with a preformed curlew at its tip can be placed at the
left ventricular apex. In patients with aortic valve prostheses,
both guidewires with performed curlew tips should be placed
at the left ventricular apex. When one or both guidewires are
placed in the left ventricular apex, the balloons should be
inflated sequentially. Care should be taken to avoid forward
movement of the balloons and guidewires to prevent left
ventricular perforation. Two balloon-dilating catheters,
chosen according to the patient’s body surface area, are then
advanced over each of the guidewires and positioned across
the mitral valve parallel to the longitudinal axis of the left
ventricle. The balloon valvotomy catheters are then inflated
by hand until the indentation produced by the stenotic mitral
valve is no longer seen. Generally one but occasionally two
560
or three inflations are performed. After complete deflation
the balloons are removed sequentially.
The Inoue Technique
The PMV can also be performed using the Inoue technique
(Fig. 23.2).12 The Inoue balloon is a 12-French (F) shaft, coaxial,
double-lumen catheter. The balloon is made of a double layer
of rubber tubing with a layer of synthetic micromesh in
between. Following transseptal catheterization, a stainless
steel guidewire is advanced through the transseptal catheter
and placed with its tip coiled into the left atrium and the
transseptal catheter removed. A 14F dilator is advanced over
the guidewire and used to dilate the femoral vein and the
chapter 23
FIGURE 23.1. Double-balloon percuta-
neous technique of percutaneous mitral
valvulotomy (PMV).
atrial septum. A balloon catheter chosen according to the
patient’s height is advanced over the guidewire into the left
atrium. The distal part of the balloon is inflated and advanced
into the left ventricle with the help of the spring wire stylet
that has been inserted through the inner lumen of the cath-
eter. Once the catheter is in the left ventricle, the partially
inflated balloon is moved back and forth inside the left ven-
tricle to ensure that it is free of the chordae tendineae. The
catheter is then gently pulled against the mitral plane until
resistance is felt. The balloon is then rapidly inflated to its
full capacity and then deflated quickly. During inflation of
the balloon, an indentation should be seen in its midportion.
The catheter is withdrawn into the left atrium and the mitral
gradient and cardiac output measured. If further dilatations
FIGURE 23.2. Inoue balloon technique of
percutaneous technique of PMV.
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s 5 61

FIGURE 23.3. Cribier metallic tech-

nique of PMV.

are required, the stylet is introduced again and the sequence
of steps described above repeated at a larger balloon volume.
After each dilatation, its effect should be assessed by pres-
sure measurement, auscultation, and 2D-echocardiography.
If mitral regurgitation occurs, further dilation of the valve
should not be performed.
Mechanism
The mechanism of successful PMV is splitting of the fused
commissures toward the mitral annulus, resulting in com-
missural widening. This mechanism has been demonstrated
by pathologic, surgical, and echocardiographic studies.39–43 In
addition, in patients with calcific mitral stenosis, the bal-
loons could increase mitral valve flexibility by the fracture
of the calcified deposits in the mitral valve leaflets.44
Although rare, undesirable complications, such as leaflet
tears, left ventricular perforation, tear of the atrial septum
and rupture of chordae, mitral annulus, and papillary muscle
could also occur.
Immediate Outcome
Figure 23.4 shows the hemodynamic changes produced by
PMV in one patient. The PMV resulted in a significant
decrease in mitral gradient, mean left atrium pressure, and

Pre-PMV Post-PMV

FIGURE 23.4. Hemodynamic

changes produced by a success-
ful PMV in one patient with
severe mitral stenosis. At the top
panels simultaneous left atrium
and left ventricular pressures
before (upper left panel) and after
(upper right panel) PMV. LV/LA Pre-PMV LV/LA Post-PMV
562 chapter 23

TABLE 23.4. Immediate changes in mitral valve area after percutaneous mitral valvuloplasty
Author Institution No. of patients Age Pre-PMV Post-PMV

Palacios et al. Massachusetts General Hospital 879 55 ± 15 0.9 ± 0.3 1.9 ± 0.7
Vahanian et al. Tenon 1514 45 ± 15 1.0 ± 0.2 1.9 ± 0.3
Hernández et al. Clínico Madrid 561 53 ± 13 1.0 ± 0.2 1.8 ± 0.4
Stefanadis et al. Athens University 438 44 ± 11 1.0 ± 0.3 2.1 ± 0.5
Chen et al. Guangzhou 4832 37 ± 12 1.1 ± 0.3 2.1 ± 0.2
NHLBI Multicenter 738 54 ± 12 1.0 ± 0.4 2.0 ± 0.2
Inoue et al. Takeda 527 50 ± 10 1.1 ± 0.1 2.0 ± 0.1
Inoue Registry Multicenter 1251 53 ± 15 1.0 ± 0.3 1.8 ± 0.6
Ben Farhat et al. Fattouma 463 33 ± 12 1.0 ± 0.2 2.2 ± 0.4
Arora et al. G.B. Pan 600 27 ±8 0.8 ± 0.2 2.2 ± 0.4
Cribier et al. Ruen 153 36 ± 15 1.0 ± 0.2 2.2 ± 0.4

mean pulmonary artery pressure; and an increase in cardiac
output and mitral valve area (MVA). Table 23.4 shows the
changes in MVA reported by several investigators using dif-
ferent techniques of PMV. In most series, PMV is reported to
increase MVA from less than 1.0 cm2 to approximately
2.0 cm2.18–20,23,25–28,34
At the Massachusetts General Hospital, 879 consecutive
patients with mitral stenosis have undergone 939 PMVs
between July 1986 and July 2000.28 As shown in Figure 23.5,
in this group of patients, PMV resulted in a significant
decrease in mitral gradient from 14 ± 6 to 6 ± 3 mm Hg. The
mean cardiac output significantly increased from 3.9 ± 1.1 to
4.5 ± 1.3 L/min, and the calculated MVA from 0.9 ± 0.3 to
1.9 ± 0.7 cm2. In addition, mean pulmonary artery pressure
significantly decreased from 36 ± 13 to 29 ± 11 mm Hg and
the mean left atrial pressure decreased from 25 ± 7 to
17 ± 7 mm Hg, and consequently, the calculated pulmonary
vascular resistances decreased significantly following PMV.
A successful hemodynamic outcome [defined as a post-
PMV mitral valve area ≥1.5 cm2 and post-PMV mitral regur-
gitation (MR) <3 Sellers’ grades] was obtained in 72% of the
patients. Although a suboptimal result occurred in 28% of
the patients, a post-PMV MVA ≤1.0 cm2 (critical mitral valve
area) was present in only 8.7% of these patients.
Predictors of Increase in Mitral Valve Area and
Procedural Success
Univariate analysis demonstrated that the increase in MVA
with PMV is directly related to the balloon size employed as
it reflects in the effective balloon dilating area (EBDA) and is
inversely related to the echocardiographic score, the presence
of atrial fibrillation, the presence of fluoroscopic calcium, the
presence of previous surgical commissurotomy, older age,
NYHA pre-PMV class, and the presence of MR before PMV.
Multiple stepwise regression analysis identified balloon size

Changes in MVA Post-PMV MR ≥3+

1.9 ± 0.6
12
2
p <.001 9.0
1.8
10
1.6
1.4 8
Patients (%)
MVA (cm2)

1.2 0.9 ± 0.3

6
1 6.3
0.8 4
0.6
0.4 2
2.7
0.2
0
0
Pre-PMV Post-PMV MR 3+ FIGURE 23.5. Mean changes in mitral
MR 4+ valve area after PMV (A) and post-PMV
Success: 72%
development of severe (≥3+) mitral regur-
A B gitation (B).
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s
(p < .02), the echocardiographic score (p < .0001), and the pres-
ence of atrial fibrillation (p < .009) and MR before PMV (p <
.03) as independent predictors of the increase in MVA with
PMV.
Univariate predictors of procedural success included age,
pre-PMV MVA, mean pre-PMV pulmonary artery pressure,
male sex, echocardiographic score, pre-PMV MR ≥2+, history
of previous surgical commissurotomy, presence of atrial
fibrillation, and presence of mitral valve calcification under
fluoroscopy.
Multiple stepwise logistic regression analysis identified
larger pre-PMV MVA [odds ratio (OR) 13.05, 95% confidence
interval (CI) 7.74 to 22.51; p < .001], less degree of pre-PMV
MR (OR 3.85, CI 2.27 to 6.66; p < .001), younger age (OR 3.33,
CI 1.41 to 7.69; p = .006), absence of previous surgical com-
missurotomy (OR 1.85, CI 1.20 to 2.86; p = .004), male sex
(OR 1.92, CI 1.19 to 3.13; p = .008), and echocardiographic
score ≤8 (OR 1.69, CI 1.18 to 2.44; p = .004).
Echocardiographic Score
The echocardiographic examination of the mitral valve can
accurately characterize the severity and extent of the patho-
logic process in patients with mitral stenosis. The most uti-
lized score to identify the anatomic abnormalities of the
stenotic mitral valve is that described by Wilkins et al.42
(Table 23.5). This echocardiographic score is an important
predictor of the immediate and long-term outcome of PMV.
In this morphologic score, leaflet rigidity, leaflet thickening,
valvular calcification, and subvalvular disease are scored
from 0 to 4. A higher score represents a heavily calcified,
thickened, and immobile valve with extensive thickening
and calcification of the subvalvular apparatus. The increase
in MVA with PMV is inversely related to the echocardio-
graphic score. The best outcome with PMV occurs in those
patients with echocardiographic scores ≤8. The increase in
MVA is significantly greater in patients with echocardio-
graphic scores ≤8 than in those with echocardiographic
scores >8. Among the four components of the echocardio-
563
graphic score, valve leaflets thickening and subvalvular
disease correlate best with the increase in MVA produced by
PMV.44 Therefore, suboptimal results with PMV are more
likely to occur in patients with valves that are more rigid
and more thickened, and those with more subvalvular fibro-
sis and calcification.
Balloon Size and Effective Balloon Dilating Area
The increase in mitral valve area with PMV is directly related
to balloon size. This effect was first demonstrated in a sub-
group of patients who underwent repeat PMV.45 They ini-
tially underwent PMV with a single balloon, resulting in a
mean mitral valve area of 1.2 ± 0.2 cm2. They underwent
repeat PMV using the double-balloon technique, which
increased the EBDA normalized by body surface area (EBDA/
BSA) from 3.41 ± 0.2 to 4.51 ± 0.2 cm2/m2. The mean mitral
valve area in this group after repeat PMV was 1.8 cm2 ±
0.7 cm2. The increase in MVA in patients who underwent
PMV at the Massachusetts General Hospital using the
double-balloon technique (EBDA of 6.4 ± 0.03 cm2) was sig-
nificantly greater than the increase in MVA achieved in
patients who underwent PMV using the single-balloon tech-
nique (EBDA of 4.3 ± 0.02 cm2). The mean MVAs were 1.9 ±
0.7 and 1.4 ± 0.1 cm2 for patients who underwent PMV with
the double-balloon and the single-balloon techniques, respec-
tively. However, care should be taken in the selection of
dilating balloon catheters so as to obtain an adequate final
MVA and no change or a minimal increase in MR.
Mitral Valve Calcification
The immediate outcome of patients undergoing PMV is
inversely related to the severity of valvular calcification seen
by fluoroscopy. Patients without fluoroscopic calcium have
a greater increase in MVA after PMV than patients with cal-
cified valves. Patients with either no or 1+ fluoroscopic
calcium have a greater increase in MVA after PMV (1.1 ± 0.6
and 0.9 ± 0.5 cm2, respectively) than those patients with 2, 3,
or 4+ of calcium (0.8 ± 0.6, 0.8 ± 0.5, and 0.6 ± 0.4 cm2,
respectively).

TABLE 23.5. The echocardiographic score: echocardiographic grading of the severity and extent of the anatomic abnormalities in
patients with mitral stenosis
Grade Leaflet mobility Valvular thickening Valvular calcification Subvalvular thickening

0 Normal Normal Normal Normal

1 Highly mobile valve
with restriction of
only the leaflet tips
2 Middle portion and
base of leaflets
reduced mobility
3 Valve leaflets move
forward in diastole
mainly at the base
4 No or minimal
forward movement
of the leaflets
in diastole
* The total score is the sum of each of these echocardiographic features (maximum 16).
Leaflet near normal A single area of
(4–5 mm) increased echo
brightness
Mid-leaflet thickening, Scattered areas of
marked at the brightness confined
margins to thickening of
leaflet margins
Thickening Brightness extending
extending into the midportion
through the of leaflets (5–8 mm)
entire leaflets
Marked thickening Extensive brightness
of all leaflet tissue throughout most of
(>8–10 mm) the leaflet tissue
Minimal thickening of chordal
structures just below the valve
Thickening of chordae
extending up to one third of
chordal length
Thickening extending to the
distal third of the chordae
Extensive thickening and
shortening of all chordae
extending down to the
papillary muscles
564 chapter 23

Previous Surgical Commissurotomy severity of MR determined by angiography before the proce-

Although the increase in MVA with PMV is inversely related
to the presence of previous surgical mitral commissurotomy,
PMV can produce a good outcome in this group of patients.
The post-PMV mean MVA in 154 patients with previous
surgical commissurotomy was 1.8 ± 0.7 cm2 compared with
a valve area of 1.9 ± 0.6 cm2 in patients without previous
surgical commissurotomy (p < .05). In this group of patients,
an echocardiographic score ≤8 was an important predictor of
a successful hemodynamic immediate outcome.
Age
The immediate outcome of PMV is directly related to the age
of the patient. The percentage of patients obtaining a good
result with this technique decreases as age increases. A suc-
cessful hemodynamic outcome from PMV was obtained in
only <50% of patients ≥65 years old.46 This inverse relation-
ship between age and the immediate outcome from PMV is
due to the higher frequency of atrial fibrillation, calcified
valves, and higher echocardiographic scores in elderly
patients.
Atrial Fibrillation
The increase in MVA with PMV is inversely related to the
presence of atrial fibrillation; the post-PMV MVA of patients
in normal sinus rhythm was 2.0 ± 0.7 cm2 compared with a
valve area of 1.7 ± 0.6 cm2 of those patients in atrial fibrilla-
tion. The inferior immediate outcome of PMV in patients
with mitral stenosis who are in atrial fibrillation is more
likely related to the presence of clinical and morphologic
characteristics associated with inferior results after PMV.
Patients in atrial fibrillation are older and present more fre-
quently with echocardiographic scores >8, NYHA functional
class IV, calcified mitral valves under fluoroscopy, and a
previous history of surgical mitral commissurotomy.
Mitral Regurgitation Before PMV
The presence and severity of mitral regurgitation before PMV
is an independent predictor of unfavorable outcome of PMV.
The increase in MVA after PMV is inversely related to the
dure. This inverse relationship between presence of MR and
immediate outcome of PMV is in part due to the higher fre-
quency of atrial fibrillation, higher echocardiographic scores,
calcified mitral valves under fluoroscopy, and older age in
patients with MR before PMV.
Complications
Table 23.6 shows the complications reported by several
investigators after PMV.18–20,23,25–28,34 Mortality and morbidity
with PMV are low and similar to surgical commissurotomy.
Overall, there is <1% mortality. Severe MR (four grades by
angiography) has been reported in 1% to 5.2% of the patients.
Some of these patients required in-hospital mitral valve
replacement. Thromboembolic episodes and stroke have
been reported in 0% to 3.1% and pericardial tamponade in
0.2% to 4.6% of cases in these series. Pericardial tamponade
can occur from transseptal catheterization and more rarely
from ventricular perforation. The PMV is associated with a
3% to 16% incidence of left to right shunt immediately after
the procedure. However, the pulmonary to systemic flow
ratio is ≥2 : 1 in only a minimum number of patients.
We have demonstrated that severe MR (four grades by
angiography) occurs in about 3% of patients undergoing
PMV.28 An undesirable increase in MR (two or more grades
by angiography) occurred in 10.1% of patients. This undesir-
able increase in MR is well tolerated in most patients. Fur-
thermore, more than half of them have less MR at follow-up
cardiac catheterization. We have demonstrated that the ratio
of the effective balloon dilating area to body surface area
(EBDA/BSA) is the only predictor of increased MR after
PMV.47–49 The EBDA is calculated using standard geometric
formulas. The incidence of MR is lower if balloon sizes are
chosen so that EBDA/BSA is ≤4.0 cm2/m2. The single-balloon
technique results in a lower incidence of MR but provides
less relief of mitral stenosis than the double-balloon tech-
nique. Thus, there is an optimal effective balloon dilating
area between 3.1 and 4.0 cm2/m2, which achieves a maximal
MVA with a minimal increase in MR. An echocardiographic
score for the mitral valve that can predict the development
of severe MR following PMV has also been described.43 This

TABLE 23.6. Complications following percutaneous mitral valvuloplasty

Author No. of patients Mortality Tamponade Severe mitral regurgitation Embolism

Palacios et al. 879 0.6% 1.0% 3.4% 1.8%

Vahanian et al. 1514 0.4% 0.3% 3.4% 0.3%
Hernández et al. 561 0.4% 0.6% 4.5%
Stefanadis et al. 438 0.2% 0.0% 3.4% 0.0%
Chen et al. 4832 0.1% 0.8% 1.4% 0.5%
NHLBI 738 3.0% 4.0% 3.0% 3.0%
Inoue et al. 527 0.0% 1.6% 1.9% 0.6%
Inoue registry 1251 0.6% 1.4% 3.8% 0.9%
Ben Farhat et al. 463 0.4% 0.7% 4.6% 2.0%
Arora et al. 600 1.0% 1.3% 1.0% 0.5%
Cribier et al. 153 0.0% 0.7% 1.4% 0.7%
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s 565
score takes into account the distribution (even or uneven) of 100
leaflet thickening and calcification, the degree and symme-
90
try of commissural disease, and the severity of subvalvular Echo score ≤8
disease. 80
Left to right shunt through the created atrial communi- 70 Total group
cation occurred in 3% to 16% of the patients undergoing

PMV. The size of the defect is small as reflected in the pul-
monary to systemic flow ratio of <2 : 1 in the majority of
patients. Older age, fluoroscopic evidence of mitral valve
calcification, higher echocardiographic score, pre-PMV lower
cardiac output, and higher pre-PMV NYHA functional class
are the factors that predispose patients to develop left to right
shunt post-PMV.49 Clinical, echocardiographic, surgical, and
hemodynamic follow-up of patients with post-PMV left to
right shunt demonstrated that the defect closed in approxi-
mately 60%. Persistent left to right shunt at follow-up is
small (QP/QS <2 : 1) and clinically well tolerated. In the series
from the Massachusetts General Hospital, there is one patient
in whom the atrial shunt remained hemodynamically sig-
nificant at follow-up. This patient underwent percutaneous
transcatheter closure of her atrial defect with a clamshell
device. Desideri et al.50 reported atrial shunting determined
by color flow transthoracic echocardiography in 61% of 57
patients immediately after PMV. The shunt persisted in 30%
of patients at 19 ± 6 (range 9–33) months follow-up. The
authors identified the magnitude of the post-PMV atrial
shunt (QP/QS >1.5:1), use of a Bifoil balloon (two balloons on
one shaft) and smaller post-PMV MVA as independent pre-
dictors of the persistence of atrial shunt at long-term
follow-up.
Clinical Follow-Up
Long-term follow-up studies after PMV are encourag-
ing.21,22,23,25,26,28,34 Following PMV, the majority of patients
have marked clinical improvement and are assessed as
NYHA class I or II. The symptomatic, echocardiographic,
and hemodynamic improvement produced by PMV persists
in intermediate- and long-term follow-up. The best long-term
results are seen in patients with echocardiographic scores ≤8.
When PMV produces a good immediate outcome in this
group of patients, restenosis is unlikely to occur at follow-up.
Although PMV can result in a good outcome in patients with
echocardiographic scores >8, hemodynamic and echocardio-
graphic restenosis is frequently demonstrated at follow-up
despite ongoing clinical improvement. Table 23.7 shows
long-term follow-up results of patients undergoing PMV at
Survival (%)
60
50 Echo score >8
40
30
20
10
p < .0001
0
0 20 40 60 80 100 120 140 160 180
Time of follow-up (months)
Figure 23.6. Fifteen-year survival for all patients, and for patients
with echocardiographic score ≤8 and >8, undergoing percutaneous
mitral balloon valvotomy at the Massachusetts General Hospital.
different institutions. We reported an estimated 12-year sur-
vival rate of 74% in a cohort of 879 patients undergoing PMV
at the Massachusetts General Hospital (Fig. 23.6). Death at
follow-up was directly related to age, post-PMV pulmonary
artery pressure, and pre-PMV NYHA functional class IV. In
the same group of patients, the 12-year event-free survival
(alive and free of mitral valve replacement or repair and redo
PMV) was 33% (Fig. 23.7). Cox regression analysis identified
age [risk ratio (RR) 1.02; CI 1.01–1.03; p <.0001], pre-PMV
NYHA functional class IV (RR 1.35; CI 1.00–1.81; p = .05),
prior commissurotomy (RR .150; CI 1.16–1.92; p = .002), the
echocardiographic score (RR 1.31; CI 1.02–1.67; p = .003), pre-
PMV mitral regurgitation ≥2+ (RR 1.56; CI 1.09–2.22; p = .02),
post-PMV mitral regurgitation ≥3+ (RR 3.54; CI 2.61–4.72;
p <.0001), and post-PMV mean pulmonary artery pressure
(RR 1.02; CI 1.01–1.03; p < .0001) as independent predictors
of combined events at long-term follow-up.
Actuarial survival and event-free survival rates through-
out the follow-up period were significantly better in patients
with echocardiographic scores ≤8. Survival rates were 82%
for patients with echocardiographic score ≤8 and 57% for
patients with score >8 at a follow-up time of 12 years (p <
.0001). Event-free survival (38% versus 22%; p < .0001) at 12
years’ follow-up were also significantly higher for patients

TABLE 23.7. Clinical long-term follow-up after percutaneous mitral valvuloplasty

Author No. of patients Age Follow-up (years) Survival Event-free survival

Palacios et al. 879 55 12 74% 33%#

Iung et al. 1024 49 10 85% 56%#
Hernández et al. 561 53 7 95%* 69%
Orrange et al. 132 44 7 83% 65%#
Ben Farhat et al. 30 29 7 100% 90%
Stefanadis et al. 441 44 9 98% 75%
* Only cardiovascular death considered.
# Survival without intervention and in NYHA class I to II.
566
100
90
80
Event-free survival (%)
70
60 Echo score ≤8
50
40
Total group
30
20 Echo score >8
10
0 ment. However, technical complications were similar to
0 20 40 60 80 100 120
Time of follow-up (months)
Figure 23.7. Fifteen-year event-free survival for all patients, and for
patients with echocardiographic score ≤8 and >8, undergoing percu-
taneous mitral balloon valvotomy at the Massachusetts General
Hospital.
with echocardiographic score ≤8. Similar follow-up studies
have been reported in other series with the double-balloon
technique and with the Inoue technique of PMV.21,23,25,26 Over
90% of young patients with pliable valves, in sinus rhythm
and with no evidence of calcium under fluoroscopy remain
free of cardiovascular events at approximately 5 years
follow-up.17,22,34
Functional deterioration at follow-up is late and related
primarily to mitral restenosis.26 The incidence of restenosis,
as assessed by sequential echocardiography, is approximately
40% after 7 years.25 Repeat PMV can be proposed if recurrent
stenosis leads to symptoms. At the moment, we have only
a small number of series available on redo PMV. They show
encouraging results in selected patients with favorable char-
acteristics when restenosis occurs several years after an
initially successful procedure, and if the predominant
mechanism of restenosis is commissural refusion.45
Follow-Up in the Elderly
Tuzcu et al.46 reported the outcome of PMV in 99 elderly
patients (≥65 years of age). A successful outcome (valve area
≥1.5 cm2 without ≥2+ increase in MR and without left to right
shunt of ≥1.5 : 1) was achieved in 46 patients. The best multi-
variate predictor of success was the combination of echocar-
diographic score, NYHA functional class, and inverse of
MVA. Patients who had an unsuccessful outcome from PMV
were in a higher NYHA functional class, had higher echocar-
diographic scores, and smaller MVAs pre-PMV compared to
those patients who had a successful outcome. Actuarial sur-
vival and combined event-free survival at 3 years were signifi-
cantly better in the successful group. Mean follow-up was 16
± 1 months. Actuarial survival (79% ± 7% vs. 62% ± 10%; p =
.04); survival without mitral valve replacement (71% ± 8% vs.
41% ± 8%; p = .002); and event-free survival (54% ± 12% vs.
38% ± 8%; p = .01) at 3 years were significantly better in the
successful group of 46 patients than the unsuccessful group
of 53 patients. Low echocardiographic score was the indepen-
chapter 23
dent predictor of survival and lack of mitral valve calcifica-
p <.0001 tion was the strongest predictor of event-free survival.
Recently, data reported in 96 patients ≥75 years of age
have shown that these patients present a lower pre-PMV
MVA (0.8 ± 0.3 vs. 0.9 ± 0.3; p = .005), a lower post-PMV MVA
(1.6 ± 0.6 vs. 1.9 ± 0.7; p < .0001), and a lower procedural
success (51.0% vs. 71.4%; p < .0001) compared with patients
younger than 75 years of age.51 Patients ≥75 years exhibited
a higher in-hospital mortality than patients younger than 75
years (3.1% vs. 0.3%) with no significant differences in the
other procedure-related complications (cardiac tamponade,
severe MR, significant left to right shunt, and embolism).
Although, in-hospital mortality was higher, in the majority
of these patients PMV was considered as a palliative treat-
140 160 180 those more favorable patients aged <75. Survival and event-
free survival rates were 60% and 49% for patients ≥75 years
at a follow-up time of 3 years. The echo score is an imperfect
predictor of hemodynamic improvement in elderly
patients.51,52
Unfortunately, no randomized study is available for
elderly patients, and a comparison of the results of PMV with
those of the surgical series is difficult because of the differ-
ences in the patients and surgical techniques involved.
Follow-Up of Patients with Calcified
Mitral Valves
The presence of fluoroscopically visible calcification on the
mitral valve influences the success of PMV. Patients with
heavily (≥3 grades) calcified valves under fluoroscopy have a
poorer immediate outcome as reflected in a smaller post-
PMV MVA and greater post-PMV mitral valve gradient.
Immediate outcome is progressively worse as the calcifica-
tion becomes more severe. The long-term results of percuta-
neous mitral balloon valvuloplasty are significantly different
in calcified and uncalcified groups and in subgroups of the
calcified group.53 The estimated 2-year survival is signifi-
cantly lower for patients with calcified mitral valves than for
those with uncalcified valves (80% vs. 99%). The survival
curve becomes worse as the severity of valvular calcification
becomes more severe. Freedom from mitral valve replace-
ment at 2 years was significantly lower for patients with
calcified valves than for those with uncalcified valves (67%
vs. 93%). Similarly, the estimated event-free survival at 2
years in the calcified group became significantly poorer as
the severity of calcification increased. The estimated event-
free survival at 2 years was significantly lower for the calci-
fied than for the uncalcified group (63% vs. 88%). The
actuarial survival curves with freedom from combined
events at 2 years in the calcified group became significantly
poorer as the severity of calcification increased. These find-
ings are in agreement with several follow-up studies of surgi-
cal commissurotomy that demonstrate that patients with
calcified mitral valves had a poorer survival compared to
those patients with uncalcified valves.54,55
Follow-Up of Patients with Previous
Surgical Commissurotomy
The PMV also has been shown to be a safe procedure in
patients with previous surgical mitral commissurotomy.56–61
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s
Although a good immediate outcome is frequently achieved
in these patients, follow-up results are not as favorable as
those obtained in patients without previous surgical com-
missurotomy. Although there is no difference in mortality
between patients with or without a history of previous surgi-
cal commissurotomy at 4-year follow-up, the number of
patients who required mitral valve replacement (26% vs. 8%)
or were in NYHA class III or IV (35% vs. 13%) was signifi-
cantly higher among those patients with previous commis-
surotomy. However, when the patients are carefully selected
according to the echocardiographic score (≤8), the immediate
outcome and the 4-year follow-up results are excellent and
similar to those seen in patients without previous surgical
commissurotomy.
Follow-Up of Patients with Atrial Fibrillation
We have reported that the presence of atrial fibrillation is
associated with inferior immediate and long-term outcome
after PMV as reflected in a smaller post-PMV MVA and a
lower event-free survival (freedom of death, redo-PMV, and
mitral valve surgery) at a median follow-up time of 61 months
(32% vs. 61%; p < .0001).62 Analysis of preprocedural and
procedural characteristics revealed that this association is
most likely explained by the presence of multiple factors in
the atrial fibrillation group that adversely affect the immedi-
ate and long-term outcome of PMV. Patients in atrial fibril-
lation are older and presented more frequently with NYHA
class IV, echocardiographic score >8, calcified valves under
fluoroscopy, and a history of previous surgical commissur-
otomy. In the group of patients in atrial fibrillation, we iden-
tified severe post-PMV mitral regurgitation (≥3+) (p = .0001),
echocardiographic score >8 (p = .004) and pre-PMV NYHA
class IV (p = .046) as independent predictors of combined
events at follow-up. The presence of atrial fibrillation per se
should not be the only determinant in the decision process
regarding treatment options in a patient with rheumatic
mitral stenosis. The presence of an echocardiographic score
≤8 primarily identifies a subgroup of patients with atrial
fibrillation in whom percutaneous balloon valvotomy is very
likely to be successful and provide good long-term results.
Therefore, in this group of patients, PMV should be the pro-
cedure of choice.
Follow-Up of Patients with Pulmonary
Artery Hypertension
The degree of pulmonary artery hypertension before PMV is
inversely related to the immediate and long-term outcome of
PMV.28 Chen et al.63 divided 564 patients undergoing PMV at
the Massachusetts General Hospital into three groups on the
basis of the pulmonary vascular resistance (PVR) obtained at
cardiac catheterization immediately prior to PMV: group I
with a PVR ≤250 dynes-sec/cm−5 (normal/mildly elevated
resistance) comprised 332 patients (59%); group II with a PVR
between 251 and 400 dynes-sec/cm−5 (moderately elevated
resistance) comprised 110 patients (19.5%) ; group III with a
PVR ≥400 dynes sec/cm−5 comprised of 122 patients (21.5%).
Patients in groups I and II were younger, had less severe heart
failure symptoms measured by NYHA class, and had a lower
incidence of echocardiographic scores >8, atrial fibrillation,
and calcium noted on fluoroscopy than patients in group III.
5 67
Before and after PMV, patients with higher PVR had a smaller
MVA, lower cardiac output, and higher mean pulmonary
artery pressure. For groups I, II, and III, the immediate
success rates for PMV were 68%, 56%, and 45%, respectively.
Therefore, patients in the group with severely elevated pul-
monary artery resistance before the procedure had lower
immediate success rates of PMV. At long-term follow-up
patients with severely elevated pulmonary vascular resis-
tance had a significant lower survival and event-free survival
(survival with freedom from mitral valve surgery or NYHA
class III or IV heart failure).
Follow-Up of Patients with
Tricuspid Regurgitation
The degree of tricuspid regurgitation before PMV is inversely
related to the immediate and long-term outcome of PMV.
Sagie et al.64 divided patients undergoing PMV at the Massa-
chusetts General Hospital into three groups on the basis of
the degree of tricuspid regurgitation determined by 2D and
color flow Doppler echocardiography before PMV. Patients
with severe tricuspid regurgitation before PMV were older,
had more severe heart failure symptoms measured by NYHA
class, and had a higher incidence of echocardiographic scores
>8, atrial fibrillation, and calcified mitral valves on fluoros-
copy than patients with mild or moderate tricuspid regurgi-
tation. Patients with severe tricuspid regurgitation had
smaller MVAs before and after PMV than the patients with
mild or moderate tricuspid regurgitation. At long-term
follow-up, patients with severe tricuspid regurgitation had
significantly lower survival and event-free survival (survival
with freedom from mitral valve surgery or NYHA class III
or IV heart failure). The degree of tricuspid regurgitation can
be diminished when the transmitral pressure gradient is suf-
ficiently relieved with PMV.65
Follow-Up of the Best Patients for PMV
In patients identified as optimal candidates for PMV, this
technique results in excellent immediate and long-term
outcome. Optimal candidates for PMV are those patients
meeting the following characteristics: (1) age ≤45 years old;
(2) normal sinus rhythm; (3) echocardiographic score ≤8; (4)
no history of previous surgical commissurotomy; and (5) pre-
PMV mitral regurgitation ≤1+ Sellers’ grade. From 879 con-
secutive patients undergoing PMV, we identified 136 patients
with optimal preprocedure characteristics. In these patients,
PMV results in an 81% success rate and a 3.4% incidence
of hospital combined events (death and/or MVR). In these
patients, PMV results in a 95% survival and 61% event-free
survival at 12-year follow-up.28
The Double Balloon vs. the Inoue Techniques
Today, the Inoue approach of PMV is the technique more
widely used. There was controversy as to whether the double-
balloon or the Inoue technique provided superior immediate
and long-term results. We compared the immediate proce-
dural and the long-term clinical outcomes after PMV using
the double-balloon technique (n = 659) and Inoue technique
(n = 233).66 There were no statistically significant differences
in baseline clinical and morphologic characteristics between
568 chapter
the double balloon and Inoue patients. Although the post-
PMV MVA was larger with the double-balloon technique
(1.94 ± 0.72 cm2 vs. 1.81 ± 0.58 cm2; p = 0.01), success rate
(71.3% vs. 69.1%; p = NS), incidence of ≥3+ MR (9% vs. 9%),
in-hospital complications, and long-term and event-free sur-
vival were similar with both techniques. In conclusion, both
the Inoue and the double-balloon techniques are equally
effective techniques of PMV. The procedure of choice should
be performed based on the interventionist's experience in the
technique.
Echocardiographic and Hemodynamic Follow-Up
Follow-up studies have shown that the incidence of hemo-
dynamic and echocardiographic restenosis is low after
PMV.25,26,67 A study of a group of patients undergoing simul-
taneous clinical evaluation, 2D-Doppler echocardiography,
and transseptal catheterization 2 years after PMV reported a
90% of patients in NYHA classes I and II and 10% of patients
in NYHA class ≥III.67 In this study hemodynamic determi-
nation of MVA using the Gorlin equation showed a signifi-
cant decrease in MVA from 2.0 cm2 immediately after PMV
to 1.6 cm2 at follow-up. However, there was no significant
difference between the echocardiographic MVAs immedi-
ately after PMV and at follow-up (1.8 cm2 and 1.6 cm2, respec-
tively; p = NS). Although there was a significant difference
in the MVA after PMV determined by the Gorlin equation
and by 2D echocardiography (2.0 cm2 vs. 1.8 cm2), there was
no significant difference between the MVA determined by
the Gorlin equation and the echocardiographic calculated
MVA (1.6 cm2 for both) at follow-up. The discrepancy between
the 2D-echocardiographic and Gorlin equation determined
post-PMV MVAs is due to the contribution of left to right
shunting (undetected by oximetry) across the created inter-
atrial communication, which results in both an erroneously
high cardiac output and an overestimation of the MVA by
the Gorlin equation.68 Desideri et al.50 showed no significant
differences in MVA (measured by Doppler echocardiography)
at 19 ± 6 (range 9–33) months’ follow-up between the post-
PMV and follow-up MVAs. Mitral valve areas were 2.2 ±
0.5 cm2 and 1.9 ± 0.5 cm2, respectively.50 Echocardiographic
restenosis (MVA ≤ 1.5 cm2 with >50% reduction of the gain)
was estimated in 39% at 7 years’ follow-up with the Inoue
technique.25 A mitral area loss ≥0.3 cm2 was seen in 12%,
22%, and 27% of patients at 3, 5, and 7 years, respectively.
Predictors of restenosis included a post-MVA <1.8 cm2 and an
echo score >8.
PMV vs. Surgical Mitral Commissurotomy
Results of surgical closed mitral commissurotomy have
demonstrated favorable long-term hemodynamic and symp-
tomatic improvement from this technique. A restenosis rate
of 4.2 to 11.4 per 1,000 patients per year was reported by John
et al.69 in 3724 patients who underwent surgical closed mitral
commissurotomy. Survival after PMV is similar to that
reported after surgical mitral commissurotomy. Although
freedom from mitral valve replacement and freedom from all
events after PMV are lower than reported after surgical com-
missurotomy, freedom from both mitral valve replacement
and all events in patients with echocardiographic scores
23
≤8 are similar to that reported after surgical mitral
commissurotomy.28,55,69–76
Restenosis after both closed and open surgical mitral
commissurotomy has been well documented.69–76 Although
surgical closed mitral commissurotomy is uncommonly per-
formed in the United States, it is still used frequently in
other countries. Long-term follow-up of 267 patients who
underwent surgical transventricular mitral commissurot-
omy at the Mayo Clinic showed a 79%, 67%, and 55% sur-
vival at 10, 15, and 20 years, respectively. Survival with
freedom from mitral valve replacement was 57%, 36%, and
24%, respectively.77 At the patient ages in this study, atrial
fibrillation and male gender were independent predictors of
death, whereas mitral valve calcification, cardiomegaly, and
MR were independent predictors of repeat mitral valve
surgery.
Because of similar patient selection and mechanism of
mitral valve dilatation, similar long-term results should be
expected after PMV. Indeed, prospective, randomized trials
comparing PMV and surgical closed or open mitral commis-
surotomy have shown no differences in immediate and 3-
year follow-up results between both groups of patients.29–34
Furthermore, restenosis at 3-year follow-up occurred in 10%
and 13% of the patients treated with mitral balloon valvulo-
plasty and surgical commissurotomy, respectively.33
Interpretation of long-term clinical follow-up of patients
undergoing percutaneous mitral balloon valvuloplasty as
well as their comparison with surgical commissurotomy
series are confounded by heterogeneity in patient popula-
tions. Most surgical series have involved a younger popula-
tion with optimal mitral valve morphology, with a pliable
valve and no calcification and no evidence of subvalvular
disease. Comparisons were also made at the beginning of
PMV. Therefore, surgeons were more experienced than inter-
ventional cardiologists. Differences in age and valve morphol-
ogy may also account for the lower survival and event-free
survival in PMV series from the United States and Europe.28
Several studies have compared the immediate and early
follow-up results of PMV versus closed surgical commissur-
otomy in optimal patients for these techniques. The results
of these studies have been controversial, showing either supe-
rior outcome from PMV or no significant differences between
both techniques.29–34 Patel et al.29 randomized 45 patients
with mitral stenosis and optimal mitral valve morphology to
closed surgical commissurotomy and to PMV. They demon-
strated a larger increase in MVA with PMV (2.1 ± 0.7 vs. 1.3 ±
0.3 cm2). Shrivastava et al.30 compared the results of single-
balloon PMV, double-balloon PMV, and closed surgical com-
missurotomy in three groups of 20 patients each. The MVA
postintervention was larger for the double-balloon technique
of PMV. Postintervention valve areas were 1.9 ± 0.8, 1.5 ± 0.4,
and 1.5 ± 0.5 cm2 for the double balloon, the single balloon,
and the closed surgical commissurotomy techniques, respec-
tively. On the other hand, Arora et al.31 randomized 200
patients with a mean age of 19 ± 7 years and mitral stenosis
with optimal mitral valve morphology to PMV and to closed
mitral commissurotomy. Both procedures resulted in similar
postintervention MVAs (2.39 ± 0.9 vs. 2.2 ± 0.9 cm2 for the
PMV and the mitral commissurotomy groups, respectively)
and no significant differences in event-free survival at a
mean follow-up period of 22 ± 6 months. Restenosis docu-
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s
mented by echocardiography was low in both groups, 5% in
the PMV group, and 4% in the closed commissurotomy group.
Turi et al.32 randomized 40 patients with severe mitral steno-
sis to PMV and to closed surgical commissurotomy. The pos-
tintervention MVA at 1 week (1.6 ± 0.6 vs. 1.6 ± 0.7 cm2) and 8
months (1.6 ± 0.6 vs. 1.8 ± 0.6 cm2) after the procedures were
similar in both groups. Reyes et al. 33 randomized 60 patients
with severe mitral stenosis and favorable valvular anatomy to
PMV and to surgical commissurotomy. They reported no sig-
nificant differences in immediate outcome, complications,
and 3.5 years’ follow-up between both groups of patients.
Improvement was maintained in both groups, but MVAs at
follow-up were larger in the PMV group (2.4 ± 0.6 vs. 1.8 ±
0.4 cm2).
Ben Farhat et al.34 reported the results of a randomized
trial designed to compare the immediate and long-term
results of double-balloon PMV versus those of open and
closed surgical mitral commissurotomy in a cohort of
patients with severe rheumatic mitral stenosis. This group
of patients was from the clinical and morphologic point of
view optimal candidates for both PMV and surgical commis-
surotomy (closed or open) procedures. They had a mean age
of less than 30 years, absence of mitral valve calcification on
fluoroscopy and 2D echocardiography, and an echocardio-
graphic score ≤8 in all patients. The results demonstrate that
the immediate and long-term results of PMV are comparable
to those of open mitral commissurotomy and superior to
those of closed commissurotomy. The hemodynamic
improvement, inhospital complications, and long-term reste-
nosis rate and need for reintervention were superior for the
patients treated with either PMV or open commissurotomy
than for those treated with closed commissurotomy. The
postintervention MVAs achieved with PMV were similar to
the one obtained after open surgical commissurotomy (2.5 ±
0.5 vs. 2.2 ± 0.4 cm2) but larger than those obtained after
closed commissurotomy. These initial changes resulted in
an excellent long-term follow-up in the group of patients
treated with PMV, which was comparable with the open
commissurotomy group and superior to the closed commis-
surotomy group. The inferior results of closed mitral com-
missurotomy presented by Ben Farhat et al. are in disagreement
with previous studies showing no significant differences in
immediate and follow-up results between PMV and closed
surgical mitral commissurotomy.29–31 However, the increase
in MVA after closed commissurotomy is not uniform and
often unsatisfactory. Since open commissurotomy is associ-
ated with a thoracotomy, need for cardiopulmonary bypass,
higher cost, longer length of hospital stay, and a longer period
of convalescence, PMV should be the procedure of choice for
the treatment of patients with rheumatic mitral stenosis who
are from the clinical and morphologic point of view optimal
candidates for PMV.35
PMV in Pregnant Women
Surgical mitral commissurotomy has been performed in
pregnant women with severe mitral stenosis. Since the risk
of anesthesia and surgery for the mother and the fetus are
increased, this operation is reserved for those patients with
incapacitating symptoms refractory to medical therapy.78–80
Under these conditions, PMV can be performed safely after
569
the 20th week of pregnancy with minimal radiation to the
fetus.80–82 Because of the definite risk in women with severe
mitral stenosis of developing symptoms during pregnancy,
PMV should be considered when the patient is considering
becoming pregnant.
Conclusions
The PMV should be the procedure of choice for the treatment
of patients with rheumatic mitral stenosis who are, from the
clinical and morphologic points of view, optimal candidates
for PMV. Patients with echocardiographic scores ≤8 have the
best results particularly if they are young, are in sinus
rhythm, and have no pulmonary hypertension and no evi-
dence of calcification of the mitral valve under fluoroscopy.
The immediate and long-term results of PMV in this group
of patients are similar to those reported after surgical mitral
commissurotomy. Patients with echocardiographic scores >8
have only a 50% chance to obtain a successful hemodynamic
result with PMV, and long-term follow-up results are less
good than those from patients with echocardiographic scores
≤8. In patients with echocardiographic scores ≥12, it is
unlikely that PMV could produce good immediate or long-
term results. They preferably should undergo open-heart
surgery. The PMV could be performed in these patients if
they are non–high-risk surgical candidates. Finally, much
remains to be done in refining indications for patients with
few or no symptoms and those with unfavorable anatomy.
However, surgical therapy for mitral stenosis should actually
be reserved for patients who have ≥2 grades of Sellers’ MR
by angiography, which can be better treated by mitral valve
repair, and for those patients with severe mitral valve thick-
ening and calcification or with significant subvalvular scar-
ring who warrant valve replacement.
Percutaneous Aortic Balloon Valvuloplasty
Aortic valve replacement is the treatment of choice for symp-
tomatic, severe aortic stenosis in the elderly.82–88 However,
associated major medical comorbid conditions increase peri-
operative complications significantly, and in some cases, the
risk is so high that surgeons classify these patients as non-
surgical candidates. Previous bypass surgery, severe conges-
tive heart failure, low left ventricular ejection fraction, recent
myocardial infarction, diabetes mellitus, renal failure, and,
most of all, emergent operation, are independent predictors
for operative death in elderly patients undergoing aortic valve
replacement. Furthermore, 54% of octogenarians require
concomitant surgical procedures, including coronary artery
bypass surgery or mitral valve replacement.89,90 Elective peri-
operative mortality for octogenarians undergoing aortic valve
replacement and coronary artery bypass graft is 24%.89 Emer-
gent perioperative mortality increases to 37% in patients
with severe congestive heart failure requiring pressors, and
can be as high as 50% in patients with cardiogenic shock.91,92
Finally, complicated postoperative course, including enceph-
alopathy with discharge to a rehabilitation facility is present
in 38% of the patients.93
Since the initial report by Cribier et al.94 in 1986, per-
cutaneous aortic balloon valvuloplasty (PAV) has been
570 chapter 23

TABLE 23.8. Recommendations for percutaneous aortic valvuloplasty in adults with aortic stenosis
Current indication Class Level of evidence

A “bridge” to surgery in hemodynamically unstable patients who are at IIa Grade B

high risk for aortic valve replacement
Palliation in patients with serious comorbid conditions IIb Grade B
Patients who require urgent noncardiac surgery IIb Grade B
An alternative to aortic valve replacement III Grade B

considered a palliative form of treatment for elderly patients Retrograde Technique

with calcific aortic stenosis. It is associated with significant
immediate clinical and hemodynamic improvement.
However, the risk of major complications and the high reste-
nosis rate during the first year are major limitations of this
technique.95–99 In fact, since PAV does not change the natural
history of severe aortic stenosis,100–103 its use in some institu-
tions has been abandoned.104 Therefore, elderly patients with
profound hemodynamic instability due to severe aortic ste-
nosis present a challenging dilemma in critical care medi-
cine. If surgery is not an option, PAV can be effectively used
as a lifesaving procedure for immediate relief of the trans-
aortic valve gradient with subsequent hemodynamic stabili-
zation and further consideration for an elective bridge to
aortic valve replacement (Table 23.8).
In contrast, balloon valvuloplasty is an efficacious treat-
ment option for adolescents and young adults in their early
20s with aortic stenosis. Balloon valvuloplasty has resulted
in good long-term palliation with little morbidity and little
or no short- or long-term mortality in these patients. Thus,
the indications for intervention are considerably more liberal
than those in older adults (Table 23.9).
Technique
The technique of percutaneous balloon aortic valvuloplasty
is not complex and can be performed using either the retro-
grade or the antegrade techniques.95
After crossing the aortic valve and determining resting
hemodynamics, a 0.038-inch Amplatz-type heavy exchange
wire is advanced through the retrograde catheter and placed
into the left ventricular cavity. The retrograde catheter is
then removed leaving the guidewire across the stenotic aortic
valve coiled in the left ventricular apex. A dilating balloon
catheter chosen according to the size of the aortic annulus
is then advanced over the guidewire, placed across the aortic
valve, and inflated by hand (Fig. 23.8).
Antegrade Technique
The left atrium is entered using transseptal catheterization
with a modified Brockenbrough needle and a Mullins sheath.
A balloon-wedge catheter is advanced through the Mullins
sheath and passed into the left ventricle and then antegrade
through the stenotic aortic valve. A soft 0.038-inch exchange
wire is advanced through the catheter into the ascending and
descending aorta, and the catheter and Mullins sheath are
removed. A chosen dilating balloon catheter is then advanced
antegrade across the mitral valve, placed across the aortic
valve, and inflated. A variation of the transseptal antegrade
technique using the Inoue balloon has also been reported.
With this technique, a 26-mm Inoue balloon catheter (at
maximum balloon volume of 22 to 25 cc) is advanced ante-
grade over a 0.025-inch exchange-length guidewire that has
been advanced transseptally from the right atrium into the

TABLE 23.9. Recommendations for percutaneous aortic valvuloplasty in adolescent or young adults
(£21) with aortic stenosis and normal cardiac output
Current indication Class Level of evidence

Symptoms of angina, syncope and dyspnea on exertion, with I Grade B

catheterization peak gradient >50 mm Hg
Catheterization peak gradient >60 mm Hg I Grade B
New-onset ischemic or repolarization changes on ECG at rest or with I Grade B
exercise (ST depression, T-wave inversion over left precordium)
with a gradient >50 mm Hg
Catheterization peak gradient >50 mm Hg if patient wants to play IIa Grade C
competitive sports or desires to become pregnant
Catheterization gradient <50 mm Hg without symptoms or ECG changes III Grade C
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s 571

A B

FIGURE 23.8. Cineangiographic

frames of retrograde percutaneous
aortic balloon valvuloplasty. (A)
The guidewire in place across the
aortic valve with a loop into the
left ventricle. (B) The dilating
balloon catheter is placed across
the aortic valve. (C) The dilating
balloon catheter is partially
inflated across the stenotic aortic
valve. Note the indentation in the
balloon caused by the stenotic
aortic valve. (D) Full inflation of
the dilating balloon across the
aortic valves. C D

left atrium and left ventricle and then antegrade across the
aortic valve into the ascending and descending aorta. Advanc-
ing of the balloon catheter is facilitated by snaring the guide-
wire into the descending aorta from either of the femoral
arteries (Fig. 23.9).
With both techniques, multiple balloon inflations are
performed to relieve the stenosis. To monitor systemic blood
pressure during and immediately after balloon inflations, a
radial arterial line should be in place before the inflations.
In two thirds of the patients, inflations are well tolerated and

Figure 23.9. Transseptal, antegrade aortic balloon valvuloplasty
using the Inoue balloon catheter. Following transseptal left heart
catheterization a balloon tip catheter is advanced from the right
atrium into the left atrium and then across the mitral valve into the
ascending and descending aorta across the stenotic aortic valve. A
0.025-inch Amplatzer exchange wire is advanced through the balloon
catheter into the ascending aorta. The tip of the guidewire is snared
from the descending aorta with the use of a 5-French Microvena
snare catheter and the balloon catheter removed. Thereafter, a 26-
mm Inoue balloon catheter is advanced antegrade across the aortic
valve and inflated at a volume between 20 to 24 cc according to the
aortic annulus until the indentation produced by the stenotic valve
is resolved.
572 chapter
longer balloon inflations (>30 seconds) can be performed. In
the other third of the patients only short balloon inflations
(15 to 30 seconds) can be performed because of significant
hypotension during balloon inflation. Short balloon infla-
tions and a longer period between inflations are used in
patients with severe depression of left ventricular ejection
fraction as well as in patients with severe coronary artery
disease or carotid disease. The size of the dilating balloon
catheter (18 to 25 mm in diameter) is chosen according to the
size of the aortic annulus (not greater than 100% of annulus)
determined by 2D-echocardiography or angiography.
Hemodynamic measurement and cardiac output using
the thermodilution method are determined before and after
completion of the procedure. For patients with significant
tricuspid regurgitation or left to right shunting, cardiac
output is determined using the Fick method. The aortic valve
area (cm2) is calculated using the Gorlin equation.105 Aortic
valve resistance (dynes-sec/cm−5) proposed as a better indica-
tor of the hemodynamic significance of aortic stenosis before
and after PAV, can be calculated as previously described.106
Left ventricular ejection fraction is calculated by contrast
ventriculography or 2D-echocardiography.
Mechanism
The final aortic valve area obtained with PAV is most likely
related to the underlying valve pathology.107,108 Fresh post-
mortem studies of patients with degenerative calcific aortic
stenosis in whom commissural fusion, is minimal have
shown that the increase in aortic valve area in these patients
occurs as the result of fracture of calcium deposit in the
aortic leaflets.108 In patients with commissural fusion such
as rheumatic aortic stenosis and some patients with noncal-
cific bicuspid valve stenosis, PAV produces commissural
splitting with or without cuspal crack. In addition, PAV pro-
duces stretching of the aortic wall at nonfused commissural
sites. Stretching is probably transient and is responsible for
the cases of early restenosis seen in some patients. Although
opening of fused commissures is probably the most effective
mechanism of PAV, commissure fusion seldom occurs in the
elderly with calcific aortic stenosis.109
Immediate Results
Between February 1986 and February 1993, 394 PAV proce-
dures were performed at the Massachusetts General Hospital
in 310 symptomatic patients with severe, calcific, aortic ste-
nosis.101 The patients were considered nonsurgical or very
high risk surgical candidates at the time of presentation
because of associated major comorbid conditions. In addi-
TABLE 23.10. Immediate results of percutaneous aortic valvuloplasty101
Variable
Mean aortic gradient, mm Hg
Cardiac output, L/min
Aortic valve area, cm 2
Systolic aortic pressure, mm Hg
Systolic pulmonary artery pressure, mm Hg
23
tion, PAV was performed in patients with severe aortic
stenosis discovered at the time of evaluation for major non-
cardiac surgery, in 65 patients who presented with symptom-
atic aortic valve restenosis after a previous successful
procedure (redo-PAV), and in 21 patients who presented in
cardiogenic shock due to critical aortic stenosis. There were
180 women and 130 men with a mean age of 79 ± 1 (range:
35–96) years. Mean left ventricular ejection fraction was 48%
± 15% (range: 10–81%). Ninety percent of the patients were
in NYHA functional classes III to IV. All patients had more
than one major comorbid condition (average 1.3/patient) at
the time of presentation, including chronic renal failure
(21%), severe chronic obstructive pulmonary disease (21%),
peripheral vascular disease (17%), previous stroke (15%),
cancer (15%), and other major comorbidities (38%; liver
failure, hip fracture, pulmonary hemorrhage, pulmonary
embolism, Alzheimer’s disease, sepsis, diabetes with multi-
ple organ complications, thyroid disease, bleeding disorders,
incapacitating arthritis, multiple myeloma, and AIDS).
Percutaneous aortic balloon valvuloplasty results in a
decrease in aortic gradient and a modest increase in aortic
valve area in the great majority of patients with degenerative
calcific aortic stenosis. The hemodynamic changes produced
by PAV are shown in Table 23.10. Percutaneous aortic balloon
valvuloplasty resulted in a significant decrease in mean sys-
tolic aortic gradient from 56 ± 1 to 25 ± 1 mm Hg (p = .0001)
and a significant increase in both cardiac output from 3.7 ±
0.06 to 3.9 ± 0.06 L/min (p = 0.0001) and aortic valve area
from 0.5 ± 0.01 to 0.9 ± 0.02 cm2 (p = .0001). Failure of PAV
(no change in aortic valve area) occurred in only 3% of the
patients. An aortic valve area ≤0.7 cm2 was obtained in about
38% of the patients. An aortic valve area >0.7 cm2 was
obtained in 59% of the patients, including 27% of patients
in whom PAV results in an aortic valve area ≥1.0 cm2. The
increase in aortic valve area with PAV is inversely related to
the NYHA functional class before PAV and to the severity
of aortic stenosis as reflected in higher aortic gradient and
smaller aortic valve area before PAV.
Complications
Procedural mortality (death in the catheterization labora-
tory) occurred in 12 patients (3%), in-hospital (30-day) mor-
tality occurred in 34 patients (8.6%); and local vascular
complications in 49 patients (12%), including the need for
vascular surgery in 38 patients (9.6%), two of whom required
leg amputation (0.5%). Cerebrovascular accident occurred in
five patients (1.2%), severe aortic regurgitation in six patients
(1.5%), acute renal failure in seven patients (1.7%), significant
atrial septal defect in two patients (0.5%) who had antegrade
Pre-PAV Post-PAV p value
56 ± 1 25 ± 1 .0001
3.7 ± 0.1 3.9 ± 0.1 .0001
0.49 ± 0.01 0.87 ± 0.02 .0001
129 ± 2 144 ± 2 .0001
49 ± 1 45 ± 1 .003
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s
PAV, cholesterol emboli in three patients (0.8%), nonfatal
ventricular fibrillation in seven patients (1.7%), myocardial
infarction in six patients (1.5%), and left ventricular perfora-
tion in one patient (0.2%).101
Long-Term Follow-Up
Although PAV results in immediate hemodynamic and
symptomatic improvement in the great majority of patients,
the long-term results of PAV show that clinical restenosis
occurs frequently 6 to 12 months after PAV.102,104 Estimated
actuarial survival at 1-, 3-, and 5-year follow-up of the Mas-
sachusetts General Hospital series were 55% ± 3%, 25% ±
3%, and 22% ± 3%, respectively (Fig. 23.10). The correspond-
ing estimated actuarial event-free survival were 33% ± 2%,
13% ± 2%, and 2% ± 1%, respectively (Fig. 23.11). Clinical
follow-up of the patients who have undergone percutaneous
aortic valvuloplasty have demonstrated that cardiac mortal-
ity and clinical restenosis (defined as cardiac mortality and
patients returning to the pre-PAV NYHA functional class)
after balloon valvuloplasty is very high. Although mortality
is greater in those patients in whom PAV resulted in an aortic
valve area <0.7 cm2 than in those with post-PAV valve areas
>0.7 cm2 (Fig. 23.10), the survival curve of the natural history
of patients with severe aortic stenosis treated medically is
unaffected by balloon valvuloplasty. The presence of left
ventricular dysfunction and the presence of coronary artery
disease adversely affect the prognosis of patients undergoing
PAV. The decrease in aortic valve area at follow-up is inversely
related to the post-PAV aortic valve area (Fig. 23.10). One-year
clinical restenosis is greater in patients in whom post-PAV
aortic valve area was ≤0.7 cm2 than in those in whom post-
PAV aortic valve area was >0.7 cm2. A high restenosis rate
(>50%) was also present in patients who have a second or
third PAV with larger balloon sizes.
A high incidence of restenosis after PAV in elderly patients
with calcific aortic stenosis is not unexpected. Previous
attempts at surgical aortic valvuloplasty using a wide variety
1.0
0.8 AVA ≥ 1.0 cm2
AVA 0.8 - 0.9 cm2
AVA < 0.7 cm2
0.6
% valve area increased from 0.6 ± 0.04 to 1.0 ± 0.07 cm2 (p <
0.4
0.2
0 PAV. There was a significant improvement in symptoms after
0 4 8 12 16 20 24 28 32 36
Months FIU
FIGURE 23.10. Actuarial survival curves for patients with severe
aortic stenosis treated with percutaneous aortic balloon valvulo-
plasty at the Massachusetts General Hospital. Curves for three dif-
ferent post–percutaneous aortic balloon valvuloplasty (PAV) aortic
valve areas achieved with the procedure are shown. AVA, aortic
valve area post-PAV.
573
1.0
0.8 AVA ≥ 1.0 cm2
AVA 0.8 - 0.9 cm2
AVA ≤ 0.7 cm2
0.6
%
0.4
0.2
0
0 4 8 12 16 20 24 28 32 36 40
Months FIU
FIGURE 23.11. Curves for clinical restenosis after PAV for patients
with severe aortic stenosis treated with percutaneous aortic balloon
valvuloplasty at the Massachusetts General Hospital. Curves for
three different post-PAV aortic valve areas achieved with the proce-
dure are shown. AVA, aortic valve area post-PAV.
of instruments were accompanied by a high rate of resteno-
sis. Healing of the fracture calcium nodules could be expected
to occur early after PAV, resulting in the high incidence of
restenosis. However, it is possible that if commissure split-
ting had occurred at the time of PAV, restenosis may not be
as rapid. Although only speculative, this mechanism may
account in part for those patients with a superior long-term
result.
PAV as a Bridge to Aortic Valve Replacement
From our cohort of 310 patients who underwent PAV at the
Massachusetts General Hospital, there were 40 patients
(13%), 21 men and 19 women, mean age of 75 ± 2 years, who
underwent aortic valve replacement 6 ± 1 months after PAV.101
When compared with the group that did not undergo aortic
valve replacement after PAV (n = 270), the group of patients
bridged to surgery were younger (p = .003), had a higher
cardiac output (p < .003), higher aortic valve area (p = .006),
and higher left ventricular end diastolic pressure (p < .034)
before PAV. Left ventricular ejection fraction was similar in
both groups. With PAV, the mean aortic gradient decreased
from 57 ± 3 to 26 ± 2 mm Hg (p < .001), the cardiac output
increased from 4.2 ± 1 to 4.5 ± 1 L/min (p = .11), and the aortic
.001). Patients who underwent aortic valve replacement had
both higher cardiac output (p < .001) and larger aortic valve
area (p = .03) after PAV than the group of patients that did
not undergo surgery. In-hospital surgical mortality was 10%.
There were seven deaths occurring at 18 ± 6 months after
40
aortic valve replacement. At a mean follow-up of 35 ± 3
months, 87% of the patients bridged to aortic valve replace-
ment after PAV were in NYHA class I-II and 13% were in
class III-IV. As shown in Figure 23.12 estimated actuarial
survival curves at 1, 3, and 5 years were significantly better
for the group of patients bridged to aortic valve replacement
after PAV.
5 74 chapter
100
PAV + AVR
80
Survival (%)
60
p = .0001
40
20 PAV
0
1 4 8
12 16 20 24 28 32 36
Time (months)
FIGURE 23.12. Comparative actuarial survival for patients under-
going percutaneous aortic balloon valvuloplasty at the Massachu-
setts General Hospital as a bridge to aortic valve replacement with
those who did not undergo AVR.
PAV for Patients in Cardiogenic Shock
Percutaneous aortic balloon valvuloplasty can be performed
successfully in patients with cardiogenic shock due to severe
aortic stenosis.110 In these patients, PAV resulted in a signifi-
cant decrease in aortic gradient and a significant increase in
aortic valve area and systolic arterial pressure in 90% of
these moribund patients. From our cohort of 310 patients
who underwent PAV at the Massachusetts General Hospital,
there were 21 patients, 10 men and 11 women, mean age of
74 ± 3 (range 35–90) years, mean left ventricular ejection
fraction of 29% ± 3% (range 15–61%) who underwent PAV for
cardiogenic shock. All patients met the following criteria of
cardiogenic shock: (1) sustained arterial hypotension with
systolic blood pressure <90 mm Hg despite maximal inotro-
pic and pressor pharmacologic support; (2) cardiac index
<2.2 L/min/m2; (3) mean pulmonary capillary wedge pressure
or left ventricular end-diastolic pressure (LVEDP) >20 mm Hg;
(4) urinary output <0.5 mL/kg/h; and (5) clinical evidence of
decreased tissue perfusion.
Before PAV, patients with cardiogenic shock exhibit a
lower left ventricular ejection fraction (p = .001), and lower
cardiac index (p < .0003) than the group of patients without
cardiogenic shock. Percutaneous aortic balloon valvuloplasty
resulted in a significant reduction in mean aortic gradient
from 49 ± 4 to 21 ± 3 mm Hg (p = .0001), a borderline improve-
ment in cardiac index from 1.8 ± 0.1 to 2.2 ± 0.1 L/min/m2
(p = .06), and a significant improvement in aortic valve area
from 0.5 ± 0.04 to 0.8 ± 0.06 cm2 (p = .0001) in the group of
patients presenting in cardiogenic shock. Sixteen of these
patients were successfully weaned from the inotropic support
in the first 24 hours after the valvuloplasty procedure. Com-
plications in this cohort of patients included procedural mor-
tality in two patients (9.5%), total in-hospital (30-day)
mortality in nine patients (43%), local vascular complica-
tions in five patients (24%), local vascular surgery in three
patients (14%), cerebrovascular accident in one patient (5%),
severe aortic regurgitation in one patient (5%), and choles-
terol embolization in one patient (5%). The major cause of
in-hospital mortality was multiorgan failure despite success-
ful PAV.
23
Actuarial survival was 38% ± 11% at 27 months’ follow-
up. Cox regression analysis identified post-PAV cardiac index
as the only predictor for longer survival (p = .02). Although
high, the procedure-related mortality after PAV in this group
of patients with cardiogenic shock compares favorably with
the extremely high mortality rate reported in previous surgi-
cal studies in patients with cardiogenic shock and severe
aortic stenosis.91,92 Even though surgical correction with
aortic valve replacement is the only therapy that alters the
natural history of severe, symptomatic aortic stenosis in the
elderly, there are important guidelines that have to be kept
in mind when managing elderly patients with cardiogenic
shock due to critical aortic stenosis: (1) sustained hypoten-
sion-associated severe congestive heart failure constitutes a
medical emergency, and pharmacologic therapy and bedside
hemodynamic monitoring should be started immediately; (2)
there is no time for procrastination, and emergent interven-
tional therapy (PAV or aortic valve replacement) should
be done as soon as possible; (3) PAV should be considered
as a bridge to aortic valve replacement, and aortic valve re-
placement with myocardial revascularization, if needed,
should be performed early after percutaneous balloon
valvuloplasty.
Palliation PAV
Percutaneous aortic balloon valvuloplasty is a palliative
treatment for adult patients with aortic stenosis who are not
candidates for aortic valve replacement.94,104,110 It provides
immediate hemodynamic and clinical improvement with a
low incidence of life-threatening complications. However,
the major limitation of PAV is the high incidence of resteno-
sis within 1 year after the procedure. Although PAV results
in immediate hemodynamic and symptomatic improvement
in the great majority of patients, the long-term results of PAV
show that clinical restenosis occurs frequently 6 to 12
months after PAV.
PAV for Patients Undergoing Emergency
Noncardiac Surgery
Some studies have shown that patients with severe aortic
stenosis undergoing noncardiac surgery could benefit from
PAV, resulting in a significant improvement in aortic valve
gradient and aortic valve area with very low complications
during noncardiac surgery.111–113 However, O´Keefe et al.,114 in
48 patients with severe aortic stenosis who underwent non-
cardiac surgery without preoperative PAV, found no major
perioperative complications if patients were managed with
careful monitoring of systemic and pulmonary artery pres-
sure during anesthesia. Therefore, PAV should be limited to
those patients with critical aortic stenosis and low ejection
fraction, heart failure, or cardiogenic shock, in whom tran-
sient hemodynamic improvement may decrease the risk of
perioperative complications.
PAV in Pregnant Women
As aortic stenosis in pregnant patients is most commonly
bicuspid with two commissures, PAV should provide effec-
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s
tive gradient relief in these patients. However, only very
limited information is available.115,116
PAV for Patients with Congenital Aortic Stenosis
Lababidi et al.119 introduced balloon aortic valvuloplasty
for congenital valvular aortic stenosis in 1984. The aortic
valve in patients with congenital aortic stenosis is most
commonly bicuspid with two commissures, less frequently
is unicommissural or noncommissural, and rarely is
tricuspid with fusion of one or more of the three commis-
sures. Balloon valvuloplasty in this patient population
provides effective gradient relief with minimal restenosis
at follow-up, though progressive aortic insufficiency has
been reported.11,117–122 In this patient cohort, PAV is a
good alternative to surgical valvuloplasty, and this later
technique should be reserved for those patients with con-
genital aortic stenosis in whom PAV is unsuccessful or
impossible (Table 23.9). Complications are rare and most of
them transient. Arterial access problems due to the large
balloon size are the most common complications. The inci-
dence of a degree of aortic regurgitation post-PAV is compa-
rable to that associated with surgical open valvuloplasty.
Appropriate balloon sizing (a balloon diameter equal to or
less than the aortic annulus measured by echocardiography
or cineangiography) is essential to decrease the incidence of
severe aortic regurgitation and or disruption of the aortic
annulus after PAV.
Patient Selection
It is well known that the onset of symptoms in patients
with severe aortic stenosis begins after a latent period of
several years, during which increasing left ventricular
obstruction and myocardial overload occurs.123 After the
onset of symptoms, the prognosis of patients with aortic
stenosis without aortic valve replacement is very poor.
The 5-year survival is less than 50% when congestive
heart failure, syncope, or angina develops in patients treated
medically. Congestive heart failure carries the worse
prognosis; the 50% survival of these patients is 2 years
if surgery is not performed. Thus, once symptoms
develop, medical therapy has a limited role in the treatment
of patients with aortic stenosis. Aortic valve replacement
is the treatment of choice for these patients. This technique
has been clearly demonstrated to change the natural
history of patients with severe aortic stenosis. Aortic
valve replacement can be performed with low operative mor-
tality and morbidity. Follow-up studies of these patients dem-
onstrated significant improvement in symptoms and
excellent long-term survival. Although aortic valve replace-
ment in elderly patients, particularly those octogenarians
with severe aortic stenosis, is associated with a greater mor-
bidity and mortality, it can be performed safely with low
mortality in a selected group of these patients. Furthermore,
after surgery, the survival of these patients is not different
from the survival of other octogenarians with no cardiac
diseases.93
Although the hemodynamic and clinical improvement
produced by PAV in more patients with degenerative calcific
5 75
aortic stenosis is short lived, it provides a window of oppor-
tunity, making this technique an attractive alternative for a
select group of patients with symptomatic calcific aortic
stenosis. Today, the PAV indications for patients with severe
degenerative aortic stenosis include the following:
1. Patients who are not surgical candidates or are very
high risk surgical candidates and are incapacitated by symp-
toms of aortic stenosis: Consultation with a cardiac surgeon
is recommended to identify patients who are truly not can-
didates for cardiac surgery. Elderly patients with aortic ste-
nosis should not be denied the opportunity for aortic valve
replacement solely on the basis of age.
2. As a bridge to aortic valve replacement in patients with
calcific aortic stenosis who require urgent major noncardiac
surgical intervention for other organ dysfunction: These
patients may have PAV done to transiently improve their
hemodynamics, and therefore, the safety of their urgent
major surgical procedure. After recovery from this surgery,
the decision to replace the aortic valve should be made.
3. As a bridge to aortic valve replacement in patients with
severe heart failure or cardiogenic shock due to aortic
stenosis.
4. In patients with “the Gorlin conundrum” character-
ized by poor left ventricular function, low cardiac output,
and small transaortic gradient whose calculated aortic valve
areas by the Gorlin formula are small: In these patients, the
low left ventricular ejection fraction could be secondary to a
myopathic left ventricle with an aortic valve that is not ste-
notic, but with a low flow state that results in a falsely low
calculated aortic valve area, or secondary to afterload mis-
match due to severe stenotic aortic valve. In the former,
surgery will not be of benefit and the surgical risk is very
high, and in the latter, aortic valve replacement should be
performed. A PAV can be used to solve this dilemma. Improve-
ment of left ventricular ejection fraction after a successful
PAV indicates that aortic stenosis was present and the patient
should undergo aortic valve replacement. In contrast, the
lack of improvement in the left ventricular ejection fraction
after a successful PAV indicates that aortic stenosis was
never present and the patient was suffering from a cardiomy-
opathy. Under these later conditions, aortic valve replace-
ment should not be performed.
Percutaneous Tricuspid Balloon Valvuloplasty
Tricuspid stenosis is rare and is associated with mitral ste-
nosis. Percutaneous tricuspid balloon valvuloplasty (PTV)
has been performed in few isolated cases with good
outcome.124–126 Because of the large tricuspid annulus, the
double-balloon technique is preferable. Results from PTV
have been similar to those reported for surgery. The PTV
results in a dramatic clinical and hemodynamic improve-
ment in patients with tricuspid stenosis. With PTV, there is
a decrease in tricuspid gradient and an increase in cardiac
output. Significant tricuspid regurgitation rarely occurs, and
restenosis at follow-up is infrequent. Patients with associated
moderate or severe tricuspid regurgitation are not candidates
for PTV.
5 76 chapter
Future Research
After more than 15 years of extensive clinical evaluation, the
technique of percutaneous valvuloplasty, which for practical
purposes can be summed up as PMV, has a significant place in
the treatment of mitral stenosis. Pragmatically, a larger use of
PMV will depend on the solution of economic problems that
limit the use of the technique in the countries in which rheu-
matic disease is still endemic but in which means are lacking.
In the industrialized countries, the debate on the use of PMC
in patients with unfavorable anatomy will require further
studies, including a large number of patients and a long follow-
up. Further proof of the efficacy of PMV in the prevention of
embolism and atrial fibrillation are necessary to further
extend the indications to asymptomatic patients. New tools,
such as 3D-echocardiography, may help to refine patient selec-
tion and better assess the results. Intracardiac echocardiogra-
phy could avoid the need for transesophageal echocardiography
to exclude left atrial thrombosis and help in transseptal punc-
ture, the pitfall being the price of the device. Finally, in the
future, it could be possible to perform PMV in combination
with other percutaneous procedures, such as coronary revas-
cularization, ablation in patients with supraventricular
arrhythmias, or occlusion of the left atrial appendage to
prevent stroke. The question with PAV is to know whether it
still has a place. It would, however, appear important to evalu-
ate PAV better in rheumatic aortic stenosis, where it might
ultimately be an attractive application of the technique.
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 2 Valvular Heart Disease:
4 Surgical Treatment
William E. Cohn, O.H. Frazier, and
Denton A. Cooley

General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . 582 Postoperative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586

Mitral Valve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583 Redo Valve Procedures. . . . . . . . . . . . . . . . . . . . . . . . . . . . 587
Aortic Valve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585 Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588
Tricuspid Valve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588

Key Points surotomy, posterior leaflet resection, and annuloplasty.

When deterioration is advanced, valve replacement is
• In adults in the Western world, cardiac valve lesions are
often unavoidable.
usually caused by degenerative heart disease, which pro-
• Recent techniques using artificial chordae tendineae
duces aortic valve stenosis and insufficiency and mitral
have expanded the indications for mitral valve repair.
insufficiency.
• Tricuspid valve disease can be alleviated by an annulo-
• In developing countries, rheumatic heart disease is the
plasty, a valvotomy, both of these procedures, or valve
most frequent cause of valve lesions, including stenosis,
replacement. Functional tricuspid insufficiency accom-
insufficiency, or both. It is the leading cause of mitral
panying mitral stenosis will sometimes resolve after cor-
stenosis.
rection of the mitral condition.
• A common cause of aortic stenosis is a congenitally
• Postoperatively, the main complication of valve replace-
bicuspid aortic valve that calcifies later in life.
ment is thromboembolism, which is associated mostly
• Myocardial ischemia, as well as nonischemic cardiomy-
with mechanical prostheses, especially in the mitral posi-
opathy, can alter mitral valve geometry and result in
tion. Patients with mitral mechanical prostheses should
severe mitral regurgitation.
routinely take an anticoagulant such as sodium warfarin.
• Treatment should be considered for any patient with
In addition, those with aortic mechanical prostheses should
symptoms of heart valve disease.
undergo long-term anticoagulation. Most patients with
• Asymptomatic patients with critical aortic stenosis
chronic atrial fibrillation should also receive warfarin.
should be referred for surgical intervention. In these
• For redo valve procedures, the operative mortality is
cases, the onset of symptoms (chest pain, congestive
increased, particularly in patients with poor cardiac
heart failure, and syncope) is associated with poor sur-
functional status and a need for emergency surgery.
vival without surgery.
• Limited-access heart valve surgery, with the use of a
• Asymptomatic patients with aortic insufficiency should
small incision, is gaining popularity. It may be performed
be referred for surgery on the basis of enlarged left ven-
via the port access approach, which entails peripheral
tricular size on echocardiography.
perfusion and use of a balloon catheter for aortic occlu-
• In adults, symptomatic aortic valve disease almost always
sion; with standard cannulation and a specially designed
necessitates valve replacement.
aortic cross-clamp; or with a combination of these two
• Stenotic mitral valves can often be repaired by interven-
approaches. The results are similar to those obtained in
tional cardiologists, using a double-balloon valvotomy
conventional procedures using a sternotomy, but some
technique.
patients report less musculoskeletal discomfort after the
• Balloon valvotomy has fallen into disfavor for repairing
limited-access procedure.
stenotic aortic valves, because the results are not long
• A number of promising new catheter-based valve-
lasting.
treatment technologies are on the medical horizon but
• When mitral valve surgery is necessary, repair is pre-
are not yet ready for clinical use.
ferred over valve replacement.
• If the anterior leaflet is relatively normal, most mitral Although the first direct attack on valvular heart disease
lesions can be repaired by means of a combined commis- occurred in the 1920s, valve surgery was not taken seriously

5 81
582 chapter 24

by most surgeons until World War II, when Harken1 success-

fully removed foreign bodies from the heart. Once surgeons
realized that the heart could be operated on successfully,
attention turned toward correcting congenital defects,
including valve stenosis and insufficiency, and modern valve
surgery began to evolve. In the late 1940s, Harken et al.,2
Bailey,3 and Brock’s group4 reported the successful repair of
mitral valve disease. Not until the development of cardiopul-
monary bypass and open-heart surgery in the 1950s, however,
were surgeons able to attack acquired valve disease. By the
end of that decade, the caged-ball valve design, pioneered by
Harken, Starr, and Edwards, made valve replacement possi-
ble. The ensuing decades have seen a continual advancement
in valve prostheses and repair techniques. More than 300,000
patients worldwide were expected to undergo heart valve
surgery in 2004.5
Of the 2,500 open-heart operations performed each year
at the Texas Heart Institute in Houston, Texas, about 20%
involve the repair of valve lesions. This chapter describes our
standard surgical approaches for treating acquired valvular FIGURE 24.1. The On-X® Prosthetic Heart Valve, aortic position.
heart disease.6–13

General Considerations made with pyrolytic carbon (Fig. 24.1). When valve replace-
ment is unavoidable, we prefer bileaflet mechanical pros-
Whereas the aortic and mitral valves may be diseased either theses in our younger patients. These valves are reliable
alone or in combination, the tricuspid valve is rarely subject and have a low profile, excellent hemodynamic qualities,
to isolated disease, except when affected by endocarditis, as and an extremely low incidence of complications, including
often seen in intravenous drug abusers. thromboembolism.
Today, diseased stenotic valves can often be repaired non- Bioprostheses are less durable than mechanical valves
surgically by interventional cardiologists, using a double- and are vulnerable to structural deterioration and calcifica-
balloon valvotomy technique. Although highly successful tion, which occurs mainly in adolescent patients. The newer
for repairing the stenotic mitral valve, this approach is less generation of bioprosthetic valves offers longer operative-free
useful for aortic valve repair, because its benefits are not long survival than previous models, especially in the aortic posi-
lasting; after the procedure, many patients have a decreased tion (Fig. 24.2). As a result, the age of patients considered
gradient across the aortic valve, but this effect has been candidates for these valves has been gradually lowered.
reported to last for only a short time.14–17 Complications of Today, to avoid the need for anticoagulants, many younger
balloon mitral valvuloplasty include regurgitation, annular patients opt for a bioprosthesis and accept the risk of requir-
rupture, and an atrial septal defect. ing a reoperation at some later date.
When valve surgery becomes necessary, the indications
should be based on symptoms, as well as physiologic and
pathologic findings, and the risk-benefit ratio should be care-
fully examined in each case. Unfortunately, few evidence-
based guidelines are available to facilitate surgical decision
making in valvular heart disease.
The optimal surgical approach depends on the degree of
physiologic disturbance, the extent and nature of the patho-
logic changes, and the expertise of the surgeon. Whenever
possible, we perform valve repair rather than replacement.
Repair has a number of advantages, eliminating not only the
need for lifelong anticoagulation but also the threat of
mechanical dysfunction and paravalvular leakage. Trans-
esophageal echocardiography is becoming widely used intra-
operatively for assessing the valve anatomy before repair and
for determining the adequacy of repair at the end of the
procedure.
Since the advent of valve replacement surgery, much
experience has been gained with both mechanical and bio-
prosthetic valves. Either type of valve has benefits and draw- FIGURE 24.2. Mosaic UltraTM porcine bioprosthetic valve (Med-
backs. Early mechanical valves were vulnerable to mechanical tronic, Inc., Minneapolis, MN) being maneuvered into position in a
failure, but today’s models are quite durable, especially when patient undergoing aortic valve replacement.
 va lv u l a r h e a r t d i s e a s e : s u r g i c a l t r e a t m e n t
After trying various methods of suturing valve prosthe-
ses, some surgeons at our institution have reverted to using
a continuous monofilament polypropylene suture in some
cases.12 This simple technique expedites implantation in any
valve position and provides even more security than do indi-
vidual mattress sutures. The continuous-suture technique
also eliminates the need for porous felt pledgets, which can
become a source of infection.
To prevent infective endocarditis, we routinely adminis-
ter bactericidal antibiotics to all patients undergoing pros-
thetic valve replacement. Antibiotics are given before surgery
and are continued until all catheters are removed.
The valve is approached through a standard median ster-
notomy. After heparin (3 mg/kg) has been administered,
access to the systemic arterial system is gained by cannulat-
ing the ascending aorta. Cannulation for venous outflow
depends on which valve is involved. For aortic valve proce-
dures, we position the tip of a single right atrial cannula in
the orifice of the inferior vena cava so that some of the per-
forations are in the right atrium. For single or combined
procedures involving the mitral valve, the venae cavae are
often cannulated separately.
In patients undergoing valve replacement, we routinely
use moderate systemic hypothermia and cardiac hypother-
mia as well as a membrane oxygenator. Patients with severe
left ventricular hypertrophy may benefit from the addition
of propranolol to the cardioplegic solution (approximately
1 mg for a normal adult). In such patients, retrograde coro-
nary sinus blood cardioplegia may also be useful for myocar-
dial protection. Our cardiopulmonary bypass time rarely
exceeds 1 hour.
In combined mitral and aortic procedures, the mitral
valve is treated first. Traditionally, double valve replacement
necessitates two separate incisions to visualize the valve
apparatus. When this approach is impractical, as in patients
who have undergone a previous median sternotomy, the
mitral valve can be replaced through the aortic root after the
aortic valve has been excised.7
Mitral Valve
The mitral valve may be affected by stenosis, insufficiency,
or both. The type of surgical treatment depends on the opera-
tive findings. Many mitral lesions can be repaired by means
of a commissurotomy, posterior leaflet resection, and annu-
loplasty. When deterioration is advanced, however, valve
replacement may be unavoidable.
Mitral Stenosis
Indications for Surgery
Surgery should be considered for any patient with symptom-
atic mitral stenosis, including persons in New York Heart
Association (NYHA) class III or IV who have atrial fibrilla-
tion, increasing pulmonary hypertension, systemic emboli-
zation, or infective endocarditis. In addition, class II patients
should be considered for surgery if they are older than 40
years, have a significantly reduced valve area, or have valve-
related lifestyle limitations.
583
Mitral Repair Techniques
The time-honored method for alleviating “pure” mitral ste-
nosis with minimal or no calcification is a commissurotomy
with subvalvular dissection of fibrosed chordae tendineae
and papillary muscles. Usually, the valve is fused at both
commissures and has a slit-like opening. Freeing the fused
commissures produces a functional, near-normal valve.
Although a closed commissurotomy is possible with the
aid of a transventricular dilator, we always perform an
open procedure with cardiopulmonary bypass support. This
approach enables us not only to assess the extent of disease
and determine the best operative strategy but also to perform
an anatomic repair. Moreover, the open approach facilitates
accurate division of the commissure and allows left atrial
thrombi to be extracted.
Mitral Valve Replacement
For patients with extensive calcification or severe fibrotic
distortion, especially in the subvalvular area, valve replace-
ment is the only option.
Recently, it has become clear that, to ensure maximal
postoperative ventricular function, the chordal attachments
to papillary muscles should be preserved.18–20 Therefore,
insofar as possible, we remove only the anterior mitral leaflet,
sparing the posterior leaflet and the chordal attachments.
In excising the mitral valve, the surgeon must take care
not to damage the posterior annulus, which can rupture if
an oversized valve is inserted or excessive tissue removed.
(This uncommon complication is most frequently seen
in patients with severe annular calcification and is asso-
ciated with a high operative mortality.) Furthermore,
the nearby circumflex coronary artery may be injured if
sutures are placed too deeply during valve replacement or
annuloplasty.
The valve is usually approached through a standard left
atrial incision. If the case is complex, however, or if the
patient has undergone previous mitral surgery, a transseptal
route may be more appropriate. For combined mitral-aortic
procedures, a single transverse aortotomy can be used, as
described above.
Mitral Insufficiency
Indications for Surgery
Close follow-up observation is essential for patients with
mitral insufficiency. If regurgitation is mild (1 to 2+), surgery
may be postponed indefinitely. However, operation should
be considered for patients with moderately severe or severe
(3 to 4+) regurgitation or for any patient with atrial fibrilla-
tion, increasing pulmonary hypertension, or disabling
symptoms. For those with infective endocarditis, surgery
can be performed electively if antibiotic therapy is success-
ful; otherwise, emergency valve replacement is usually
necessary.
According to Haan and colleagues,21 the following vari-
ables are associated with a heightened operative risk: age >75
years, renal failure, and the need for an emergent or a salvage
procedure. These researchers found that for most patients
with ventricular dysfunction, mitral valve surgery did not
584 chapter 24

entail a prohibitive operative risk. In fact, mortality rates

remained fairly constant regardless of the ejection fraction
for low-risk to medium-risk patients, increasing only in the
high-risk category (predicted risk >10%). Various recent mitral
valve surgery series involving patients with an ejection frac-
tion of <20% have had an operative mortality of <2%.22,23 In
this respect, clinical experience is at variance with the Amer-
ican College of Cardiology (ACC)/American Heart Associa-
tion (AHA) guidelines,24 which state that valve replacement
for mitral insufficiency should be performed only in patients
who have an ejection fraction of at least 30%.

Mitral Valve Repair

In many series, repair is appropriate for incompetent non-
rheumatic mitral valves in more than 90% of the cases. As
long as the anterior leaflet is functional, there are no absolute
contraindications to reconstruction.25 Compared with valve
replacement, repair is associated with improved left ven-
tricular function and better long-term survival. A variety
of reconstructive techniques have been described.18,26–30
Although we still occasionally perform annuloplasty by
means of commissural plication, we prefer to insert an
annuloplasty ring or a posterior annuloplasty band (Fig. 24.3).
Both of these methods reduce the annular circumference
without necessitating the placement of restrictive sutures
in either the anterior leaflet or the anterior portion of the
annulus.
We also use an annuloplasty ring to treat mitral incom-
petence secondary to valve prolapse. Depending on the
surgeon’s preference, a Carpentier, Cooley, Duran, or Puig-
Massana-Shiley ring11 or a Cosgrove band can be used. The
device reduces the overall circumference of the annulus, FIGURE 24.3. Mitral valve repair involving wedge resection of the
eliminating prolapse of the posterior leaflet. We occasionally posterior leaflet and continuous suturing of an annuloplasty ring in
use a cut section of a 22-mm Dacron graft. This ring is simple place.
and inexpensive to produce.
In patients with ischemic mitral regurgitation, the valve
structure tends to be normal. When these patients have
annular dilatation or ruptured chordae tendineae on the prolapsed anterior leaflet. Later, this technique was applied
posterior leaflet without calcification or leaflet fibrosis, an to other conditions involving mitral insufficiency. When per-
annuloplasty and leaflet repair or resection are usually formed with a septal myectomy, the edge-to-edge technique
satisfactory. To decrease the overall annular circumference, addresses both causes of dynamic obstruction in hyper-
we again insert an annuloplasty ring, thereby making the trophic cardiomyopathy. By sparing the natural valve and
best use of available valve tissue and rendering the valve submitral apparatus, this approach preserves ventricular
competent. Even for combined coronary-valvular procedures, function.
our mean ischemic time is 55 minutes. If chordae tendineae For patients with advanced congestive heart failure, open
are ruptured, they should be removed; the leaflet is then surgery may entail a prohibitive risk. New catheter-based
either excised or imbricated. When chordal or papillary technology has recently been developed to address mitral
rupture affects the anterior leaflet, artificial chordae may regurgitation by means of a percutaneous approach, which
be fashioned from a polytetrafluoroethylene suture. In our may allow these patients to undergo mitral repair without
experience, however, the valve has often needed to be stopping the heart or opening the chest. One such device
replaced. facilitates placement of a clip that attaches the free edges of
For mitral incompetence associated with a ventricular the anterior and posterior leaflets, effecting an edge-to-edge
aneurysm, we perform an endoaneurysmorrhaphy10 by insert- repair (Evalve, Redwood City, CA). In other investigational
ing an oval patch graft inside the left ventricle to restore the approaches (Viacor, Inc., Wilmington, MA), the operator
ventricular anatomy. Once the papillary muscles have works through the coronary sinus to geometrically manipu-
returned to their normal position, mitral regurgitation is late the posterior annulus and thereby improve coaptation
often alleviated. of the leaflet edges (Fig. 24.4). Although these methods are
In 1991, Alfieri introduced the “edge-to-edge” technique 31 still undergoing development, early clinical experience is
for repairing mitral valves that are insufficient because of a promising.
 va lv u l a r h e a r t d i s e a s e : s u r g i c a l t r e a t m e n t
FIGURE 24.4. Digital rendering of a regurgitant mitral valve before
(A) and after (B) introduction of a percutaneous transvenous mitral
annuloplasty device (Viacor, Inc., Wilmington, MA) into the coro-
nary sinus around the valve.
Mitral Valve Replacement
In advanced rheumatic heart disease with foreshortening and
thickening of the mitral leaflets and in instances of subacute
bacterial endocarditis, valve replacement (see above) is the
only available option.
Intravalvular Implantation
In patients with sound, flexible mitral leaflets and supple
chordae, we sometimes use a technique known as in situ
intravalvular implantation, particularly if the annular tissue
is of poor quality.9 To prevent obstruction of the valve pros-
thesis, we divide the anterior leaflet and insert it into the
annulus. We then implant a low-profile prosthesis, affixing
it to the valve leaflet and annulus with continuous sutures.
585
In this manner, we are able to spare both the anterior and
posterior chordal and papillary mechanisms.
Aortic Valve
Although congenital aortic valve disease in children is often
amenable to repair, the same cannot be said for acquired
aortic valve disease. Therefore, in adults, operations for
incompetent or stenotic aortic valves almost always entail
valve replacement. Some surgeons believe that the currently
recommended age threshold (≥65 years) for implanting a bio-
prosthesis in the aortic position could be lowered further.32
A good outcome depends on optimal surgical timing, but
this can be hard to judge, especially in asymptomatic patients
with severe disease and symptomatic patients with highly
advanced disease.
Indications for Surgery
The primary indication for aortic valve surgery is the pres-
ence of symptoms (angina, syncope, or dyspnea on exertion).
As long as patients are asymptomatic, their prognosis remains
good, even if the stenosis itself is severe. However, the ACC/
AHA recommends valve replacement for patients with left
ventricular systolic dysfunction, as characterized by a sub-
normal resting ejection fraction (documented by two con-
secutive measurements or independent tests). Even if the
ejection fraction is normal, valve replacement should be con-
sidered for patients with an end-diastolic dimension of
>75 mm or an end-systolic dimension of >55 mm. In small
patients of either sex, these threshold values may need to be
reduced appropriately.
Once symptoms develop, aortic valve replacement should
be undertaken. Patients with congestive heart failure related
to aortic stenosis have a 50% chance of dying within 2 years
after the onset of symptoms. Similarly, patients who present
with syncope or angina have a 50% chance of dying within
3 and 5 years, respectively. A fairly objective indicator is the
pressure flow gradient across the left ventricular outflow
tract. When this gradient is >50 mm Hg, operative correction
is generally indicated. According to Carabello,33 however,
patients with a low aortic valve gradient and low ejection
fraction without inotropic reserve will probably not benefit
from valve replacement.
Valve-Sparing Aortic Root Surgery
When the aortic valve is affected by an aneurysm of the
aortic root, the entire root and valve are traditionally replaced
with a composite valved graft. Recently, however, we began
using a new valve-sparing technique whenever possible (Fig.
24.5). Once the entire aneurysmal segment, including the
sinuses of Valsalva, has been removed, the aorta is recon-
structed with a Dacron graft. The native valve is then incor-
porated into the inner wall of the graft. This technique is
suitable for patients whose aortic valve is structurally normal
and not calcified, torn, or infected (see also Percutaneous
Valve Replacement, below).
586
FIGURE 24.5. Valve-sparing aortic root repair: the patient’s native
valve (A) is fixed inside a Dacron tube graft (B), which is used to
replace the aneurysmal aortic segment.
Tricuspid Valve
Acquired lesions of the tricuspid valve may be either primary
or secondary. In managing tricuspid disease, the surgeon
must weigh each case carefully and select the treatment plan
that offers the best chance of long-term success. Surgery is
generally required for concomitant tricuspid and mitral valve
disease with pulmonary hypertension and right ventricular
failure. However, functional tricuspid insufficiency, which
sometimes accompanies mitral stenosis, often resolves after
correction of the mitral condition.
When tricuspid insufficiency accompanies disease of the
mitral or aortic valve or both, the prognosis is unfavorable.
According to Bernal and colleagues,34 predictors of hospital
chapter 24
mortality are renal insufficiency, prolonged cardiopulmo-
nary bypass, use of a biologic prosthesis, and use of inotropic
drugs; predictors of late mortality are age >60 years, left
ventricular ejection fraction <50%, and NYHA functional
class IV status.
Primary Lesions
Primary tricuspid lesions include rheumatic valvulitis, bac-
terial endocarditis, carcinoid valvulopathy, and traumatic
rupture. Stenosis or regurgitation caused by rheumatic val-
vulitis can be alleviated by an annuloplasty, a valvotomy, or
a combination of these procedures. Alternatively, valve
replacement can be performed.
When bacterial endocarditis results in advanced tricuspid
valve destruction, as it frequently does in drug addicts, the
surgeon is advised to perform a total valvectomy rather than
implant a foreign body or an artificial valve.35 If patients
survive, they may then undergo elective valve replacement
once the infectious process has resolved.
Tricuspid valve disease secondary to chronic placement
of transvalvular pacing leads and defibrillator coils is being
seen with increasing frequency. When surgical correction is
required, the leads must be removed and replaced with
epicardial ones if indicated.
Traumatic disruption of the tricuspid valve can result
from a closed, crushing chest injury. We have treated several
automobile accident victims with papillary muscle dis-
ruption. Such cases always necessitate valve replacement
or repair.36,37
Secondary Lesions
Secondary tricuspid lesions tend to be more common than
primary ones. Secondary lesions arise when rheumatic val-
vulitis in the mitral (and perhaps also the aortic) position
results in pulmonary hypertension and increased pulmonary
vascular resistance, thereby straining the right ventricle and
causing pulmonary and tricuspid valve insufficiency by sec-
ondary annular dilatation. Treatment of secondary lesions
requires sound surgical judgment and expertise. If the leaf-
lets are relatively normal, repair can be achieved by decreas-
ing the overall circumference of the tricuspid annulus.
However, if the leaflets are calcified or eroded because of
infection or ruptured chordae tendineae, valve replacement
may be necessary.
Postoperative Care
Most patients who undergo valve replacement receive tem-
porary pacing electrodes to prevent heart block or other
arrhythmias during the early postoperative period. The
pacing wires are usually removed after 4 or 5 days. A medi-
astinal chest tube is left in place for 48 hours.
Optimal postoperative care depends on familiarity with
the potential complications of valve surgery. The most feared
threat is thromboembolism, which is mainly associated with
mechanical prostheses. Patients with these devices in the
mitral position should routinely take an anticoagulant such
as sodium warfarin (Coumadin). Those with aortic prosthe-
 va lv u l a r h e a r t d i s e a s e : s u r g i c a l t r e a t m e n t
ses should also undergo anticoagulation on a long-term basis.
However, patients with low-profile bileaflet valves such as
the St. Jude valve (St. Jude Medical, St. Paul, MN), Carbomed-
ics valve (Sorin Group, Burnaby, British Columbia, Canada),
and ON-X® valve (Medical Carbon Research Institute, LLC,
Austin, TX) can be kept at lower levels of anticoagulation,
particularly if the valve is implanted in the aortic position.
Although anticoagulants are not always prescribed for
patients with bioprostheses, patients with chronic atrial
fibrillation or extensive left atrial dilatation should receive
sodium warfarin for an indefinite period.
Infection is a relatively rare complication of prosthetic
valve implantation. In patients with valve prostheses, we
routinely continue postoperative bactericidal antibiotic
therapy until all invasive catheters have been removed.
Subsequently, these patients should receive prophylactic
antibiotics whenever they undergo dental procedures or
operations on the lower genitourinary or gastrointestinal
tract.
When bacterial endocarditis is diagnosed, a second opera-
tion may be necessary to replace the prosthetic valve.
Although we begin antibiotic therapy to sterilize the blood-
stream before surgery, we do not wait when valve replace-
ment is needed, because we have found valve replacement
to be successful even in the presence of active infection.
Moreover, delay can be dangerous if it results in irreversible
hemodynamic deterioration or ongoing destruction of peri-
prosthetic structures.
Valve dehiscence may occasionally result from infection,
technical errors, or tissue failure. This complication can be
alleviated by a repeat open cardiac procedure in which addi-
tional sutures are inserted to secure the valve.
Today’s mechanical prostheses are extremely durable,
and valve fracture or failure is quite uncommon. When such
problems do arise, a repeat operation is mandatory.
Redo Valve Procedures
Redo valve procedures can present technical challenges,
including dissection of adhesions from previous surgery. The
operative mortality may be two or three times higher than
for initial valve operations,38 particularly in patients with
poor NYHA functional status and a need for emergency
surgery. For this reason, reoperation should be undertaken
before cardiac functional status deteriorates and other organs
are adversely affected.
In patients with tissue valves, the following factors do
not significantly increase the mortality of redo surgery: age
at surgery, previous coronary artery bypass grafting (CABG),
position of the valve replaced, type of implant, and the pres-
ence of coronary artery disease.39 Therefore, lowering the age
range for tissue valve implantation may be justified.
In selected patients, limited-access valve surgery can
achieve results comparable to those of traditional operations
while hastening recovery.
Limited-Access Valve Surgery
A number of techniques have been introduced for perform-
ing limited-access valve surgery. These nonsternotomy
587
approaches reduce the trauma of access and minimize the
need for cardiac dissection for all types of valve repair and
replacement. Because limited-access valve surgery avoids a
full median sternotomy, it is especially suited for patients at
high risk for sternal infection or redo procedures. A number
of incisions and techniques have been described for mitral
and aortic valve surgery. One technique, popularized by
Gundry40 utilizes a mini-sternotomy that extends from the
sternal notch to the second or third interspace. A mini-
sternotomy can be performed through a 7- or 8-cm skin inci-
sion and avoids division of the lower sternum, the site most
frequently involved in postoperative complications. This
approach is suited for both aortic and mitral valve proce-
dures. Another option is a right mini-thoracotomy, as popu-
larized by Cosgrove,41 which is excellent for mitral valve
procedures.
Some variations of these and other limited-access inci-
sions involve a port access approach, which entails peripheral
perfusion and use of a balloon catheter for aortic occlusion.42
Other approaches use a modified incision but standard
central cannulation and a modified aortic cross-clamp. One
of the main challenges of this approach is to keep the car-
diopulmonary bypass time within an acceptable range. In a
few centers, limited-access valve surgery is performed with
the aid of endoscopic visualization and robotic surgical
systems. This approach has the potential to reduce further
the size of the surgical incision.
Limited-access aortic valve replacement with the aid of
high thoracic epidural anesthesia in a conscious patient
has been reported.43 This approach avoids the potential
morbidity related to general anesthesia and endotracheal
intubation.
Many surgeons are reluctant to adopt limited-access
valve surgery, but this approach has been so widely publi-
cized that patients often request it. Though a reasonable
approach for most patients with single-valve disease, it is not
well suited for obese patients or those with complex valve
procedures, multivalve disease, or severe atherosclerosis pro-
hibiting peripheral cannulation.
Percutaneous Valve Replacement
For many elderly or debilitated patients with multiple comor-
bidities, conventional valve replacement may pose a signifi-
cant risk. Percutaneous valve replacement is an attractive
nonsurgical alternative that is currently being developed and
that offers numerous potential benefits. In 2002, Cribier and
coworkers44 successfully implanted an aortic valve percuta-
neously using the antegrade approach, passing the collapsible
valve up the femoral vein, across the atrial septum and mitral
valve to reach the aortic annulus. More recently, Paniagua
and colleagues,45 at our hospital, performed a similar proce-
dure using a collapsible prosthesis that needs no supportive
struts; these researchers used the retrograde approach, which
has several advantages over the antegrade one. This technol-
ogy is associated with numerous challenges, but early clini-
cal work shows promise. If the technical hurdles can be
surmounted, percutaneous aortic valve replacement may
prove to be an important advance in the treatment of valve
disease.
588 chapter
Outcomes
Heart valve surgery can be performed safely and effectively,
restoring countless patients to normal, healthy lives. The
Cleveland Clinic,46 which performs the largest number of
valve procedures in the United States, reported a 2.9% overall
mortality for the 2,254 valve operations that it performed in
2003. Valve replacement generally entails a higher morbidity
and mortality than most other routine heart operations,47
and its outcome often depends more on patient risk factors
than on valve choice or technical considerations. After aortic
and mitral valve replacement, respectively, the 10- and 15-
year mortality is as high as 20%.48
Isolated Versus Combined Operations
Mitral Position
As of late 2004, the National Cardiac Database maintained
by the Society of Thoracic Surgeons49 reported an unadjusted
operative mortality of approximately 2% for mitral valve
repair alone, 7.5% for mitral repair plus CABG, 6.4% for
mitral replacement alone, and 11% for mitral replacement
plus CABG.
Aortic Position
In the National Cardiac Database, the unadjusted operative
mortality was approximately 4.6% for aortic valve replace-
ment alone, 6.2% for aortic valve replacement plus CABG,
and 10% for combined aortic and mitral valve replacement
in late 2004.
Mechanical Versus Bioprosthetic Valves
Mitral Position
The Department of Veterans Affairs randomized trial50
showed that, 15 years after mitral valve replacement, all-
cause mortality was no different with mechanical valves
than with bioprosthetic ones. Although the bioprostheses
had more structural deterioration in all age groups, this com-
plication was more prevalent in younger patients (<65 years
old). Both valve types had similar thromboembolism rates,
but mechanical valves tended to cause more bleeding com-
plications. Similarly, the Edinburgh randomized trial,51
which followed patients for 20 years, showed that both types
of valves yielded similar mortality and thromboembolism
rates but that mechanical valves resulted in increased
bleeding.
Aortic Position
At 18 years’ follow-up, Veterans Affairs patients with an
aortic mechanical valve had lower mortality and reoperation
rates than those with an aortic bioprosthesis.51 This differ-
ence was first noticed at 10 years. Primary valve failure
occurred more frequently after mitral valve replacement
(MVR) and in patients younger than 65 years; this complica-
tion arose 5 to 6 years postoperatively in MVR patients and
7 to 8 years postoperatively in aortic valve replacement (AVR)
patients. As in the mitral position, bleeding was more
24
common in the patients with mechanical valves, and other
complications were similar with both valve types.
Limited-Access Versus Conventional Valve Surgery
Mitral Position
In one of the largest single-center studies to compare the
outcomes of limited-access versus conventional valve proce-
dures, Mihaljevic and coworkers52 documented a periopera-
tive mortality of 0.2% for limited-access mitral procedures
and 0.3% for conventional mitral procedures. At 1, 3, and 5
years, the actuarial survival rates were 98%, 97%, and 95%
versus 97%, 91%, and 86% after these two types of surgery,
respectively.
Aortic Position
The same study showed a perioperative mortality of 2% for
limited-access aortic valve surgery versus 2.7% for conven-
tional aortic valve surgery. At 1, 3, and 5 years, the two
respective approaches yielded actuarial survival rates of 98%,
94%, and 82% versus 94%, 90%, and 86%.
Summary
Introduced in the mid-20th century, valve repair and replace-
ment continue to account for a large share of the cardiac
surgeon’s caseload. Treatment should be considered for any
patient with symptoms. Stenotic mitral valves can often be
repaired by an interventional cardiologist using a double-
balloon valvotomy technique, but this approach should
be avoided for aortic valve repair, as it does not offer long-
lasting results. When surgery is necessary, repair (if possible)
is preferred over valve replacement. If replacement is un-
avoidable, surgeons can choose from a wide array of pros-
thetic valves and operative techniques, including
limited-access approaches. Postoperatively, the most dreaded
complication is thromboembolism. To prevent this problem,
patients with mitral mechanical prostheses should routinely
take an anticoagulant such as sodium warfarin; those with
aortic mechanical prostheses should also undergo long-term
anticoagulation. When repeat valve surgery is necessary, it
should be undertaken before cardiac functional status dete-
riorates and other organs are adversely affected. Catheter-
based approaches for valve repair are currently being
developed, but their merit is not yet clear. Nevertheless, the
currently available options are offering even high-risk surgi-
cal patients a chance to overcome their valve disease and
enjoy a normal life.
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retrograde transcatheter implantation of an aortic valve pros-
thesis. Tex Heart Inst J 2005;32(3):393–398.
590 chapter
47. Gulbins H, Pritisanac A, Hannekum A. Minimally invasive
heart valve surgery: already established in clinical routine?
Expert Rev Cardiovasc Ther 2004;2:837–843.
48. Pepper JR. Interventions on the aortic valve. In: Treasure
T, Keogh B, Pagano D, Hunt I, eds. The Evidence for Cardio-
thoracic Surgery. Shrewsbury, UK: tfm Publishing Ltd, 2005:
221–230.
49. Society of Thoracic Surgeons. National Cardiac Database.
Executive Summary, STS Fall 2004 Report. http://www.
ctsnet.org/file/STS-ExecutiveSummary-Fall2004.pdf. Retrieved
March 1, 2005.
24
50. Hammermeister K, Sethi GK, Henderson WG, Grover FL,
Oprian C, Rahimtoola SH. Outcomes 15 years after valve
replacement with a mechanical versus a bioprosthetic valve:
final report of the Veterans Affairs randomized trial. J Am Coll
Cardiol 2000;36:1152–1158.
51. Oxenham H, Bloomfield P, Wheatley DJ, et al. Twenty year
comparison of a Bjork-Shiley mechanical heart valve with
porcine bioprostheses. Heart 2003;89:715–721.
52. Mihaljevic T, Cohn LH, Unic D, Aranki SF, Couper GS, Byrne
JG. One thousand minimally invasive valve operations: early
and late results. Ann Surg 2004;240:529–534.
SEC TION IV

Coronary Artery
Disease
 2 Coronary Artery Disease:
5 Pathologic Anatomy
and Pathogenesis
L. Maximilian Buja and
Hugh A. McAllister, Jr.
Coronary Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . .
Coronary Thrombosis and Other Acute Coronary
Lesions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Nonatherosclerotic Coronary Vascular Diseases . . . . . .
Pathology of Angina Pectoris and Sudden Cardiac
Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pathology of Acute Myocardial Infarction . . . . . . . . . . .
Pathogenesis of Myocardial Ischemic Injury. . . . . . . . . .
Key Points
• Coronary atherosclerosis is the dominant underlying
cause of coronary artery disease (CAD) although non-
atherosclerotic types of coronary (ischemic) heart disease
do occur.
• Vulnerable coronary plaques usually have thin fibrous
capsules and are prone to erosion, septum and thrombo-
sis leading to acute myocardial ischemia.
• The clinical spectrum of CAD includes angina pectoris,
myocardial infarction (MI), sudden cardiac death and
chronic coronary heart disease. Fallowing coronary occlu-
sion, irreversible myocardial ischemic injury beginner
within 20–30 minutes in the subendocardium, and MI
then progresses over 3 or more hours in a wavefront pattern
through the myocardial bed-at-risk. MI is produced by
ischemic myocardial cell death mediated by the distinc-
tion pathological processes of oncosis and apoptosis.
• The myocardium can be preconditioned resist the pro-
gression of MI by prior brief periods of reversible myocar-
dial ischemic (myocardial preconditioning).
• The consequences to the myocardium of coronary reper-
fusion include reperfusion injury, salvage of myocardium,
stumming and hibernation.
• Major cleternuinants of the prognosis of CAD are MI size
and the quality of remodeling of the remaining visable
myocardium.
• Distinctive pathobiological features are seen with estab-
lished treatments for CAD, including coronary angio-
plasty and coronary artery surgery, and new approaches,
593 Determinants of Infarct Development and Size and
Remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
595 Reperfusion, Preconditioning, Stunning, and
596 Hibernation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
Pathology of Interventionally Treated Coronary
596 Artery Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
598 New Approaches to Myocardial Modulation . . . . . . . . . 606
600 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
including gene therapy and stem cell therapy, are under
retina investigation.
The clinical manifestations of coronary artery disease (CAD),
also known as coronary (ischemic) heart disease, are diverse,
with a spectrum that encompasses various forms of angina
pectoris, myocardial infarction (MI), sudden cardiac death,
and chronic coronary heart disease. These syndromes result
from complex interactions between the coronary circulation
and the myocardium, usually with coronary atherosclerosis
as the major anatomic substrate for disease.1–3
Coronary Atherosclerosis
The blood supply to the heart is provided by the left and right
coronary arteries and branches of these major vessels (Fig.
25.1).1–3 The anterior wall of the left ventricle (LV) and the
anterior portion of the interventricular septum are supplied
by the left anterior descending (LAD) coronary artery and its
diagonal and septal branches. The lateral wall of the LV is
supplied by the left circumflex coronary artery (LCCA). The
posterior wall of the left ventricle and posterior interven-
tricular septum are usually perfused by the right coronary
artery (RCA), which also supplies the right ventricle (RV).
Further details about coronary artery anatomy are presented
in the first chapter of this book.
The major cause of CAD is coronary atherosclerosis (arte-
riosclerosis), a process that develops as an inflammatory
response of the vessel wall to chronic, multifactorial injury
593
594 chapter 25

Post Descending A

RCA

A.V. Node A. L. Circ. A.

S.A. Node A. L. Main A.

L. Circ. Marginal A.

LAD L. Marginal A.
R. Marginal A.

Septal A. L. Diagonal A.

FIGURE 25.1. Diagram of the usual anatomic distribution of the
coronary arteries also showing a typical distribution of atheroscle-
rotic plaques (dark areas).
FIGURE 25.2. Left main coronary artery from a 6-year-old girl with
homozygous familial hypercholesterolemia. The artery is severely
involved by atherosclerotic plaque. The plaque is composed of
fibrous tissue (dark areas) and foam cells and lipid (light areas). Low
magnification photomicrograph.

and leads to the formation of atherosclerotic plaques (fibrous
plaques, atheromas).4–6 These plaques are regions of thick-
ened intima and are composed of various mixtures of fibrous
tissue, cells, and lipid (Fig. 25.2).7–9
Initially, atherosclerosis is a focal disease. There is a
predilection for formation of atherosclerotic plaques adjacent
to branch points in areas of nonlaminal flow and low-shear
stress adjacent to areas of high-shear stress.10 It is postulated
that the flow patterns in such regions promote endothelial
dysfunction and increased contact of endothelium with
leukocytes and platelets. Areas of predilection for severe
atherosclerosis in the coronary system include the proximal
LAD coronary artery and the proximal and distal RCAs
(Fig. 25.1). Established atherosclerosis involves all three
layers of the arterial wall such that, in addition to intimal
thickening, diseased areas exhibit medial degeneration and
weakening and intimal fibrosis, with lymphocytic inflam-
matory infiltrates.7–9
Atherosclerotic disease leads to extensive remodeling
of the vessel wall. Dilatation of the vessel occurs in such a
way that the lumen is maintained despite the presence of
intimal plaque, which may develop in an eccentric or concen-
tric pattern (Fig. 25.3).10–12 Luminal narrowing occurs only
when atherosclerotic disease is advanced. Approximately
50% narrowing of luminal diameter (75% luminal area) is
needed before blood flow is affected. Areas of severe narrow-
ing often develop in the setting of multifocal disease. All of
these changes can lead to underestimation of the extent and
severity of coronary atherosclerosis on visual inspection of
coronary arteriograms (“luminograms”) (Fig. 25.4).13 Quanti-
tative coronary arteriography can provide more objective
measurements of absolute coronary dimensions and flow.

35

30

25
IEL area, mm2

20

15

10 FIGURE 25.3. Compensatory enlargement of human coronary arter-

ies in relation to plaque formation. In graph, area encompassed by
5 internal elastic lamina (IEL area) is plotted against lesion area for
sections of left main coronary artery from 136 adult hearts obtained
0 postmortem. The IEL area is potential lumen area if no plaque was
0 5 10 15 20 present. The IEL area progressively increases as lesion area increases
Lesion area, mm2 in a linear manner (r = .44; p < .001; standard error of 4.8 mm2 indi-
cated by the dotted lines above and below regression line). Below
graph is diagrammatic representation of sequence of changes in ath-
erosclerotic arteries, which may eventually lead to lumen narrowing.
A Arteries initially enlarge, preserving nearly normal lumen cross
section, but it appears that normal lumen area may not be maintained
once lesion occupies more than 40% of IEL area (A).
 c oro n a r y a r t e r y d i s e a s e : pat h ol o g ic a n at om y a n d pat h o g e n e s i s 595

A 0
25% Coronary arteries
Angiographic 50% atherosclerosis of variable severity
100% 50% 25%
view 25%
(diameter) 0
Platelet Spasm
aggregation
Platelet
Spasm aggregation
Histologic
view Plaque erosion-
(area) rupture-hemorrhage
Increased myocardial
oxygen demand
Normal 50% ↓ Diameter 75% ↓ Diameter Occlusive
75% ↓ X-sectional 95% ↓ X-sectional Other predisposing
area area thrombosis factors

Minimal diameter Minimal diameter

B Maximal diameter –75% ↓ from normal 88% ↓ Acute myocardial ischemia
–50% ↓ but only 50% ↓ from from normal but
from normal maximal diameter 75% ↓ from
in adjacent segment maximal diameter
Acute myocardial Angina pectoris
0 infarction
Angiographic 25%
view 50% 75% 88%
50%
(Diameter) 25% Healed infarct Sudden cardiac death
0 altered electrical activity arrhythmia

FIGURE 25.5. Pathogenetic mechanisms of acute ischemic heart

Histologic disease and potential clinical outcomes.
view
(area)

50% ↓ Diameter 75% ↓ Diameter 88% ↓ Diameter

75% ↓ X-sectional 95% ↓ X-sectional area 98% ↓ X-sectional area susceptible to such changes are atheromatous plaques with
area (20% ↓ from maximal (23% ↓ from maximal thin fibrous capsules and large cores of lipid-rich debris, and
(maximal area) X-sectional area) X-sectional area) these lesions are designated as vulnerable plaques (Fig. 25.7).24
FIGURE 25.4. Relationship between reduction in diameter (as seen However, endothelial erosion predisposing to thrombosis
by selective coronary arteriography) and cross-sectional area (as seen
by histologic examination). (Top) A coronary artery with a 50%
can involve fibrocellular plaques without significant lipid
reduction in diameter narrowing has a 75% diminution in cross- content.23
sectional area, and a coronary artery with a 75% reduction in diam- Inflammation adjacent to the plaque surface is important
eter narrowing has a 95% reduction in cross-sectional area. (Bottom) in the pathogenesis of alterations predisposing to thrombosis
In many patients who undergo coronary arteriography, stenosed regardless of the plaque morphology.25,26 Thus, high risk or
segments are not being compared to totally normal segments but
rather to segments of the coronary artery that are somewhat nar- vulnerable plaques are characterized by inflammation asso-
rowed diffusely. Thus, if the least-narrowed segment actually is ciated with a variety of plaque morphologies.25,26 Factors that
itself 50% narrowed, what appears to be a 50% diameter narrowing
in an adjacent segment is in fact a 75% diameter narrowing and,
therefore, a 95% cross-sectional area reduction. Similarly, what
appears to be a 75% diameter narrowing is in fact an 88% diameter
narrowing, which in turn is a 98% cross-sectional diameter narrow-
ing. Because many patients with coronary artery disease have
diffuse luminal narrowings in addition to discrete stenoses, the
bottom panel reflects more accurately the true clinical situation
in such cases.

Coronary Thrombosis and Other Acute

Coronary Lesions
Acute ischemic heart disease is often initiated by acute
changes superimposed on atherosclerotic plaques (Fig.
25.5).3,14 The spectrum of thrombotic lesions includes platelet
aggregates, mural (nonocclusive) thrombi, and occlusive
thrombi (Figs. 25.6 to 25.9).3,14–26 Major thrombi are frequently
FIGURE 25.6. Gross photograph of sections of a coronary artery
associated with significant disruptions of the plaque surface, with an atherosclerotic plaque and occlusive thrombus. A break in
which may appear as fissures, erosion, ulceration, or rupture the plaque capsule has given rise to plaque hemorrhage (arrow) and
(Figs. 25.6 to 25.8). Coronary lesions that are particularly occlusive thrombosis.
596 chapter
FIGURE 25.7. Coronary artery shows a ruptured plaque capsule
(arrows) and intraluminal and intraplaque thrombus. Low-power
photomicrograph.
probably contribute to endothelial injury and disruption of
the plaque surface include hemodynamic trauma, local
attachment and activation of platelets and blood cells, inflam-
matory processes in the plaques, and cytotoxic effects of
plaque contents, including metalloproteinases and other
enzymes released from macrophages at sites of plaque
rupture.3,14–26 The likely pathogenetic sequence of plaque
rupture is endothelial injury, influx of blood components,
increase in intraplaque pressure, and outward rupture of the
fibrous capsule (Fig. 25.10).17,21 Localized erosion and plaque
fissuring also can give rise to platelet aggregation and throm-
bosis.22–25 Disruption of the plaque surface, by any mecha-
nism, predisposes to formation of intraluminal and intramural
(intraplaque) thrombus (Fig. 25.7).
Plaque hemorrhage may occur with or without thrombo-
sis. Two mechanisms of intraplaque hemorrhage are influx
of blood across the damaged endothelial surface of the plaque
and influx of blood from small intraplaque vessels derived
from the vasa vasorum. Intraplaque hemorrhage can
increase plaque destabilization by contributing to the deposi-
tion of lipid, macrophage infiltration, and enlargement of the
necrotic core.27 Due to coronary remodeling, plaque rupture
FIGURE 25.8. Coronary artery shows an erosion of the endothelial
surface (arrows) leading to superficial hemorrhage in the plaque (H)
and thrombosis (T) of the lumen. Low-power photomicrograph.
25
with occlusive thrombosis often occurs without prior signifi-
cant luminal narrowing by the vulnerable plaque.10–12
Little information is available regarding anatomic corre-
lates of coronary spasm.28 Spasm is usually associated with
atherosclerotic lesions but in some cases occurs without
angiographically evident disease.29–31 Alterations associated
with coronary spasm have included coronary lesions exhibit-
ing neointimal hyperplasia,31 unusual transverse ridges in
the coronary artery,32 and increased numbers of adventitial
mast cells.33 Prominent adventitial inflammation has been
found to be more prevalent in coronary arteries of patients
with a recent history of unstable angina pectoris at rest than
in controls, further suggesting a role for inflammatory medi-
ators in the pathophysiology of coronary spasm.34 Further-
more, increased numbers of mast cells have been found in
the adventitia of ruptured plaques in infarct-related coronary
arteries, suggesting a role for histamine release and coronary
spasm in the development of acute coronary syndromes.35
Mediators released from abnormal myocardium also can
induce coronary spasm in experimental models.36
Nonatherosclerotic Coronary
Vascular Diseases
In a small number of cases of ischemic heart disease, the
coronary arteries are free of atherosclerosis and the clinical
disease is related to some other condition. There is an inter-
esting spectrum of nonatherosclerotic causes of ischemic
heart disease, including congenital anomalies, dissection
(Figs. 25.11 and 25.12), emboli, vasculitis, and other condi-
tions of the coronary arteries (Table 25.1).37,38 Cocaine use can
precipitate acute myocardial ischemia and infarction as a
result of coronary spasm and/or thrombosis.39,40
Pathology of Angina Pectoris and Sudden
Cardiac Death
The usual pathologic correlate of angina pectoris is coronary
atherosclerosis with significant luminal narrowing of one or
more of the major coronary arteries.3,14,28 However, there is
considerable variation in the anatomic extent of large vessel
FIGURE 25.9. Coronary artery with a small mural thrombus
attached to the surface of an atherosclerotic plaque. High-power
photomicrograph.
 c oro n a r y a r t e r y d i s e a s e : pat h ol o g ic a n at om y a n d pat h o g e n e s i s
FIGURE 25.10. Characteristics of the
Vulnerable plaque
vulnerable plaque and mechanisms
contributing to disruption of the plaque
capsule and thrombosis.
CAD associated with the development of symptomatic isch-
emic heart disease. The variability is influenced by a number
of interrelated factors, including the rate of progression of
large vessel disease and the development of the coronary
collateral circulation. Depending on the extent of coronary
collateral blood flow, coronary occlusion may lead to a major
MI or to little or no myocardial damage.41
Unstable angina pectoris and related syndromes (prein-
farction angina, coronary insufficiency) are associated with
a high incidence of acute alterations of plaques (“unstable
plaques”) with superimposed thrombotic lesions, usually
platelet aggregates or nonocclusive thrombi, as well as plate-
let aggregates in the microcirculation of the myocar-
dium.14,22,28,42,43 The accumulation of macrophages at sites of
unstable, vulnerable plaques indicates an inflammatory
component to these vascular lesions, as has also been
demonstrated.23–26
Coronary atherosclerosis is the most frequent anatomic
substrate of sudden cardiac death.44,45 In large series, ap-
proximately 90% of cases exhibit significant atherosclerotic
narrowing of at least one coronary artery.46,47 Many of the
cases also show evidence of previous myocardial injury,
manifest as multifocal myocardial scarring or healed
infarction.45–52 Although most cases do not exhibit an
FIGURE 25.11. Gross photograph of a spontaneously dissected
coronary artery with a hematoma in the wall and marked compres-
sion of the lumen.
597
Thin fibrous capsule
Large lipid-rich core
Accumulation of
macrophages under
capsule
Vascularization
Endothelial damage
Influx of plasma and
erythrocytes
Increased pressure in plaque
Fissure or rupture of capsule
Influx of blood into plaque
Thrombosis
Discharge of foam cells and
cholesterol into lumen
Disrupted plaque with thrombus
, macrophages; , cholesterol; , vessel; , thrombotic material
anatomically demonstrable acute MI, a subset of cases of
sudden death are related to acute MI.48–52 There is consider-
able variability in the reported incidence of acute plaque
alterations and thrombotic lesions.48–52 However, evidence of
coronary plaque disruption and thrombosis has been docu-
mented in a significant subset of patients, particularly those
with a prior history of unstable angina pectoris, an acute MI,
or single vessel disease.48–52 Such patients also frequently
show evidence of platelet aggregation in the coronary
microcirculation.42,43
Women and men exhibit differences regarding sudden
cardiac death.52–56 Sudden cardiac death occurs more fre-
quently in men than in women. Differences in coronary
lesions also have been observed, with superficial plaque
erosion rather than plaque rupture occurring more frequently
in younger individuals and women.53 There is evidence of a
higher incidence of plaque rupture in men dying suddenly
during exertion than in men dying suddenly at rest.56 Fur-
thermore, plaque rupture with exertion is characterized by a
relatively thin fibrous capsule, relatively numerous vasa
vasorum, and rupture in mid-capsule, whereas plaque rupture
at rest tends to occur at the shoulder region of the fibrous
capsule.56 In summary, clinicopathologic studies support the
concept of three major mechanisms of sudden cardiac death:
FIGURE 25.12. Coronary artery with spontaneous dissecting
hematoma (DH) in the vessel wall. Low-power photomicrograph.
598 chapter 25

TABLE 25.1. Causes of myocardial ischemia and infarction Pathology of Acute Myocardial Infarction
without coronary atherosclerosis
Coronary artery disease other than atherosclerosis Myocardial infarction is defined as the death of heart muscle
Arteritis resulting from severe, prolonged ischemia. It usually involves
Luetic
Granulomatous (Takayasu’s disease) the LV.3,57–61 The relatively unusual RV infarcts occur in asso-
Polyarteritis nodosa ciation with LV infarcts, particularly posterior transmural
Mucocutaneous lymph node (Kawasaki’s) syndrome LV infarcts, or as isolated entities, usually in association
Disseminated lupus erythematosus with pulmonary hypertension. Most MIs are confined to the
Rheumatoid arthritis
Ankylosing spondylitis
distribution of a single coronary artery and are designated as
Trauma to coronary arteries anterior, anteroseptal, lateral, and posteroinferior. Multire-
Laceration gional infarcts also occur. Myocardial infarctions are desig-
Thrombosis nated as subendocardial (non–Q-wave) when the necrosis is
Iatrogenic limited to the inner half of the ventricular wall (Fig. 25.13)
Coronary mural thickening with metabolic diseases or intimal
proliferative disease or transmural (Q-wave) when the necrosis involves not only
Mucopolysaccharidoses (Hurler’s disease) the inner half but significant amounts of the outer half of
Homocystinuria the ventricular wall (Figs. 25.14 and 25.15). The electrocar-
Fabry’s disease diographic (ECG) correlates are the ST segment elevation
Amyloidosis
Juvenile intimal sclerosis
with Q-wave pattern for transmural infarcts and the ST
(idiopathic arterial calcification of infancy) segment depression without Q-wave pattern for subendocar-
Intimal hyperplasia associated with contraceptive steroids or dial infarcts.3,57–61
with the postpartum period The overall incidence of occlusive coronary thrombosis
Pseudoxanthoma elasticum and associated plaque fissure or rupture is high (greater than
Coronary fibrosis caused by radiation therapy
Luminal narrowing by other mechanisms 75%) for acute MI.3,14–28 The thrombus typically involves the
Spasm of coronary arteries major coronary artery in the distribution of the infarcted
(Prinzmetal’s angina with normal coronary arteries) myocardium. However, there is a significant difference
Spasm after nitroglycerin withdrawal in incidence of thrombosis according to the type of infarct.
Dissection of the aorta
Dissection of the coronary artery
In autopsy studies, occlusive coronary thrombi are found in
Emboli to coronary arteries more than 90% of cases of transmural (Q-wave) MI but in
Infective endocarditis only about one third of cases of subendocardial (non-Q-wave)
Prolapse of mitral valve MI.3,14–28 Subendocardial MI without occlusive thrombosis is
Mural thrombus from left atrium, left ventricle related to the influence of other factors, such as more subtle
Prosthetic valve emboli
Cardiac myxoma coronary lesions (platelet aggregation, nonocclusive thrombi)
Associated with cardiopulmonary bypass surgery and and factors that increase myocardial oxygen demand (e.g.,
coronary arteriography aortic stenosis, systemic hypertension, cardiac hypertrophy,
Paradoxical emboli excessive stress, or exertion) (Fig. 25.5). The occurrence of
Papillary fibroelastoma of the aortic valve (“fixed embolus”)
Congenital coronary artery anomalies
subendocardial MI without occlusive thrombosis highlights
Anomalous origin of left coronary from pulmonary artery
Left coronary artery from anterior sinus of Valsalva
Coronary arteriovenous and arteriocameral fistulae
Coronary artery aneurysms
Myocardial oxygen demand–supply disproportion
Aortic stenosis, all forms
Incomplete differentiation of the aortic valve
Aortic insufficiency
Carbon monoxide poisoning
Thyrotoxicosis
Prolonged hypotension
Hematological (in situ thrombosis)
Polycythemia vera
Thrombocytosis
Disseminated intravascular coagulation
Hypercoagulability
Hypercoagulability, thrombosis, thrombocytopenic purpura
Miscellaneous
Myocardial contusion
Myocardial infarction with normal coronary arteries

ischemia-induced ventricular arrhythmia without acute MI;

FIGURE 25.13. Heart section demonstrates an acute subendocar-
acute MI with ventricular arrhythmia; and primary ventric- dial myocardial infarct involving the anterior left ventricle. The
ular arrhythmia associated with old myocardial damage and necrotic subendocardial myocardium is pale yellow and rimmed by
altered electrical conduction (Fig. 25.5).44,45 a red area of congestion.
 c oro n a r y a r t e r y d i s e a s e : pat h ol o g ic a n at om y a n d pat h o g e n e s i s 599

FIGURE 25.16. Heart shows a rupture of the posterior papillary

FIGURE 25.14. Transverse sections of the heart demonstrate a large muscle (arrows) due to an acute myocardial infarct.
acute transmural anteroseptal myocardial infarct related to an
occlusive thrombus (arrow) of the proximal left anterior descending
coronary artery.

the increased susceptibility of the human subendocardium

to ischemic injury. This susceptibility is caused by a more
tenuous oxygen supply-demand balance in this region versus
the subepicardium. This, in turn, is related to the pattern of
distribution of the collateral circulation and to local meta-
bolic differences in subendocardial versus subepicardial
myocytes.3
The major complications of acute MI are infarct expan-
sion (shape change leading to stretching and thinning of the
ventricular wall), infarct extension (additional necrosis), car-
diogenic shock and recurrent ventricular arrhythmias related
to large infarct size (generally greater than 33% to 40% of
LV mass), papillary muscle dysfunction, papillary muscle
rupture (Fig. 25.16), external cardiac rupture (Fig. 25.17), ven-
tricular aneurysm (Fig. 25.18), ventricular pseudoaneurysm
(due to sealing off of a relatively slowly evolving rupture),
ventricular septal rupture, pericarditis (nonspecific and
FIGURE 25.17. Section of heart shows an acute transmural poste-
rior myocardial infarct with an external rupture site (arrow).

FIGURE 25.15. Acutely infarcted myocardium contains necrotic

myocytes with contraction bands (black arrows) and an infiltrate of FIGURE 25.18. Left ventricular aneurysm with mural thrombus
neutrophils (white arrows). High-magnification micrograph. resulting from healing of a transmural myocardial infarct.
600
autoimmune, e.g., Dressler’s syndrome) systemic emboliza-
tion from an LV mural thrombus, and pulmonary
thromboembolism.58
The risk of infarct rupture is significant during the first
week of MI before significant organization of the necrotic
tissue.57,58 Healing of MI involves neutrophil infiltration fol-
lowed by formation of granulation tissue. Granulation tissue
is grossly visible at approximately 10 days and completely
replaces the necrotic tissue by 2 to 3 weeks. Thereafter, the
granulation tissue is converted to a dense scar; this process
is completed in 2 to 3 months.
Pathogenesis of Myocardial Ischemic Injury
The pathogenesis of ischemic myocardial cell injury and
necrosis involves complex metabolic and structural altera-
tions induced by severely reduced blood flow (Fig. 25.19).59–67
As a result of oxygen deprivation, mitochondrial oxidative
phosphorylation rapidly ceases, with resultant loss of the
major source of adenosine triphosphate (ATP) synthesis. Ini-
tially, there is a compensatory increase in anaerobic glycoly-
sis. However, this process leads to accumulation of hydrogen
ions and lactate, with a resultant intracellular acidosis and
inhibition of glycolysis as well as mitochondrial fatty acid
and energy metabolism.59
O2
↓ATP ↑H2PO4 ↑Lactate
Plasmalemma
↓K+ ↑Na+ ↑Cl– ↑H2O ↓Mg2+ ↑Ca2+
Protease ↑TG
activation ↑FFA
and/or other ↑Acyl-CoA
mechanisms ↑Acyl-carnitine
Alterations of Disruption of Accumulation
myofibrillar proteins cytoskeleton of amphipathic
↓ Ca2+ sensitivity lipids
↓ Contraction
FIGURE 25.19. Postulated sequence of alterations involved in the
pathogenesis of irreversible myocardial ischemic injury. Oxygen
deficiency induces metabolic changes, including decreased adeno-
sine triphosphate (ATP), decreased pH, and lactate accumulation, in
ischemic myocytes. The altered metabolic milieu leads to impaired
membrane transport with resultant derangements in intracellular
electrolytes. An increase in cytosolic Ca 2+ triggers the activation of
proteases and phospholipases with resultant cytoskeletal damage
and impaired membrane phospholipid balance. Alterations of myo-
fibrillar contractile proteins lead to decreased Ca 2+ sensitivity and
decreased contraction in spite of the increased cytosolic Ca 2+ . Lipid
chapter 25
The metabolic alterations are associated with inhibition
of contraction (excitation-contraction uncoupling) and asso-
ciated alterations in ionic transport systems located in the
sarcolemma and organellar membranes.59 The initial altera-
tion is loss of intracellular K + due to increased efflux of the
ion.66,67 Although the mechanism is unclear, it may involve
activation of ATP-dependent K + channels due to change in
the ATP/adenosine diphosphate (ADP) ratio or a mechanism
to reduce osmotic load. Another early change is an increase
in free Mg2+ , followed by a decrease in total Mg 2+ . Once ATP
decreases substantially, the Na + ,K + –adenosine triphospha-
tase (ATPase) is inhibited, resulting in a further loss of K +
and an increase in Na + . The accompanying influx of extracel-
lular fluid leads to cell swelling. An early increase in cyto-
solic Ca2+ also occurs as the result of multifactorial changes
in transport systems of the sarcolemma and sarcoplasmic
reticulum.63–66 Alterations in myofibrillar proteins leads to
decreased sensitivity to Ca 2+ , resulting in impaired contrac-
tility in spite of the elevated cytosolic Ca2+ .67
Advanced ischemic myocardial cell injury is mediated by
progressive membrane damage involving several contribu-
tory factors (Fig. 25.19).61,64,67 Calcium accumulation or other
metabolic changes lead to phospholipase activation and
resultant phospholipid degradation and release of lysophos-
pholipids and free fatty acids. Impaired mitochondrial fatty
acid metabolism leads to accumulation of various lipid
Cardiac myocyte
–
↑H+ ↓pH
Endoplasmic Mitochondria
reticulum
Endothelium
Leukocytes
–
O2, H2O2, ·OH, NO
Decreased Phospholipase
phospholipid activation with
synthesis FFA & LPL release
Phospholipid Lipid
depletion peroxidation
Impaired membrane
integrity
↓↓ATP ↑↑Calcium ↑pH
↓↓↓
Irreversible injury
alterations include increased phospholipid (PL) degradation with
release of free fatty acids (FFA) and lysophospholipids (LPL) and
decreased phospholipid synthesis. Lipid peroxidation occurs as a
result of attack by free radicals produced at least in part by the gen-
eration of excess electrons (e-) in oxygen-deprived mitochondria.
Free radicals also may be derived from metabolism of arachidonic
acid and catecholamines, metabolism of adenine nucleotides by
xanthine oxidase in endothelium (species dependent), and activation
of neutrophils and macrophages. The irreversible phase of injury
appears to be mediated by severe membrane damage produced by
phospholipid loss, lipid peroxidation and cytoskeletal damage.
 c oro n a r y a r t e r y d i s e a s e : pat h ol o g ic a n at om y a n d pat h o g e n e s i s
species, including long-chain acyl coenzyme A (CoA) and
acyl carnitine, which, together with products of phospholipid
degradation, can incorporate into membranes and impair
their function. Free radicals, including toxic oxygen species,
are generated from ischemic myocytes, ischemic endothe-
lium, and activated leukocytes. These toxic chemicals induce
peroxidative damage to fatty acids of membrane phospholip-
ids. Probably as a result of protease activation, cytoskeletal
filaments, which normally anchor the sarcolemma to adja-
cent myofibrils, become damaged, and their anchoring and
stabilizing effect on the sarcolemma is lost. All of these
changes lead to a progressive increase in membrane permea-
bility, further derangements in the intracellular ionic milieu,
and ATP exhaustion. The terminal event in initiating irre-
versible myocyte injury appears to be physical disruption of
the sarcolemma of the swollen myocyte.61,64,67
The sequence of abnormalities described above consti-
tute the well-documented pathophysiologic basis of cell
injury leading to cell death in cardiac myocytes subjected to
a major ischemic or hypoxic insult. However, recent discov-
eries have indicated that other pathophysiologic mechanisms
can contribute to cell injury and death, in particular apopto-
sis or programmed cell death.68,69 Following the recognition
of apoptosis as a major and distinctive mode of cell death,
reports have been published implicating apoptosis in MI,
reperfusion injury, and other forms of cardiovascular pathol-
6 01
ogy.67,70,71 Apoptosis is characterized by a series of molecular
and biochemical events, termed programmed cell death,
including (1) gene activation (programmed cell death); (2) per-
turbations of mitochondria, including membrane permeabil-
ity transition and cytochrome c release; (3) activation of a
cascade of cytosolic aspartate-specific cysteine proteases
(caspases); (4) endonuclease activation leading to double-
stranded DNA fragmentation; and (5) altered phospholipid
distribution of cell membranes and other surface properties
with preservation of selective membrane permeability (Fig.
25.20).68,69 Apoptosis can be triggered by activation of a death
receptor pathway or a mitochondrial pathway.72,73 Apoptosis
is also characterized by distinctive morphologic alterations
featuring cell and nuclear shrinkage and fragmentation, with
subsequent phagocytosis of apoptotic bodies by adjacent
viable cells without exudative inflammation.68,69
In contrast, numerous studies have reported ischemic
myocardial damage to be characterized by cell swelling with
altered cellular ionic composition due to altered membrane
permeability.61–67 This pattern of cell injury and death with
cell swelling has been designated as oncosis.69 Some reports
have proposed a major role for apoptosis in myocardial isch-
emic injury and infarction.71,72 However, such a role for apo-
ptosis may be overstated because of overinterpretation of
evidence of DNA fragmentation based on the TUNEL
method, which is not specific for apoptosis.74,75 Evidence has

Withdrawal of Glucocorticoids
Positive
Palmitate tropic factors Tumor necrosis factor (TNF)
stimuli
other stimuli Others
Fas/TNFR-1
Death domain activation
FADD TRADD Adaptor
Bcl-2 Bax proteins
Sentrin
Mitochondrion
Cyt c
Kinase
Caspase 8 cascade
Ceramide
O2 radicals/NO
Cyt c
NF-κB/IκB
Apaf-1 Caspase 3 (CPP32)
Caspase 9
dATP Caspase
Apoptosome cascade Cell
PARP cleavage
survival Ionizing radiation
Gene transcription Altered Drugs
↑Ca2+ (c-myc, p53, etc.) chromatin
structure
Toxins
Activation of New cell surface Recognition
Ca2+ - dependent properties including by phagocytes
enzymes ↑ phosphatidyl serine
in outer leaflet Phagocytosis
Endonuclease(s) Protease(s) Transglutaminase
without
DNA fragmentation Disruption of Cross-linking inflammation
and chromatin cyloskeleton of cytoplasmic
condensation proteins and
cell shrinkage

FIGURE 25.20. Mechanisms of cell death by apoptosis. Apoptosis
may be caused by self-activation of a lethal metabolic pathway (pro-
grammed cell death) or can be triggered by exogenous factors. Apo-
ptosis may be initiated by activation of a death receptor pathway or
a mitochondrial pathway, with loci of interaction between the two
pathways. The death receptor pathway involves activation of the
Fas/tumor necrosis factor receptor (TNFR) and its death domains,
FADD and TRADD, and subsequent activation of a cysteine prote-
ase (caspase) cascade, with activation of caspase-3 (CPP32) as the
key event. Mitochondria have an important role through the release
of cytochrome C, which is regulated by bcl-2 (which itself is regu-
lated by related proteins Bax/Bak), and subsequent activation of
apoptotic protease-activating factor-1 (Apaf-1).
602 chapter
been presented showing TUNEL labeling of ischemic myo-
cytes with classic features of oncosis as well as viable myo-
cytes undergoing DNA repair.76,77 Although certain assays
have been proposed to be more reliable for detection of pat-
terns of DNA fragmentation characteristic of apoptosis, the
DNA labeling data need to be interpreted in relation to other
features of cell injury.78–80 Other studies have found that
ischemic myocytes with the apoptotic markers of annexin V
membrane labeling also exhibit ultrastructural features of
oncotic damage.81 Nevertheless, work using caspase inhibi-
tors does suggest that apoptosis as well as oncosis may con-
tribute to the overall magnitude of ischemic necrosis.82,83
The rate and magnitude of ATP reduction may be a criti-
cal determinant of whether an injured myocyte progresses
to death by apoptosis or oncosis, because an ATP analogue,
d-ATP, is a key component of a molecular complex that medi-
ates cytochrome c release with activation of the caspase
cascade and apoptotic death.67,74,84 The severity of hypoxia
and reperfusion influence whether myocytes die by apoptosis
or oncosis, as does the severity of metabolic inhibition in
experimental studies.85,86 It is possible then that severely
ischemic myocytes progress rapidly to cell death with swell-
ing (oncosis), whereas less severely ischemic myocytes may
develop apoptosis. It is likely, however, that the same injured
myocyte may undergo activation of the apoptotic pathway
with activation of the caspase cascade followed by activation
of oncotic mechanisms, leading to cell membrane damage
and terminal cell swelling and rupture.67,74–81 Thus, apoptotic
and oncotic mechanisms may be operative in the same myo-
cytes during progression to irreversible ischemic injury and
necrosis.
Cross-section
of myocardium
Coronary
thrombus
25
Determinants of Infarct Development and Size
and Remodeling
After coronary artery occlusion, the myocardium can with-
stand up to about 20 minutes of severe ischemia without
developing irreversible injury. However, after about 20 to 30
minutes of severe ischemia, irreversible myocardial injury
begins.61 The subsequent degradative changes give rise to
recognizable myocardial necrosis. In the human and dog,
myocardial necrosis first appears in the ischemic subendo-
cardium, because this area usually has a more severe reduc-
tion in perfusion compared with the subepicardium. Over
the ensuing 3 to 6 hours, irreversible myocardial injury pro-
gresses in a wavefront pattern from the subendocardium into
the subepicardium (Fig. 25.21).60 In the experimental animal
and probably in humans as well, most MIs are completed
within approximately 6 hours after the onset of coronary
occlusion. However, a slower pattern of evolution of MI can
occur when the coronary collateral perfusion is abundant or
when the stimulus for myocardial ischemia is intermittent
(e.g., in the case of episodes of intermittent platelet aggrega-
tion before occlusive thrombosis).
Established myocardial infarcts have distinct central and
peripheral regions (Fig. 25.22).61–63 In the central zone of
severe ischemia, the necrotic myocytes exhibit clear sarco-
plasm with separation of organelles (evidence of edema);
clumped nuclear chromatin, stretched myofibrils with
widened I-bands, swollen mitochondria containing amor-
phous matrix (flocculent) densities composed of denatured
lipid and protein and linear densities representing fused
cristae, and defects (holes) in the sarcolemma. In the periph-
0 hrs
Necrosis
40 minutes
FIGURE 25.21. Progression of cell death
versus time as a wavefront of necrosis at
various time intervals after coronary
occlusion. Necrosis occurs first in the
Necrosis subendocardial myocardium. With
longer intervals of occlusion, a wave-
front of cell death moves from the sub-
2 hrs endocardial zone across the wall to
involve progressively more of the trans-
mural thickness of the ischemic zone. In
contrast, the lateral margins in the sub-
endocardial region of the infarct are
Necrosis established as early as 40 minutes after
occlusion and are sharply defined by the
anatomic boundaries of the ischemic
24 hrs bed.
 c oro n a r y a r t e r y d i s e a s e : pat h ol o g ic a n at om y a n d pat h o g e n e s i s
FIGURE 25.22. Patterns of myocardial injury in an
acute transmural myocardial infarct. C.B., myofibrillar
contraction band; L.D., lipid droplet; Mf., myofibril; Mt.,
mitochondrion; Mt.-A.D., mitochondrion with amor-
phous matrix (flocculent) densities; Mt.-A.D. + Ca D.,
mitochondrion with amorphous matrix densities and
calcium phosphate deposits; N., nucleus; N.-Cl. Chr.,
nucleus with clumped chromatin; SI.D., sarcolemmal Mt.
defect.
eral region of an infarct, which has some degree of collateral
perfusion, many necrotic myocytes exhibit edematous sar-
coplasm; disruption of the myofibrils with the formation of
dense transverse (contraction) bands, swollen mitochondria
containing calcium phosphate deposits as well as amorphous
matrix densities, variable amounts of lipid droplets, and
clumped nuclear chromatin. A third population of cells at
the outermost periphery of infarcts contains excess numbers
of lipid droplets but does not exhibit the features of irrevers-
ible injury just described. The pattern of injury seen in the
infarcted periphery is also characteristic of myocardial injury
produced by temporary coronary occlusion followed by reper-
fusion. In general, the most reliable ultrastructural features
of irreversible injury are the amorphous matrix densities in
the mitochondria and the sarcolemmal defects.
The myocardial bed at risk, or risk zone, refers to the
mass of myocardium that receives its blood supply from a
major coronary artery that develops occlusion (Figs. 25.21
and 25.22).60 After occlusion, the severity of the ischemia is
determined by the amount of preexisting collateral circula-
tion into the myocardial bed at risk. The collateral blood flow
is derived from collateral channels connecting the occluded
and nonoccluded coronary systems. With time there is pro-
gressive increase in coronary collateral blood flow. However,
much of this increase in flow may occur too late to salvage
significant amounts of myocardium.
The size of the MI is determined by the mass of necrotic
myocardium within the bed at risk (Figs. 25.21 and 25.22).60,61
The bed at risk will also contain viable but injured myocar-
dium. The border zone refers to the nonnecrotic but dysfunc-
tional myocardium within the ischemic bed at risk. The size
of the border zone varies inversely with the relative amount
of necrotic myocardium, which increases with time as the
wavefront of necrosis progresses. The border zone exists pri-
marily in the subepicardial half of the bed at risk and has a
very small lateral dimension, owing to a sharp demarcation
between vascular beds supplied by the occluded and patent
major coronary arteries.
The major determinants of ultimate infarct size, there-
fore, are the duration and severity of ischemia, the size of
the myocardial bed at risk, and the amount of collateral
603
N. L.D. Mf. Mt.-A.D. N.-Cl.Chr. Mf. L.D. C.B. N.-Cl.Chr. Sl.D.
Sl.D. Mt.-A.D. + Ca D.
blood flow available shortly after coronary occlusion. Infarct
size also can be influenced by the major determinants of
myocardial metabolic demand, which are heart rate, wall
tension (determined by blood pressure), and myocardial
contractility.
Infarct size also influences the overall response of the
ventricle to an ischemic insult. Myocardial remodeling refers
to a complex of compensatory changes, including structural
and functional modifications of the viable myocardium to
ventricular wall stress. The response includes hypertrophy
of cardiomyocytes, death of cardiomyocytes by apoptotic
or oncotic mechanisms, and cardiomyocyte regeneration,
probably involving activation of endogenous stem cells.67
Other changes involve connective tissue restructuring and
proliferation and microcirculatory changes. If the initial
damage is relatively limited, remodeling can be effective and
lead to normalization of wall stress. If the initial damage is
severe, remodeling may be inadequate or ineffective, leading
to fixed structural dilatation of the ventricle and congestive
heart failure. The end stage of this process is ischemic
cardiomyopathy.
Reperfusion, Preconditioning, Stunning,
and Hibernation
A number of factors can significantly modulate the myocar-
dial response and subsequent outcome following an ischemic
episode.67 The progression of myocardial ischemia can be
profoundly influenced by reperfusion (Fig. 25.23). However,
the effects of reperfusion are complex.89–91 Reperfusion clearly
can limit the extent of myocardial necrosis if instituted early
enough after the onset of coronary occlusion. However,
reperfusion also changes the pattern of myocardial injury by
causing hemorrhage within the severely damaged myocar-
dium and by producing a pattern of myocardial injury char-
acterized by contraction bands and calcification. Reperfusion
also accelerates the release of intracellular enzymes and pro-
teins from damaged myocardium. This may lead to a marked
elevation of serum levels of these infarct markers without
necessarily implying further myocardial necrosis. The timing
604 chapter 25

A The rate of progression of myocardial necrosis can be

Patchy areas undergo irreversible myocyte injury
within 30 minutes of severe ischemia
Large areas of myocardium undergo reversible injury
during 30 minutes of coronary occlusion and are
salvaged by reperfusion but with transient dysfunction
(stunning)
B sarcolemmal and mitochondrial ATP-dependent potassium
influenced by prior short intervals of coronary occlusion and
reperfusion. Specifically, experimental evidence indicates
that the extent of myocardial necrosis after 60 to 90 minutes
of coronary occlusion is significantly less in animals that
had been pretreated with one or more 5-minute intervals of
coronary occlusion before the induction of permanent occlu-
sion.67,92,93 However, after 120 minutes of coronary occlusion,
the effect on infarct size is lost. This phenomenon is known
as preconditioning (Fig. 25.24).67,92,93 A reduced rate of ATP
depletion correlates with the beneficial effects of precondi-
tioning.92,93 Further studies have indicated that classic pre-
conditioning involves activation of receptors for adenosine
and other agonists, G-protein–coupled protein kinase C, and

Inner zone myocardium undergoes irreversible injury

Shortened
during initial 40–60 minutes of severe ischemia action
Adenosine potential -
Mid-zone myocardium becomes severely injured during Adenosine K+ decreased
and related K ATP calcium
coronary occlusion and is subject to irreversible injury receptors channel influx
upon reperfusion (reperfusion-induced cell death)
Protein kinase C(PKC)
Outer zone myocardium becomes less severely injured G proteins
Ca2+
during coronary occlusion and is salvageable upon
reperfusion but with transient dysfunction (stunning)
K ATP K
+
FIGURE 25.23. Influences of duration of coronary occlusion and channel
timing of reperfusion on the response of the ischemic myocardium. Kinase cascade
(A) When reperfusion is achieved within 30 minutes of coronary Mitochondrion
ATP
occlusion, minimal irreversible injury occurs and most of the isch- Mitogen-activated
emic myocardium is salvaged but with transient dysfunction (stun- protein kinases
ning). (B) When reperfusion occurs within 2 hours of coronary ATP (MAP kinases)
reduced
occlusion, a significant amount of subendocardial myocardium rate of Myofibrils
develops irreversible injury, including some myocytes that probably ATP decline NF-ΚB
become irreversibly injured at the time of reperfusion (reperfusion- SOD– O2
–

induced cell death); however, reperfusion also results in significant Cytoskeleton

Gene Activation
salvage of subepicardial myocardium that would have developed Superoxide dismutase
irreversible injury with permanent coronary occlusion. NOS Nitric oxide synthase
Ca2+ Ca2+ Heat shock proteins
Decreased Early gene family
calcium NO
influx Nucleus
HSP27

HSP60
HSP70 HSP90

of reperfusion is critical to the outcome, with the potential
for myocardial salvage being greater with earlier interven-
tion. Although reperfusion can clearly salvage myocardium,
it may also induce additional injury. The concept of reperfu-
sion injury implies the development of further damage, as a
result of the reperfusion, to myocytes that were injured but
that remained viable during a previous ischemic episode.
Such injury may involve functional impairment, arrhyth-
mia, and progression to cell death.67,87–89 Major mediators of
reperfusion injury are oxygen radicals and neutrophils. The
oxygen radicals are generated by injured myocytes and non-
myocytes in the ischemic zone due to an oxidative burst
upon reperfusion as well as neutrophils that gain access to
the ischemic zone and become activated upon reperfu-
sion.67,89–91 The neutrophils also contribute to microvascular
obstruction and the no-reflow phenomenon in the reperfused
myocardium.67,89–91
FIGURE 25.24. Postulated mechanisms of early ischemic myocar-
dial preconditioning and second window of protection. Brief periods
of coronary occlusion lead to an initially slower rate of ATP decline
and reduced rate of progression to irreversible injury and necrosis
during subsequent prolonged coronary occlusion; this phenomenon
is ischemic preconditioning. Significant events in ischemic precon-
ditioning are activation of adenosine and related receptors, activa-
tion of protein kinase C (PKC), and opening of ATP-dependent K +
channels in the sarcolemma and mitochondria. Available evidence
supports opening of the mitochondrial K ATP channels as the critical
event, although the downstream mechanisms are still unclear. One
effect is decreased Ca 2+ influx, and subsequent blunting of injury
induced by Ca 2+ overload. Brief episodes of coronary occlusion lead
to early ischemic preconditioning followed by a refractory period
and the subsequent onset of a second window of protection. The
second window of protection is related to gene activation mediated
by a kinase cascade, including mitogen-activated protein (MAP)
kinases, and nuclear factor κB (NF-κB). Gene products implicated in
the second window of protection include superoxide dismutase,
nitric oxide synthase and its product, nitric oxide, and heat shock
proteins, including HSP27, which interacts with the cytoskeleton.
 c oro n a r y a r t e r y d i s e a s e : pat h ol o g ic a n at om y a n d pat h o g e n e s i s 605
channels, with a key role for the mitochondrial K chan-
nels.94–100 After a refractory period, a second late phase of
myocardial protection during a subsequent ischemic event
develops, a phenomenon known as the second window of
protection (SWOP),96,101,102 which is related to ischemia-
induced gene activation with production of various gene
products, including superoxide dismutase, nitric oxide syn-
thase, and stress (heat shock) proteins.96,102–104 Recently, a
protective effect on the extent of myocardial ischemic
damage has been observed with multiple, brief coronary
occlusions during early reperfusion after coronary occlusion,
a phenomenon termed postconditioning.105
Prolonged functional depression, requiring up to 24 hours
or longer for recovery, develops on reperfusion even after
relatively brief periods of coronary occlusion, on the order of
15 minutes, which are insufficient to cause myocardial
necrosis. This phenomenon has been referred to as myocar- FIGURE 25.25. Coronary artery after percutaneous transluminal
coronary angioplasty shows areas of plaque disruption (arrows)
dial stunning.67 A related condition, termed hibernation, with microthrombus on the surface. Low-magnification
refers to chronic depression of myocardial function owing to photomicrograph.
a chronic moderate reduction of perfusion.67 Preconditioning
and stunning are independent phenomena, since the precon-
ditioning effect is short term, transient, and not mediated
through stunning. Free-radical effects and calcium loading broblasts) and connective tissue matrix without lipid depos-
have been implicated in the pathogenesis of stunning, as well its. A similar lesion is seen in animal models of arterial
as other components of reperfusion injury.67,106,107 After longer injury.114 Experimental evidence supports a role for platelet
intervals of coronary occlusion, on the order of 2 to 4 hours, activation in the pathogenesis of the lesion.114 This process
necrosis of the subendocardium develops and even more of intimal proliferation leads to restenosis of lesions in 30%
severe and persistent functional depression occurs.108 In to 40% of cases within 6 months. The use of vascular stents
experimental studies, after 2 hours of coronary occlusion LV in conjunction with angioplasty has significantly improved
regional sites of moderate dysfunction during ischemia the long-term patency rates, although the stents do invoke a
recovered normal or near-normal regional contractile func- viable amount of intimal reaction.117–119 The potential of drug
tion after 1 to 4 weeks of reperfusion, whereas after 4 hours eluting stents to improve long-term outcomes is under active
of coronary occlusion, contractile dysfunction persisted after investigation.120,121
4 weeks of reperfusion.108 Degenerative changes in cardio- Saphenous vein coronary artery bypass grafts (SVCABGs)
myocytes develop in chronically underperfused, hibernating develop diffuse fibrocellular intimal thickening, medial degen-
myocardium.67 These changes can influence the degree of eration and atrophy, and vascular dilatation within several
functional recovery upon complete restoration of blood months after implantation (Figs. 25.27 and 25.28).122–124 Sub-
flow.67 sequently, the grafts are prone to development of eccentric
Therefore, depending on the interval of coronary occlu- intimal plaques with lipid deposition (atherosclerosis).122–124
sion before reperfusion, various degrees of contractile dys-
function, necrosis, or both are seen with reperfusion. These
observations emphasize the need for early intervention to
salvage myocardium.67,109 On balance, early reperfusion
results in a major net positive effect, making early reperfu-
sion an important goal in the treatment of acute ischemic
heart disease.110,111

Pathology of Interventionally Treated

Coronary Artery Disease
Percutaneous transluminal coronary angioplasty (PTCA)
can produce a variety of acute effects, including dilatation of
the vessel caused by stretching of the intima and media,
damage to the endothelial surface, multiple fissures in the
plaque, and dissection of the media (Figs. 25.25 and 25.26).112,113
The acute injury initiates a reparative response that leads to
intimal proliferation.112–114 Similar effects occur after ather- FIGURE 25.26. Close-up view of microthrombus on surface of a
ectomy and laser angioplasty.115,116 The resultant fibrocellular fissured plaque following percutaneous transluminal coronary
tissue is composed of modified smooth muscle cells (myofi- angioplasty. High-magnification photomicrograph.
606
FIGURE 25.27. Saphenous vein–coronary artery bypass graft
implanted for several months. The vein graft shows diffuse
concentric fibromuscular intimal thickening. Low-power
photomicrograph.
Plaque fissuring and thrombosis also may develop (Figs.
25.29 and 25.30). Therefore, all of the changes seen in natu-
rally occurring atherosclerosis may also develop in the
saphenous veins, thereby creating a finite limit to the benefi-
cial effects of these grafts. With improvements in surgical
technique, the use of internal mammary arteries for coro-
nary bypass has taken on more widespread application. The
internal mammary arteries are more resistant to the intimal
injury and intimal proliferation observed in saphenous veins
and, therefore, the arterial bypass grafts have prolonged
potency.125,126
FIGURE 25.28. Further detail of the fibrocellular intimal prolifera-
tion in a saphenous vein–coronary artery bypass graft. Medium-
power photomicrograph.
chapter 25
FIGURE 25.29. Severe atherosclerosis in a saphenous vein graft in
place for 7 years. Multiple cross sections through the saphenous vein
bypass graft (SVBG), distal anastomosis (arrow), and distal coronary
artery (CA). The saphenous vein shows marked atherosclerosis and
acute occlusive thrombosis with plaque hemorrhage. The distal
coronary artery has focal plaque, but a residual lumen is present.
There was a massive acute myocardial infarct in the distribution of
the occluded vein graft.
New Approaches to Myocardial Modulation
A new era is developing in the therapeutic application of new
insights regarding the pathogenesis of myocardial ischemic
disease. Ongoing testing is being conducted to understand
genetic factors influencing outcomes and to successfully
achieve genetic manipulation (gene therapy) of the processes
responsible for the response of the arterial wall to injury,
with the goals of retarding or preventing intimal prolifera-
tion and thrombosis at sites of coronary injury.127–133 Alterna-
tive approaches are being explored for the treatment of
intractable angina pectoris.134,135 One surgical approach is the
use of transmyocardial laser treatment to create new myo-
cardial microvasculature.135–138 Another approach is the
FIGURE 25.30. This segment of vein graft is involved by a large
atheroma with lipid-laden core and thin fibrous capsule. Hemor-
rhage is present in the plaque core (H). The lumen is occluded
by recent thrombus (T). Low-power photomicrograph.
 c oro n a r y a r t e r y d i s e a s e : pat h ol o g ic a n at om y a n d pat h o g e n e s i s
intravascular delivery of genetically engineered growth
factors, including vascular endothelial growth factor (VEGF)
and fibroblast growth factor (FGF).139–142 The debate regarding
whether or not the myocardium is composed of terminally
differentiated cardiac myocytes has been revived.143,144 New
insight into the issue has been provided by evidence that the
myocardium contains intrinsic cardiac stem cells that have
the potential to differentiate into cardiac myocytes, smooth
muscle cells, and endothelial cells.145,146 Bone marrow–derived
stem cells also have the potential to differentiate into mature
cardiac cells when these cells are home to the myocardium
or are injected, particularly after myocardial injury. These
insights have opened the promising field of regenerative car-
diology. Initially, primary results have been obtained with
the use of autologous stem cells for the treatment of patients
with MI and heart failure.147–149 These approaches have con-
siderable promise for the treatment of ischemic myocardial
disease.
Summary
Coronary atherosclerosis is the major anatomic substrate for
the diverse clinical syndromes of coronary heart disease.
Acute ischemic heart disease is usually initiated by erosion,
rupture, thrombosis, or spasm superimposed on vulnerable
plaques with active inflammation. The process may be self-
limited (angina pectoris), may trigger a lethal ventricular
arrhythmia (sudden cardiac death), or result in death of heart
muscle (MI). Myocardial infarction progresses as a wavefront
of necrosis extending from subendocardium into subepicar-
dium with complete evolution in 3 to 6 hours. The pathogen-
esis of irreversible myocardial cell injury involves metabolic
and electrolyte changes, leading to progressive membrane
damage and cell swelling and rupture (oncosis). Apoptosis, or
at least apoptotic mechanisms, may contribute to the process.
Timely reperfusion has a profound influence, resulting in
some further loss of critically injured cells (reperfusion injury)
and net salvage of a significant amount of myocardium. Pre-
conditioning by repetitive short intervals of coronary occlu-
sion and reperfusion can significantly retard the subsequent
development of MI. Reperfusion can be achieved clinically
with coronary angioplasty and cardiac bypass surgery, but
associated pathologic changes in coronary arteries can influ-
ence long-term outcomes.
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 2 Inflammation, C-Reactive
6 Protein, and
Vulnerable Plaques
Paolo Calabró, James T. Willerson, and
Edward T.H. Yeh
C-Reactive Protein as a Clinical Marker. . . . . . . . . . . . . 611
Biologic Effects of C-Reactive Protein . . . . . . . . . . . . . . . 615
C-Reactive Protein Receptors . . . . . . . . . . . . . . . . . . . . . . 616
Key Points
• C-reactive protein, in combination with lipid profile,
provides very good cardiovascular risk prediction.
• C-reactive protein is not only a marker of inflammation,
but also a mediator of cardiovascular pathology.
• C-reactive protein can be produced by vascular smooth
muscle cells and adipocytes, which may contribute to its
role in vascular inflammation.
• C-reactive protein levels can be modulated by statins,
which may contribute to statin’s antiatherogenic effect.
Inflammation appears to play a pivotal role in all phases of
atherosclerosis, from the fatty streak lesion formation to
the acute coronary event due to vulnerable plaque rupture.1
There are various inflammatory markers that have been
shown to predict cardiovascular events. These include cell
adhesion molecules, cytokines, acute phase reactants, such
as fibrinogen, serum amyloid A, and C-reactive protein (CRP).
This last molecule, selected a simple downstream marker of
inflammation, has recently emerged as a major cardiovascu-
lar risk factor.
A large body of evidence has shown that atherosclerosis
is an inflammatory disease. Indeed, vascular inflammation
contributes to the pathogenesis of atherosclerosis, and later
in the disease process, it is a major determinant for the acute
coronary syndromes.1 Therefore, the identification of specific
triggers and mechanisms of underlying inflammation and a
better understanding of each step involved in this complex
process might lead to new ways to manage this important
clinical problem.
Among the inflammatory markers, CRP is the most
extensively studied in cardiovascular disease.2,3
C-Reactive Protein Production . . . . . . . . . . . . . . . . . . . . . 617
Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617
Tillet and Francis working in Oswald Avery’s laboratory
in 1929 during the course of studies of patients with Strepto-
coccus pneumoniae infection first discovered CRP, and it was
classified as the first “acute phase” protein. C-reactive protein
is a pentamer of 23-kd subunits, and during the acute-phase
response preformed CRP is rapidly secreted and its blood
level, usually low in healthy individuals, can rise 100- to
200-fold or higher above the reference value within 10 hours,
declining to baseline over a period of 7 to 12 days.4
C-reactive protein has been heavily studied in part
because of its biologic profile; that is, it is not consumed or
produced during the reaction, its blood levels do not show
diurnal or seasonal variation, and it has a 19-hour half-life.
Analytical factors also play a role, including relative low cost
of the available accurate high-sensitivity assays.5
C-Reactive Protein as a Clinical Marker
C-reactive protein has been consistently shown to be a prog-
nostic marker of adverse clinical cardiac events, such as
death, acute myocardial infarction (AMI), and urgent revas-
cularization in patients with acute coronary syndromes
(ACS). In the early 1990s, Liuzzo et al.6 demonstrated that
CRP levels can predict clinical outcome of patients
with acute coronary syndromes. This study specifically
addressed the short-term predictive value of inflammatory
markers, and of CRP in particular, in ACS evaluating the in-
hospital composite rates of death, myocardial infarction (MI),
recurrent ischemia, and urgent revascularization in a selected
population of patients with unstable angina (UA), all Braun-
wald’s class IIIb, and negative troponin T values. The results
611
612 chapter 26

of this study showed that CRP levels, and, to a lesser extent, p Trend <.001
serum amyloid A (SAA) protein levels significantly predicted p <.001
3
adverse events. C-reactive protein serum levels above 3 mg/L p <.001

Relative risk of MI
(90th percentile of distribution in healthy subjects) was asso-
ciated with an approximately fivefold increased risk of recur- 2 p = .03
rent events. More recent large studies have supported the
finding that high serum CRP levels are predictors for short-
term mortality in patients with ACS.7,8 In particular, the 1
study by Morrow et al.7 showed an 18-fold increased risk of
death among patients with UA and non-ST elevation MI
(NSTEMI) (using a CRP determination and a cutoff of 15.5 mg/ 0
L). More recently, Mueller et al.8 have assessed the prognostic ≤0.055 0.056–0.114 0.115–0.210 ≥0.211
role of CRP in 1042 patients with non-ST elevation ACSs
(NSTEACSs) undergoing an early invasive strategy (within 24 Quartile of hs-CRP (range, mg/dL)
hours) and showed significantly higher in-hospital mortality FIGURE 26.1. Risk of future myocardial infarction (MI) in appar-
ently healthy men increases in higher quartiles of hs-CRP.
in patients having serum CRP levels greater than 10 mg/L
than in those with CRP less than 3 mg/L (3.7% vs. 1.2%). In
patients with NSTEACS, CRP significantly predicts the
recurrence of cardiac events even in the long term. Finally,
in the Honolulu Heart Study, the odds of MI rose not only in
the first few years of follow-up, but also for as long as 20 years
in the follow-up period. Thus, it is clear that inflammation Health Study were monitored for more than 8 years for the
plays an early as well as late role in the atherosclerotic process, development of first MI, stroke, or venous thrombosis (Fig.
and the assessment of CRP might provide a method to ascer- 26.1). In that study, baseline serum CRP levels were higher
tain that risk early in life.9 among men who developed MIs or strokes than among those
Interestingly, CRP has also been studied in sera from 302 who remained free of disease. Moreover, the men in the
autopsies from men and women whose only inflammatory quartile with the highest serum CRP values had three times
condition was atherosclerosis.10 The lowest elevation of the risk of MI as the men in the lowest quartile, whereas the
serum CRP was found in those who died of noncardiac risk of stroke was approximately doubled. Risks were stable
causes, whereas stable plaques showed a modest elevation, over long periods of time and were independent of other lipid
erosive plaques a greater elevation, and marked elevations in and nonlipid risk factors.
CRP were seen in ruptured plaques. Data from the Women’s Health Study have also been
In one study, baseline levels of CRP were significantly important in understanding the role of CRP in risk detection.
associated with the risk of sudden cardiac death over a 17- Among 28,263 apparently healthy postmenopausal women
year period (p for trend = .001).11 who were monitored prospectively for future vascular events,
C-reactive protein also has been shown to be a prognostic four inflammatory markers [CRP, SAA, interleukin-6 (IL-6),
marker of adverse clinical cardiac events in stable patients. and intercellular adhesion molecule-1 (sICAM-1)] were all
An important paper that addressed the issue of whether found to be significant predictors of risk; CRP, however, was
markers of inflammation predict risk of recurrent events the most significant predictor in univariate analysis, outper-
among stable patients with a prior history of MI was the one forming homocysteine, lipoprotein(a), and low-density lipo-
by Ridker et al.,12 a nested case-control study done in post-MI protein cholesterol (LDL-C)14,15 (Fig. 26.2).
patients as part of the Cholesterol and Recurrent Events
(CARE) trial. Blood samples from 391 participants who sub-
sequently developed recurrent nonfatal MI or a fatal event
were compared with samples from 391 age- and sex-matched
patients who did not have a recurrent event. Serum CRP and
Lipoprotein(a)
SAA levels in prerandomization samples were compared
with those at follow-up. Levels were higher among cases than Homocysteine
IL-6
controls (p = .05 for CRP; p = .006 for SAA). Those with levels
TC
in the highest quartile had a relative risk of a recurrent event
LDL-C
that was 75% higher than those in the lowest quartile (p =
slCAM-1
.02 for both CRP and SAA).12 Baseline lipid levels were virtu- SAA
ally identical among those with and without evidence of Apo B
inflammation. Thus, low-grade inflammation as assessed by TC: HDL-C
CRP predicts risk of recurrent events after MI. hs-CRP
These data in secondary prevention complement evi- hs-CRP + TC: HDL-C
dence in primary prevention that indicates that CRP levels
1.0 0 2.0 4.0 6.0
are a strong predictor of cardiac events, even after adjustment
Relative risk of future CV events
for traditional risk factors. FIGURE 26.2. Direct comparison of relative risk of future cardio-
This effect was initially described by Ridker et al.13 in vascular events associated with levels of lipid and inflammatory
1997, in which apparently healthy men from the Physicians’ risk factors in the Women’s Health Study.
 i n f l a m m at ion, c-r e ac t i v e p rot e i n, a n d v u l n e r a bl e p l aqu e s
A subgroup analysis was limited to women with LDL-C
<130 mg/dL, the National Cholesterol Education Program
(NCEP) goal for primary prevention.16 In this analysis, women
with elevated baseline serum levels of CRP, SAA, IL-6, or
sICAM-1 were at increased risk for cardiovascular (CV)
events, but the effect remained strongest for CRP and
SAA.16
One of the new features of the NCEP publication was the
inclusion of the metabolic syndrome in risk stratification.16
This syndrome refers to the presence of at least three of the
following: abdominal obesity, elevated triglycerides, reduced
levels of high-density lipoprotein cholesterol (HDL-C), high
blood pressure, and high fasting glucose. All of these char-
acteristics are also modestly associated with elevated levels
of serum CRP. Moreover, serum CRP levels correlate with
other components of the metabolic syndrome that are not
easily measured in clinical practice, including fasting
insulin, microalbuminuria, and impaired fibrinolysis.17 To
address the role of CRP in the setting of the metabolic syn-
drome, a recent study evaluated interrelationships among
serum CRP levels, the metabolic syndrome, and incident CV
events among 14,719 apparently healthy women, 24% of
whom had the metabolic syndrome, who were followed up
for an 8-year period for MI, stroke, coronary revasculariza-
tion, or CV death. In brief, at all levels of the metabolic syn-
drome, serum levels of CRP improved risk prediction for
future CV events. Furthermore, serum CRP levels were
highly predictive even among those with the metabolic syn-
drome at study entry.17 In addition to predicting thrombotic
events, serum CRP levels also predicted type 2 diabetes,
which shares common inflammatory processes with athero-
sclerosis.18 These findings have implications for therapies
targeting insulin resistance and diabetes as well as cardio-
vascular disease (CVD).
As mentioned earlier, CRP is highly stable and can be
stored for many years without degradation. There are a
number of commercially available CRP measurements, and
they are reasonably concordant in the CRP value measured.
Furthermore, there is no difference in the CRP distribution
curve between men and women. Serum CRP levels are also
independent from age and racial consideration. Finally, there
is no diurnal variation in the serum CRP level.3 Thus, CRP
can be measured in a nonfasting individual at any time of
the day. These attributes of CRP probably account for the
clinical usefulness of serum CRP levels as a marker of
inflammation.19
The American Heart Association and the Centers for
Disease Control and Prevention Consensus Report on using
inflammatory markers as prognostic predictors in patients
with CVDs was published in Circulation in January 2003.20
Although this report recommends that the entire adult popu-
lation should not be screened for serum CRP levels for the
purpose of CV risk assessment (class III, level C), it concludes
that measurement of serum CRP is reasonable for assessing
absolute risk for coronary disease risk, particularly in inter-
mediate-risk individuals. Indeed, in patients with the Fram-
ingham score of 10% to 20% risk, the CRP level may help
direct future evaluation and therapy in the primary preven-
tion of CVD (class IIa, level B) (Fig. 26.3). However, the com-
mittee considered CRP measurements to be less useful in
patients without CV risk factors (class IIb, level C). The com-
613
25
20
Relative risk
15
10
>3.0
1.0–3.0 L
5 g/
<1.0 m
,
0 RP
10+ 5 to 9 2 to 4 0 to 1 -C
h s
Framingham 10-Year risk (%)
FIGURE 26.3. C-reactive protein adds prognostic information at all
levels of risk as defined by the Framingham risk score.
mittee also recommended that serum CRP measurements
could be a useful prognosticator in patients with ACS or
stable CAD (class IIa, level B). However, the committee
emphasized that the benefit of therapy based on serum CRP
results is uncertain. This is an important first step in incor-
porating CRP into the risk prediction strategy of CV
diseases.
Recently, Danesh et al.21 reported that elevated serum
levels of CRP are associated with only a moderate increase
in the risk of congestive heart disease (CHD). Although
these findings are consistent with the literature previously
discussed, the independent relative risk associated with
increased serum CRP levels in the Danesh study is consider-
ably less than in previous reports. Using a multivariate
analysis, the authors found that the predictive value of CRP
measurement adds relatively little to that provided by assess-
ments of traditional risk factors. The new findings raised a
discussion and called into question the clinical value of mea-
suring CRP as a predictor of the risk of CHD. The authors
concluded that the recent recommendations regarding the
use of measurement of CRP in the prediction of CHD may
need to be reviewed.21 However, several concerns were raised
by experts in the field pointing out concerns about statistical
or methodologic issues and how the authors may have under-
estimated the cardiovascular risk associated with serum
CRP values.22–25
We believe that CRP and cholesterol measurements
should be the cornerstones of CV risk stratification (Fig.
26.4). C-reactive protein is particularly useful in the patients
with LDL-C between 3.4 mmol/L and 4.1 mmol/L because
that level of LDL demands a more aggressive management
strategy either through lifestyle change or drug therapy (Fig.
26.4).
Exercise and weight loss lead to reduction in serum CRP
levels.26 Furthermore, several statins have been shown to
reduce CRP levels by 25% to 50%.27–30 The Air Force/Texas
Coronary Atherosclerosis Prevention Study (AFCAPS/
TexCAPS) included men and women without CHD who had
614 chapter 26

insight into mechanisms by which more aggressive statin

regimens augment the reduction in vascular risk (Fig. 26.5
CRP level Interpretation and Table 26.1). In the study, patients assigned to receive
μg/mL 80 mg of atorvastatin daily were significantly more likely
than those assigned to receive 40 mg of pravastatin daily to
have a decrease in the levels of both LDL-C and CRP to the
target values. Nonetheless, once target levels were met, the
Repeat test in one month authors found little evidence of a differential outcome accord-
Exclude other processes ing to the specific statin given, suggesting that achieving the
target levels of LDL-C and CRP was more important in
determining the outcomes than was the specific choice of
10 statin.
Moreover, a large-scale, randomized clinical trial—Justi-
fication for the Use of Statins in Primary Prevention: an
High risk
Intervention Trial Evaluating Rosuvastatin (JUPITER)—will
evaluate the effects of statin therapy in subjects who have
3 both LDL-C levels below those currently used to target
Intermediate risk therapy and CRP levels that indicate heightened risk of a
1 CHD event. This trial is randomizing 15,000 men (>55 years)
Low risk
and women (>65 years) with no history of coronary disease,
LDL-C levels of <130 mg/dL, and hs-CRP levels of >2.0 mg/dL
to placebo or rosuvastatin, a new high-potency statin. 33,34
FIGURE 26.4. C-reactive protein level and cardiovascular risk. The
CRP levels are listed on the left and interpretations are on the Participants will be followed for a composite end point of MI,
right. stroke, unstable angina, cardiovascular death, or coronary
intervention.35 The results of JUPITER should provide impor-
tant information regarding the use of CRP values to guide
initiation of lipid-lowering therapy in a primary prevention
population deemed to be at low cardiovascular risk by current
criteria.

average total and LDL-C plasma levels and below-average

HDL-C plasma levels. Treatment with lovastatin in AFCAPS/
TexCAPS showed a risk reduction of 37% for first acute coro-
nary events over 5 years. An outcomes analysis was per-
formed (high sensitivity) with data from the participants
(aged 35 to 62 years) stratified by high or low total choles- 0.10 LDL cholesterol
terol/HDL-C ratio and hs-CRP (high sensitivity) values. ≥70 mg/dL,
Cumulative rate of recurrent myocardial infarction

Compared with results of the placebo arm, the statin arm CRP ≥2 mg/L
demonstrated marked event reduction in the high ratio/high LDL cholesterol
0.08
CRP, high ratio/low CRP, and low ratio/high CRP groups. In <70 mg/dL,
or death from coronary causes

contrast, statin therapy had little effect on the rate of events CRP ≥2 mg/L
in individuals with low ratio/low CRP values. Similar results LDL cholesterol
occurred in subjects stratified by LDL-C and hs-CRP levels 0.06 ≥70 mg/dL,
above and below baseline median values.31 These findings CRP <2 mg/L
suggest that serum CRP assay can identify individuals at LDL cholesterol
<70 mg/dL,
seemingly low risk who will nonetheless benefit from statin
0.04 CRP <2 mg/L
treatment.
Ridker et al.32 analyzed data from the pravastatin or ator-
vastatin evaluation and infection trial-thrombolysis in
myocardial infarction (PROVE-IT TIMI) 22 in order to inves- 0.02
tigate if statin treatment, lowering LDL and CRP levels,
affects clinical outcomes. The data indicate that among
patients with ACSs who are treated with a statin, achieving 0.00
a target level of CRP of less than 2 mg per liter is associated 0.0 0.5 1.0 1.5 2.0 2.5
with a significant improvement in event-free survival, an Follow-up (years)
effect present at all levels of LDL-C achieved. Furthermore, FIGURE 26.5. Cumulative incidence of recurrent myocardial
data from this study demonstrate the concomitant infarction or death from coronary causes, according to the achieved
importance of both lipid and CRP reduction, providing levels of both LDL cholesterol and CRP.
 i n f l a m m at ion, c-r e ac t i v e p rot e i n, a n d v u l n e r a bl e p l aqu e s 615
TABLE 26.1. Relative risk of recurrent coronary events after statin therapy according to the quartile of low-density lipoprotein (LDL)
and c-reactive protein (CRP) levels achieved
Quartile

Variable 1† 2 3 4

Achieved LDL cholesterol

Quartile value—mg/dL <54 54–71 72–94 >94
Relative risk adjusted for age 1.0 1.1 1.3 1.8
95% confidence interval (CI) — 0.8–1.6 0.9–1.9 1.2–2.5
p value — 0.60 0.10 0.002
Relative risk adjusted for age and achieved CRP 1.0 1.1 1.3 1.7
95% Cl — 0.7–1.6 0.9–1.8 1.2–2.4
p value — 0.70 0.20 0.006
Relative risk adjusted for age and other risk factors 1.0 1.1 1.3 1.7
95% Cl — 0.7–1.6 0.9–1.9 1.2–2.5
p value — 0.70 0.20 0.003
Relative risk adjusted for age, achieved CRP, and other risk factors 1.0 1.1 1.2 1.7
95% Cl — 0.7–1.6 0.8–1.8 1.2–2.4
p value — 0.80 0.30 0.006
Achieved CRP
Quartile value—mg/L <0.9 0.9–1.9 2.0–4.2 >4.2
Relative risk adjusted for age 1.0 1.5 1.5 1.9
95% Cl — 1.0–2.3 1.0–2.3 1.3–2.8
p value — 0.04 0.04 <0.001
Relative risk adjusted for age and achieved LDL cholesterol 1.0 1.5 1.4 1.8
95% Cl — 1.0–2.2 1.0–2.1 1.2–2.6
p value — 0.06 0.07 0.004
Relative risk adjusted for age and other risk factors 1.0 1.5 1.4 1.8
95% Cl — 1.0–2.3 0.9–2.1 1.2–2.7
p value — 0.04 0.09 0.003
Relative risk adjusted for age, achieved LDL cholesterol, and other risk factors 1.0 1.5 1.3 1.7
95% Cl — 1.0–2.2 0.9–2.0 1.1–2.5
p value — 0.06 0.15 0.01

Biologic Effects of C-Reactive Protein
The link between CRP and atherosclerosis was initially sug-
gested to be that of a surrogate biomarker versus a mediator
of atherosclerosis. This view has been recently revisited,
with a significant literature suggesting that CRP has a direct
proatherogenic and proinflammatory effect, thus participat-
ing in lesion formation and plaque vulnerability.
A growing body of evidence indicates that CRP directly
interacts with different vascular cells.
First, several reports have described effects supposed to
be atherogenic by CRP, at concentrations known to predict
vascular events, on endothelial cells. We have demonstrated
that a dose-dependent significant expression of ICAM-1, vas-
cular cell adhesion molecule-1 (VCAM-1), and E-selectin was
detected in human umbilical vein endothelial cells (HUVECs)
following CRP stimulation.36 Furthermore, CRP was demon-
strated to induce expression of monocyte chemoattractant
protein-1 (MCP-1) in HUVECs.37 An involvement of endothe-
lin-1 (ET-1) and IL-6 in these CRP-mediated effects was dem-
onstrated in saphenous vein endothelial cells.38 C-reactive
protein was also shown to inhibit nitric oxide (NO) produc-
tion and stimulation of NO release via downregulation of
endothelial NO synthase (eNOS).39 Lastly, CRP was demon-
strated to increase plasminogen activator inhibitor-1 (PAI-1)
in human aortic endothelial cells.40
Studies have also shown that CRP interacts with vascular
smooth muscle cells (VSMCs). It has been suggested that CRP
induces relaxation of human vessels independent from endo-
thelium.41 C-reactive protein causes in vitro nuclear factor
(NF)-κB activation, which could lead to the induction of
MCP-1, IL-6, and iNOS gene expression. It also activates the
mitogen-activated protein kinase (MAPK) pathway.42 C-
reactive protein was recently demonstrated to markedly
upregulate AT1-R messenger RNA (mRNA) and protein ex-
pression and increase AT1-R numbers on VSMCs. Further-
more, CRP promotes VSM migration and proliferation in vitro
and increases reactive oxygen species (ROS) production.43
Finally, several reports have shown an interaction of CRP
with monocytes and macrophages. C-reactive protein has
been demonstrated to induce tissue factor expression and
release in monocytes/macrophages.44 Furthermore, CRP acts
as a chemoattractant for monocytes.45 Importantly, soluble
CRP and immobilized CRP have been demonstrated to
mediate the uptake of native LDL into macrophages.46
Another important mechanism of CRP action in athero-
sclerosis is the ability of the protein to activate the comple-
ment system via the classic pathway.47 It has been known
for years that complement plays a role in atherosclerosis.48
It has been shown that animals lacking components of
the complement system are protected against diet-induced
atherogenesis.49 Various complement proteins, including
616 chapter
the terminal complement complex C5b-9, have been shown
to deposit in human and animal atherosclerotic lesions, but
not in healthy arterial tissue.50,51 Since there is now evidence
that CRP colocalizes with activated complement fragments
in atherosclerotic lesions and in infarcted myocardium,
CRP-mediated complement activation in the arterial
wall may be an important pathogenic feature in human
atherogenesis.51–53
However, several questions about CRP’s mechanism of
action remain unanswered. Recently, Khreiss et al.54 pro-
vided evidence suggesting that native, pentameric CRP must
undergo structural modification, forming monomeric-
modified subunits, before promoting a proinflammatory
phenotype named mCRP. This molecular finding may serve
to influence not only basic molecular research examining
CRP’s detrimental effect, but also the clinical use of CRP as
a prognostic marker. However, diagnostic differentiation
between the different forms of CRP is not available at the
present time. Though it is still unclear, the findings by
Khreiss et al. raise the possibility that patients with more
mCRP or CRP with a tendency to become modified more
readily may exhibit a greater proinflammatory phenotype
and hence be at even greater risk for adverse cardiovascular
events. C-reactive protein must undergo a structural change
on cell membrane binding for endothelial activation, and this
active component is deposited in the wall of the blood vessel,
where it can promote atherogenesis. In this paper, the authors
showed that mCRP was able to induce endothelial activation
within 4 hours, whereas with native CRP, similar results
were not obtained until 24 hours later, because mCRP actions
were based on a tissue rather than a serum environment.
Because the effects of native CRP are dependent on an
unidentified serum cofactor,36 a cofactor that may not be
present at physiologic levels in cell culture, in vitro concen-
trations of CRP may need to be higher to compensate for this
difference.
In collaboration with the Khreiss group, we have recently
tried to identify this cofactor in in vitro experiments. We did
show a clear synergy between both native and mCRP and
CD14, a molecule involved in the innate host defense,55 in
the activation of the endothelial cells evaluated by ICAM-1
expression.56 In these experiments, CD14 appeared to be a
strong cofactor enhancing proinflammatory activity of the
two structural distinct isoforms of CRP; moreover, the com-
bination of mCRP and CD14 produced stronger activation of
endothelial cells than combined treatment with mCRP and
lipopolysaccharide (LPS), another suggested serum cofactor.
More recently a contamination issue has been raised
about CRP obtained from commercial sources and some of
its biologic properties. In particular, two reports have demon-
strated that CRP has no acute vasoactive properties per se,
but commercially available preparations do because of the
presence of the preservative NaN3.57,58 It is a well-established
fact that sodium azide is a potent vasorelaxant and that the
most commonly reported health effect from azide exposure
is hypotension.59 Thus, to address if other CRP biologic
effects observed in vitro are due to NaN3 contamination, we
have performed control experiments looking at membrane
ICAM-1 expression on endothelial cells, detected by flow
cytometry, following exposure to CRP or NaN3 at concentra-
tions found in the commercial preparations. NaN3 even at
26
the concentration of 10 mM (10 times higher than present in
our experiments with CRP) does not affect ICAM-1 expres-
sion on endothelial cells.56
With the development of a human CRP-transgenic (CRP-
tg) mouse, an animal model is now available to determine
the role CRP plays in vivo. It is important to remember that
mice do not produce CRP in measurable quantities, and the
primary pentraxin for immunity in the mouse is the serum
amyloid P. Two studies revealed that expression of human
CRP in mice actively promoted adverse cardiovascular pro-
cesses. First, human CRP created a prothrombotic pheno-
type, as evidenced by higher rates of thrombotic occlusion
after arterial injury.60 Second, by crossing CRP-tg mice with
apolipoprotein E (apoE)–/– mice, CRP was shown to be an
active player in atherogenesis in vivo.61 These CRP-tg/
apoE–/– mice had accelerated aortic atherosclerosis, which
was associated with increased complement deposition and
elevated expression of angiotensin type 1 receptor, VCAM-1,
and collagen within the lesions.61 Further studies using these
CRP-tg mice will no doubt confirm the in vitro results impli-
cating CRP with endothelial dysfunction, as evidenced by
impaired NO production and enhanced endothelin-1 release.
Furthermore, it will provide a model to assess new therapeu-
tic strategies aimed at decreasing CRP levels and to deter-
mine whether this strategy has an effect on plaque initiation,
progression, and rupture.
C-Reactive Protein Receptors
C-reactive protein binding to cellular receptors has been
intensively investigated with conflicting results. There are
no clear data as to whether CRP could interact with FC
receptors or with a specific CRP receptor.62,63 In support of
the last theory, it has been reported that binding of native
CRP to monocytic U-937 cells is not prevented by a blocking
anti-CD32 (FcγRII) monoclonal antibody.62
C-reactive protein binding to FcγRs has been suggested
in monocytes, and direct evidence for binding of native
CRP to COS cells transfected with CD64 (FcγRI) has been
reported.64,65 Neutrophils, however, do not normally express
CD64, but do express the low-affinity immunoglobulin G
(IgG) receptors CD16 (FcγRIII) and FcγRII.66
The low-affinity IgG receptor FcγRIIa was proposed to be
the major CRP receptor on leukocytes,63,67 and evidence sup-
ports this theory. It has been reported that native CRP binds
phagocytic cells (neutrophils and monocytes) with a specific
FcγRIIa allelic phenotype, thereby implicating FcγRIIa R/
R131 as the receptor for native CRP on human phagocytes.67
Furthermore, CRP was reported to induce FcγRIIa signaling
in granulocytes, and experiments in mice that were FcγRII-
and γ-chain–deficient showed deficient CRP-mediated
biologic responses compared with wild-type mice.68 Certain
investigators, however, have not been able to reproduce these
findings and recommend caution in interpretation of the data
about CRP binding to FcγRs. The major criticism of these
studies is the use of anti-CRP antibodies in the detection of
CRP binding to FcγRIIa, thus possibly causing false-positive
results due to IgG contamination of the CRP reagent.69 Fur-
thermore, a recent review claims that CRP does not interact
at all with FcRs.70
 i n f l a m m at ion, c-r e ac t i v e p rot e i n, a n d v u l n e r a bl e p l aqu e s
Attempting to resolve this controversy, Manolov et al.71
used a different technique (ultrasensitive fluorescence micro-
scopy) to study the association, dissociation, and equilibrium
of CRP binding to FcγRIIa. In this report, the authors
demonstrated that CRP indeed binds to FcγRIIa with low
association and dissociation rates, thus providing the first
quantitative characterization of CRP binding to FcγRIIa.
C-Reactive Protein Production
One of the outstanding unresolved issues about CRP is
the source of production in humans. It has been assumed
that only the liver in response to microbial infection, tissue
injury, and autoimmune disorders synthesizes CRP, as with
other acute-phase proteins. It had been shown that IL-1β,
tumor necrosis factor-α (TNF-α), and IL-6 strongly induced
the expression of CRP in human hepatocytes and in hepa-
toma cell lines.72,73 Moreover, two IL-6 responsive elements
have been identified proximal to the site of initiation of
transcription of the protein.74
More recently, however, several studies expanded the
variety of cell types that could participate in CRP produc-
tion. Two studies have shown that both epithelial cells of the
respiratory tract and renal epithelium can produce CRP
under certain circumstances.75,76 Gould and Weiser75 demon-
strated that CRP is present in secretions of the human
respiratory tract, that human respiratory epithelial cells are
capable of CRP expression, and that this protein may con-
tribute to bacterial clearance in the human respiratory tract.
Jabs et al.76 showed that renal cortical tubular epithelial cells
(TECs) express CRP mRNA and protein after stimulation
with inflammatory cytokines, concluding that inflamed
kidneys represent a novel site of CRP formation in vivo.
Moreover, neuronal cells also seem to be capable of synthe-
sizing acute-phase reactants involved in the pathogenesis of
neurodegenerative disease such as Alzheimer’s disease
(AD).77 These data shed new light on the acute-phase reaction
not merely representing a systemic inflammatory pathway,
but probably being part of the local immune response. The
relevance of these observations to the pathogenesis of athero-
sclerosis is uncertain.
Interestingly, CRP has been observed to colocalize
with the terminal complement complex in atherosclerotic
plaques.51 In this report, however, the authors suggested that
CRP presence is due to deposition from circulating CRP
produced by the liver instead of local synthesis.
In contrast, work by Yasojima et al.53 using different
techniques suggested that cells in the arterial wall synthe-
size CRP. By reverse-transcriptase polymerase chain reaction
(RT-PCR), they detected the mRNAs for CRP and the
classic complement components C1 to C9 in both normal
arterial and plaque tissue, establishing that they can be
endogenously generated by arteries, with plaque levels 10.2-
fold higher than normal artery. By Western blotting, they
showed that the protein levels of CRP and complement pro-
teins were also upregulated in plaque tissue and that there
was full activation of the classic complement pathway. By
in situ hybridization, they also detected intense signals for
CRP and C4 mRNAs in smooth muscle–like cells and mac-
rophages in the thickened intima of plaques, thus not showing
617
specifically the cell type involved in the local generation of
CRP within the arterial wall.
Attempting to address this important question, we re-
cently showed that human coronary artery smooth muscle
cells (HCASMCs), but not human umbilical vein endothelial
cells (HUVECs), can synthesize CRP following stimulation
by inflammatory cytokines.78 The HCASMCs and HUVECs
were stimulated with IL-1β, IL-6, their combination, TNF-α,
or LPS at different concentrations and the cell culture super-
natants were analyzed by high-sensitivity enzyme-linked
immunosorbent assay (ELISA) specific for human CRP. C-
reactive protein production was minimal without stimula-
tion, and incubation of HCASMCs with 50 ng/mL of IL-1β or
10 ng/mL of IL-6 alone led to a small, but significant induc-
tion. Maximal CRP production was observed after the com-
bination of the two cytokines. Tumor necrosis factor-α or
LPS also induced a similar level of CRP production and
showed a dose-response relationship. In contrast, CRP pro-
duction could not be detected in HUVECs following similar
stimulation protocols.
To confirm the results of CRP protein production in
HCASMCs, we also assayed the mRNA levels in HCASMCs
by RT-PCR using specific primers for the CRP. Interleukin-1β
plus IL-6 combination caused a significant increase in CRP
mRNA level compared to baseline. Treatment with LPS and
TNF-α also upregulates the CRP mRNA levels.
Our findings, thus, provided a direct demonstration that
HCASMCs, but not HUVECs, are a source of locally pro-
duced CRP in the arterial wall.78 The locally produced CRP
may directly participate in atherogenesis and the develop-
ment of cardiovascular complications.
More recently, we have also shown for the first time
using an in vitro system that human adipocytes can produce
CRP under similar inflammatory conditions. We have inves-
tigated whether CRP is produced by cells in adipose tissue
in response to inflammatory stimuli in culture, and we have
demonstrated that human adipocytes, but not preadipocytes,
cultured in vitro produce CRP following exposure to inflam-
matory cytokines, such as IL-1β, IL-6, TNF-α, LPS, and
resistin. Moreover, the response to the different molecules
was additive, peaking in adipocytes incubated with all the
stimuli. Interestingly, resistin, the most recently identified
adipocytokine and proposed as an inflammatory marker for
atherosclerosis, also induced an increase in CRP production
by adipocytes.79
These data confirm that the adipocyte, largely thought
to be an inert storage cell whose main function was to
store excess energy in the form of triglycerides, has a
more complex role in the organism, thus suggesting a link
between inflammatory status, obesity, and cardiovascular
events.79
Summary
To better understand the role of CRP as a clinical marker,
we have to wait for more clinical data; in particular, the
results of the Jupiter trial will help regarding the use of
serum CRP values to guide initiation of lipid-lowering
therapy in a primary prevention population deemed to be at
low cardiovascular risk by means of current criteria.
618 chapter
The development and the use of a direct CRP inhibitor
and a better comprehension of the in vitro biologic effects,
along with more in vivo data, will help clarify the role played
by CRP in the development of the atherosclerotic process.
Further studies investigating other source(s) of CRP
important for the cardiovascular system (vascular CRP, from
adipose tissue, from other component of the atherosclerotic
plaque) should provide more information about this molecule
and its biology.
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2 Atherosclerotic
7 Vulnerable Plaques:
A Pathophysiology,
Detection, and Treatment
Mohammad Madjid, Samuel Ward Casscells, and
James T. Willerson
Pathologic Features of Culprit Lesions Responsible
for Acute Coronary Syndromes . . . . . . . . . . . . . . . . .
Histopathologic Features of Culprit Lesions. . . . . . . . . .
“Vulnerable Blood” and the Role of the
Coagulation System . . . . . . . . . . . . . . . . . . . . . . . . . . .
Use of Inflammatory Biomarkers for Detection
of High-Risk Patients. . . . . . . . . . . . . . . . . . . . . . . . . .
Key Points
• Atherosclerotic plaque ulceration and fissuring lead to
thrombosis and vasoconstriction.
• Local coagulation factors and blood components, in
addition to plaque fissuring and ulceration, contribute
to determining the development of thrombosis.
• Several different imaging procedures, including intra-
vascular ultrasound, elastography, thermography, optical
coherence tomography (OCT), magnetic resonance
imaging (MRI), and computed tomography (CT) are being
developed to detect vulnerable atherosclerotic plaques.
• Although it is variable among patient groups, perhaps
20% to 40% of patients with acute coronary artery
syndromes have more than one vulnerable plaque,
suggesting a relatively widespread inflammatory state
within the coronary arteries.
Cardiovascular disease is the leading cause of death for
both men and women in the United States and most other
developed countries.1 Its rate is rapidly rising in developing
countries, and will become the leading cause of death
worldwide by 2010.2 In the majority of cases, atherosclerosis
is the primary pathologic mechanism responsible for coro-
nary artery disease, ischemic stroke, and peripheral vascular
disease. Acute coronary syndromes (unstable angina, acute
Detection of Vulnerable Plaques: The Need for
623 New Imaging Techniques . . . . . . . . . . . . . . . . . . . . . . 624
623 Imaging of Vulnerable Plaques: Invasive Methods . . . . . 625
Noninvasive Imaging of Vulnerable Plaques. . . . . . . . . . 628
624 Treatment of Vulnerable Plaques . . . . . . . . . . . . . . . . . . . 630
Avoiding “Triggers” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
624 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
myocardial infarction, and sudden cardiac death) often
develop following superimposition of an arterial thrombus
and dynamic coronary vasoconstriction over an underlying
disrupted atherosclerotic plaque. Luminal narrowing by
inward-growing atherosclerotic plaques (sometimes exagger-
ated by coronary spasm) cause the ischemic manifestations
of coronary heart disease. This process is often complicated
by formation of a mural or occluding thrombus over the
atherosclerotic lesion. Coronary thrombosis is a key event
in the development of acute myocardial infarction. First
suggested in 1912 by James Herrick, the pivotal role of
thrombosis in the development of unstable angina and
myocardial infarction was finally confirmed through experi-
mental studies in animals, and angiography and angioscopy
studies in humans the last two decades of the 20th
century.3–6
Atherosclerosis is an inflammatory disease resulting
from acute or multiple repeated injuries inflicted upon
the endothelium and arterial wall, beginning early in
life.7–10
High plasma concentrations of low-density lipoprotein
(LDL) cholesterol, elevated blood pressure, diabetes, smoking,
elevated homocyst(e)ine level, oxidant stresses, systemic
and local inflammation, infections, low high-density lipo-
protein (HDL), and other factors (e.g., trauma, radiation, psy-
chosocial stress, hypercoagulability, and anatomic locations
6 21
622 chapter
that confer abnormally high or low shear stress) play impor-
tant roles in atherogenesis and development of plaques.
Together these variables account for the majority of cases.
The search for the remaining attributable risk is focused
on both genetic and lifestyle factors. Polymorphisms that
have modest associations with coronary atherosclerosis have
been described for genes involved in lipoprotein metabolism,
hypertension, inflammation, oxidation, and regulation of the
cell cycle, as well as in genes not known to be involved in
atherosclerosis, and in genes of unknown function.11,12 Some
of these associations have been found in one kindred and not
in others.
A complex set of inflammatory cytokines and different
cellular components are involved in initiation and progres-
sion of atherosclerosis (Fig. 27A.1). Persistent endothelial
injury leads to monocyte recruitment, macrophage infiltra-
tion, activation of T cells, mast cells, and recruitment of
dendritic cells (rarely neutrophils), each contributing to and
aggravating the inflammatory state in the plaques.13–15
Chronic inflammation in plaques inhibits the production of
collagen by the smooth muscle cells and, at the same time,
enhances collagen breakdown by increasing the release of
matrix metalloproteinases and decreasing the activity of
FIGURE 27A.1. A complex set of inflammatory cytokines derived from different cellular components (macrophages, smooth muscle cells,
platelets, endothelial cells, dendritic cells, T lymphocytes, and mast cells) play roles in initiation and progression of atherosclerosis.
27A
proteinase inhibitors.13,16,17 This sequence of events eventu-
ally results in the weakening and thinning of the fibrous cap,
particularly at the shoulder area of the plaque where a larger
number of inflammatory cells are usually present.18 A weak-
ened fibrous cap, coupled with high mechanical stress (again
higher at the plaque shoulder) may eventually lead to disrup-
tion of the fibrous cap and plaque rupture.19
Disruption of plaque surface or endothelium denu-
dation exposes the underlying highly thrombogenic tissue-
factor–rich matrix to circulating platelets and white blood
cells.20 These changes, usually associated with platelet
adhesion and aggregation, coupled with the release of
prothrombotic and proinflammatory cytokines, and dy-
namic vasoconstriction initiate the coagulation cascade and
chain of events leading to transition of a stable plaque
to an unstable plaque, often accompanied by thrombus
formation and resulting clinical syndromes.21 Several differ-
ent platelet- and non–platelet-derived mediators, including
thromboxane A 2, serotonin, adenosine diphosphate (ADP),
thrombin, tissue factor, oxygen-derived free radicals, plate-
let-activating factor, and endothelin contribute to throm-
bosis formation and vasoconstriction in injured arteries
(Fig. 27A.2).22–28
 at h erosclerot ic v u l n er a ble pl aqu es 623
TABLE 27A.1. Pathologic features commonly associated with
vulnerable plaques
Large lipid pool (>40% plaque volume)
Thin fibrous cap (<65 μm)
Macrophage infiltration
Activated T cells and mast cells
Outward remodeling
Decreased collagen content of cap
Necrotic core
Increased neoangiogenesis
Calcium nodule

Histopathologic Features of Culprit Lesions

Most of our current knowledge about atherosclerotic lesion-
induced coronary thrombosis, rapid lesion progression, or
symptomatic disease is derived from retrospective autopsy
studies.31,33,39 The plaques in these studies are often called
“culprit lesions.”
Histologically, the culprit lesions often show one of the
following features:
Plaque rupture: A ruptured plaque is the most common cause
of coronary thrombosis and is responsible for 60% to 70%
of cases of sudden cardiac death (SCD) or acute myocardial
infarction (AMI). Ruptured plaques present with a deep
plaque injury and a significant, real defect or gap in the
fibrous cap. This defect often exposes the thrombogenic
FIGURE 27A.2. Several different platelet- and non–platelet-derived plaque tissue to blood.31,39,40 These lesions often demon-
mediators including thromboxane A 2, serotonin, adenosine diphos- strate a large lipid pool (>40% plaque volume), a necrotic
phate (ADP), thrombin, oxygen-derived free radicals, platelet-
core, a thin fibrous cap (<65 μm), large number of macro-
activating factor, and endothelin contribute to thrombosis for-
mation and vasoconstriction in injured arteries. phages, outward remodeling, decreased collagen content
of cap, and increased neoangiogenesis (Table 27A.1). Ret-
rospective studies suggest that a thin-cap fibroatheroma
(TCFA) closely resembles a ruptured plaque and can be
considered as a prototype rupture-prone lesion (Fig. 27A.3)

Pathologic Features of Culprit Lesions

Responsible for Acute Coronary Syndromes
Retrospective autopsy studies since the 1960s have demon-
strated that a majority of sudden cardiac death and myo-
cardial infarction cases arise from coronary lesions,
demonstrating rupture or erosion and often showing consid-
erable degrees of inflammation, yet causing percent area
stenosis of only 70% to 90%, corresponding to 50% to 70%
diameter stenosis.29–35 First introduced in 1989, the terminol-
ogy and definition of vulnerable plaques have been consis-
tently debated and updated.36,37 The latest consensus by
experts in the field 38 has suggested the following terminol-
ogy: Lesions at an increased risk for thrombosis or rapid
progression are called “vulnerable” or “high-risk” plaques.38
The term thrombosis-prone may also be applied to such
plaques. These terms mainly describe the concept and
function of these lesions and do not present their histologic
characteristics. Patients may be considered “high risk” or
FIGURE 27A.3. Histopathologic features of vulnerable atheroscle-
“vulnerable” based on the presence of high-risk/vulnerable rotic plaques include a thin fibrous cap, a large lipid core, mild to mod-
plaques, or high-risk blood, or an increased conventional risk erate deep calcification, outward remodeling, neovascularization, and
factor profile.38 infiltration of inflammatory cells especially at the shoulder region.
624 chapter 27A

and a culprit for the majority of acute coronary syndromes
(ACSs). Many of these features have been used as targets
for diagnostic imaging techniques that will be described
later.41,42
Plaque erosion: Eroded plaques are more often observed in
younger smoking women.32,39 Plaque erosion features a
loss or dysfunction of endothelium, with no disruption
of the fibrous cap. These lesions do not show any struc-
tural defect or gap in the plaque, which is often rich in
smooth muscle cells and proteoglycans.35
Calcified nodule: A plaque with a calcified nodule is an
uncommon type of plaque and is responsible, at most, for
5% of acute coronary events. These lesions are character-
ized by heavy calcification and the loss or dysfunction of
endothelial cells over the calcified nodule.35
“Vulnerable Blood” and the Role of the
Coagulation System
Vulnerability of individuals to develop a clinical coronary
event not only is dictated by the presence of vulnerable
plaques, but also is affected by the status of their coagulation
system and the vulnerability of their myocardium to isch-
emic events. Vulnerable plaques and even ruptured plaques
may be found in people with no symptoms prior to their
myocardial infarction (MI). A rupture may occur at a time
when the patient’s blood is less prone to coagulation. In fact,
longitudinal studies of subjects with ruptured plaques in
their coronary arteriograms have shown a low incidence of
clinical events when they are vigorously treated with plaque-
stabilizing medications, such as statins and antiplatelet
medications.43 Coagulation may be affected by genetic dif-
ferences, diet, smoking, homocysteine levels, viscosity, and
use of different medications. There is a strong interaction
between the coagulation system and the inflammatory
processes, and their dual inhibition is an important step in
stabilizing vulnerable patients.10 Local factors, such as spasm,
stenosis, proximal location of the lesion, and shear stress
may affect thrombosis development propensity as well.
In fact, individuals vary in their genetic levels of protein
S, protein C, or activated protein C (e.g., factor V Leiden).
Moreover, even in the same individual, susceptibility to
thrombosis may substantially fluctuate over time. In fact,
animal studies have shown that individual propensity for
Use of Inflammatory Biomarkers for Detection
of High-Risk Patients
For information on this subject, see Chapter 27B.
Detection of Vulnerable Plaques: The Need for
New Imaging Techniques
Almost half of the cases of MI present as SCD with no prior
diagnosis of coronary artery disease.47,48 This suggests that
our current clinical evaluation methods (e.g., risk factor
charts, electrocardiography, angiography, and stress tests) fail
to accurately identify either vulnerable lesions or vulnerable
patients.
For decades, coronary arteriography has been the “gold
standard” technique for identifying atherosclerotic coronary
lesions and guiding in lesion-specific treatments for isch-
emic heart disease. However, serial angiogram studies in the
mid-1980s showed that up to two thirds of AMIs develop
from culprit lesions with a luminal diameter narrowing of
often <50% and without hemodynamic significance (Fig.
27A.4).49–53 In a series of classic studies, Glagov et al.54 showed
that human coronary arteries enlarge in relation to plaque
area, and therefore plaque mass (at least in lesions with <40%
cross-sectional luminal narrowing) is not correlated with
lumen size in humans. Indeed, a study by Naqvi, Shah, and
colleagues55 examined the perfusion imaging stress tests of
patients who subsequently had nonfatal MI. Only 60% of the
infarcts developed in a territory that was ischemic on the
prior study, which exceeds the 33% random expectation but
is far below the expected 100%. Techniques are needed to
identify those particular lesions that may not be stenotic, but
are at increased risk of developing an acute complication in
the near future.41
This challenge becomes more serious when one considers
the fact that these less-severely stenotic plaques are 5 to 10
times more common than severely stenotic plaques.13 In fact,
asymptomatic atherosclerotic lesions may be found in a large
200
180 27

arterial thrombosis may be more influenced by blood compo- 160

nents than by elements within the arterial wall.44 In addition
Number of MI patients

35

to the proinflammatory and prothrombotic state of athero- 140

sclerotic plaques, the loss of the normal thrombotic–throm- 120
bolytic equilibrium in the circulating blood, and local flow 100
conditions, play major roles in thrombosis formation. Coagu- 12
80
lation is more likely after ingestion of a fatty meal, smoking, 8
132
dehydration, lack of physical activity, many infections, use 60
of estrogens, stress, presence of adenocarcinoma, polycythe- 40 1
10 72
13
mia, thrombocytosis, hyperhomocyst(e)inemia, increased 20 5
6
7
circulating pool of tissue factor (TF), factor V and VII, high 11
27 23

lipoprotein (a) [Lp(a)] levels, and discontinuation of antithrom- 0 Little et al 1988 Nobuyoshi et al 1991 Giroud et al 1992
Ambrose et al 1988 ALL

botic or antiinflammatory medication.45,46 In addition to dif- <50% 50-70% >70%

ferences in the thrombotic diathesis of the patient’s plasma, FIGURE 27A.4. Majority of acute myocardial infarctions develop
coagulation will be favored by low shear stress, slow flow due from culprit lesions with a luminal diameter narrowing of often
to spasm, mural thrombosis, embolism or stenosis. <50% and without hemodynamic significance.53
 at h erosclerot ic v u l n er a ble pl aqu es
FIGURE 27A.5. Different diagnostic methods for detection of vul-
nerable plaques. Counterclockwise: Magnetic resonance imaging
(MRI), computed tomography (CT) scan, angiography, intravascular
number of people, even in the very early years of life. Ath-
erosclerosis develops in early childhood as fatty streaks along
the arterial tree, and progresses toward more advanced lesions
over the years. This was first described by William Osler,56
and later described in detail by Enos et al.,57 McNamara et
al.,58 and others59,60 who showed the presence of atheroscle-
rotic coronary artery disease in young U.S. soldiers killed
during the Korean and Vietnam Wars. These findings were
later confirmed in the Pathobiological Determinants of Ath-
erosclerosis in Youth (PDAY) and the Bogalusa studies, which
showed that atherosclerosis originates in childhood and is
related to the presence of coronary artery disease (CAD) risk
factors.59,60 This has been observed in other countries as
well.61 More recent studies using in vivo diagnostic tech-
niques, such as intravascular ultrasonography (IVUS) have
also shown a high prevalence of atherosclerotic lesions in
asymptomatic subjects.62 Using IVUS in asymptomatic
transplant donors, Tuzcu et al.62 found coronary atheromas
in 17% of donors younger than 20 years, 37% of those aged
20 to 29 years, and 60% of those aged 30 to 39 years, whereas
arteriography failed to find lesions in 97% of these individu-
als. Despite the high prevalence of atherosclerotic disease
in adults, only a relatively small fraction of these indivi-
duals develop cardiovascular complications. Therefore, new
imaging techniques need not only to detect the anatomic
presence of often nonsignificant lesions, but also to deter-
mine the functional characteristics associated with their
vulnerability.
625
ultrasound (IVUS), angioscopy, optical coherence tomography
(OCT), thermography, virtual histology, near-infrared (NIR).
Multiple new technologies for in vivo characterization of
vulnerable plaques in patients are under development (Fig.
27A.5).41 These new techniques focus on one or more histo-
logic or functional features of vulnerable plaques (e.g., struc-
ture, composition, deformability, cellular density, chemical
composition, metabolic state, temperature, etc.).
Imaging of Vulnerable Plaques:
Invasive Methods
Coronary Arteriography
First introduced in 1958, coronary arteriography has been the
method of choice for assessment of luminal stenoses in coro-
nary artery lesions. However, it has limited spatial resolution
and is unable to detect fine calcification and fine irregulari-
ties of the luminal surface, including fissuring and superfi-
cial thrombosis. Most importantly, however, arteriography,
by virtue of its reliance on luminal contrast, is in fact a
“luminography” technique and reveals almost nothing about
the plaque contents and thus, using current equipment and
techniques, angiographers are not able to assess plaque
inflammation, cap thickness, or the size of the lipid pool.
Nevertheless, several arteriographic features have been
shown to be of prognostic importance. These arteriographic
predictors of lesion progression include the presence of throm-
bosis,63,64 ulcerated lesions,65 irregular surface, and long
626 chapter
lesions.63,66 Coronary spasm could predict progression in a
few studies67,68 but not others.69 Lesions in the right coronary
artery (RCA) and the left anterior descending (LAD) are also
more prone to progress.66,67 A proximal location and a branch
point position, or being on the inner curve of a vessel (or other
region of abnormally low shear stress such as a “shelf”)
are also predictors of progression.49 Recently, “blush sign” or
transient retaining of faint contrast in the plaque after passage
of the dye column (possibly reflecting fissuring or neovascu-
larization) has been described as a strong predictor of progres-
sion in hemodynamically insignificant lesions.70
Intravascular Ultrasound
Intravascular ultrasound (IVUS) uses miniaturized crystals
incorporated at catheter tips and provides real-time, cross-
sectional and longitudinal, high-resolution images of the
arterial wall with three-dimensional (3D) reconstruction
capabilities.71 The safety of this technique is well estab-
lished.72 It is a widely available technology and is increas-
ingly used routinely in clinical practice and for research
purposes. Common two-dimensional (2D) IVUS images use
ultrasound frequencies in the range of 20 to 40 MHz and
generate an axial resolution of 100 to 200 μm and a lateral
resolution of 250 μm. Intravascular ultrasound allows precise
tomographic measurement of lumen area and plaque size,
distribution, and, to some extent, composition.73 It provides
valuable information on the remodeling state of the artery,
presence of thrombi, and, to some extent, the content of
plaque. Plaques can be characterized as echoreflective (cor-
responding to calcified plaque), hyperechoic (representing
fibrous plaque), and hypoechoic (indicating a lipid-rich core).
Intravascular ultrasound can detect macrocalcification three
times better than angiography; however, it has lower sensi-
tivity for lipid-rich than calcified lesions.73
There are disadvantages to using IVUS. The currently
available systems do not have enough resolution to visualize
vulnerable plaque caps. Intravascular ultrasound is not able
to accurately image the area behind calcified regions because
of their acoustic shadows and does not provide information
about the activity of the plaque and inflammation.74 Intra-
vascular ultrasound has a very low sensitivity to detect
microcalcification areas of <0.05 mm, and only 37% sensitiv-
ity to detect plaque rupture. In fact, IVUS cannot distinguish
caps thinner than approximately 0.4 mm, whereas pathologic
studies indicate that almost all ruptured plaques are thinner
than 0.075 mm.75,76
In IVUS studies, ruptured plaques are found in most
patients with MI, in about half with unstable angina, and in
a minority of patients with stable angina.77 Ge et al.78 used
IVUS to study 42 patients with unstable angina pectoris and
102 patients with stable angina pectoris. Intravascular ultra-
sound identified 29 ruptures (only a third of which were
identified by angiography). No patient had more than one
ruptured plaque. Of the 102 patients with stable angina pec-
toris, eight had a ruptured plaque. The disrupted plaques
averaged 56% diameter stenosis versus 68% for the nondis-
rupted but symptomatic plaques. The disrupted plaques also
had a thinner cap (0.47 ± 0.2 mm vs. 0.96 ± 0.94 mm), a larger
echolucent area, and were more likely to be eccentric (94 vs.
64%). Of the patients with unstable angina, 21 exhibited
27A
rupture, one had an erosion, and 20 had neither. Arteriogra-
phy was not as sensitive as IVUS in detecting rupture.78
Intravascular Ultrasound Elastography
Intravascular ultrasound elastography technology is based on
the differences in hardness and elasticity of tissues with dif-
ferent histopathologic composition. This technique assesses
the conformational change in coronary plaques resulting
from intracoronary pressure changes during the cardiac
cycle. By measuring the local strain over the plaque, this
technique can discriminate between soft and hard tissues.
Intravascular ultrasound elastography combines ultrasound
images with radiofrequency measurements to detect regions
of increased strain that have been shown to be vulnerable to
rupture. Elastography can assess the mechanical properties
of the arterial wall, and soft, vulnerable plaques have a higher
strain level than hard plaques. Fibrous caps of vulnerable
plaques have a high strain level and, by discriminating lipid-
rich plaques from fibrous ones, elastography can be used for
detection of plaques at risk of rupture.79,80 Ex vivo studies
have shown that measured strain is positively correlated
with the number of macrophages and is inversely correlated
with the number of smooth muscle cells.81 In vivo pig studies
have demonstrated the accuracy of IVUS elastography in
identifying lipid-rich plaques and macrophages. Fatty plaques
show higher strain compared to fibrous lesions, and high-
strain plaques have abundant macrophages.82
Integrated Backscatter
Intravascular Ultrasound
Integrated backscatter (IB) IVUS combines IB with conven-
tional 2D echo and construction of color-coded maps of arter-
ies to provide additional information about plaque composition
and aid in detection of vulnerable plaques.83 Intravascular
ultrasound, by relying on echo intensity alone, cannot accu-
rately differentiate lipid cores from fibrous tissue. In IB IVUS,
variables of the radiofrequency envelope generated from ex
vivo plaque have been correlated with histologic features of
plaque vulnerability to develop modified algorithms, which
assist in detection of the lipid-rich plaques believed to repre-
sent vulnerable plaques. 83 Increasing the transducer frequency
(40 MHz) and high sampling rate (2 GHz) allows detailed anal-
ysis by use of IB measurement. In vivo application of IB IVUS
has been shown to improve the resolution to about 40 μm.84
However, the resolution of this technique undergoes a signifi-
cant reduction as imaging moves off axis.84
Coronary Angioscopy
Intracoronary angioscopy uses a fiber optic to transmit the
visible light and provides a small field of view from the
interior surface of coronary arteries. Angioscopy has been
reported by several groups to be more sensitive than angiog-
raphy or intravascular ultrasound in detecting thrombosis
and fissuring.42,85,86 Angioscopy permits direct visualization
of the arterial surface, presence of thrombi, plaque color (red,
white, or yellow), and endothelial disruptions (tears, ulcer-
ations, and fissures).87 Specific color patterns of coronary
plaques as detected by angioscopy have been correlated with
different clinical coronary events. On angioscopy, the normal
 at h erosclerot ic v u l n er a ble pl aqu es
artery appears as glistening white. In histologic studies,
yellow plaques often show high concentrations of choles-
terol-laden crystals with a thin cap and smooth white plaques
generally have a thick fibrous cap. Yellow lipid-laden
plaques—undetected by angiography—are more common in
patients with AMI and unstable angina.88 These plaques
often show surface irregularity and an intimal flap because
of rupture or ulceration. In patients with old MI and stable
angina, smooth white lesions (presumed to be more fibrotic)
are frequently observed. Acute coronary syndromes occur
more often in patients with glistening yellow plaques than
in those with non–glistening yellow plaques.87
Angioscopy catheters are too large to use in small-caliber
vessels or cross-stenotic lesions. Angioscopy is unable to
provide the deeper plaque characterization afforded by ultra-
sound and furthermore is limited by the need to inflate a proxi-
mal balloon or flush saline solutions to provide a blood-free
visual field. This can create ischemia, limiting viewing time.
More importantly, inflation at the proximal major coronary
arteries may preclude the evaluation of those critical seg-
ments. Another major drawback is the subjective method of
color-lesion interpretation for which a number of automated
colorimetric systems are under development. Nevertheless,
angioscopy continues to provide important information
about coronary syndromes and vulnerable plaque.89,90
Optical Coherence Tomography
Optical coherence tomography (OCT) employs a laser (near-
infrared) beam as the light source that is directed to and
reflected back from the tissue. Optical coherence tomogra-
phy measures the intensity of the reflected infrared light and
has a remarkable resolution of 10 to 20 μm.91,92 Current tech-
niques have a penetration depth of 1 to 2 mm. Studies have
validated the ability of OCT in measuring cap thickness and
differentiating lipid-rich tissue from fibrous and calcified
tissues.91,92 This technique has often been quoted as “optical
biopsy.” An autopsy study has shown remarkable ability of
OCT to detect and quantify cell density within the fibrous
cap, though this ability is mainly limited to the most super-
ficial regions of the plaques.93 Optical coherence tomography
is comparable to high-resolution IVUS in its ability to detect
plaques and discriminating fibrous from calcified plaques.
Moreover, OCT has a higher resolution than IVUS, allowing
it to identify intimal hyperplasia, internal and external
elastic laminas, and histologic features of vulnerable plaques
not detected by IVUS.94
The major limitation with OCT imaging is the need for
proximal occlusion as the presence of blood significantly
reduces the OCT image quality. It also has limited tissue
penetration. Optical coherence tomography is currently
being tested in multiple human clinical trials and its poten-
tial combination with polarization imaging, spectroscopic
analysis, or elastography may further enhance its ability to
detect vulnerable plaques.42
Intravascular Thermography
Heat, as a sign of inflammation, can be used to locate foci of
inflammation in the arterial wall.95 Inflamed vulnerable
plaques may give off more heat as they usually show an
627
abundance of macrophages and T cells that are known to be
metabolically active with high consumption of glucose and
O2, and high thermogenesis.96 Thermal heterogeneity of
living carotid atherosclerotic plaques, examined ex vivo, was
first described in 1996 by Casscells et al.95 and Willerson’s
group97 (Fig. 27A.6). Stefanadis and colleagues98 described 26
patients with MI in whom thermography revealed marked
temperature heterogeneity. Plaque temperature heterogene-
ity was present in 20%, 40%, and 67% of the patients with
stable angina, unstable angina, and AMI, respectively, and
did not correlate with the degree of stenosis. Temperature
heterogeneity was absent in the control group. Among the 30
patients with stable angina pectoris, some had uniform tem-
peratures like the patients without coronary disease, but a
few had culprit plaques with lesions as warm as 0.2°, 0.3°, or
even 0.5°C above the reference temperature elsewhere in the
vessel.98 The temperature heterogeneity correlates not only
with symptoms but also with serum levels of C-reactive
protein (CRP) and serum amyloid A.99 In a follow-up study
after patients undergoing angioplasty, temperature was a pre-
dictor of adverse events.100 In this study, the mean tempera-
ture of the culprit plaque in patients with stable angina
pectoris who had an adverse event in follow-up was 0.5°C,
versus 0.1°C in patients without an event.100 Stefanadis and
colleagues101 also showed that coronary temperature hetero-
geneity is decreased by statin therapy.
More recently, lesser degrees of temperature heterogene-
ity have been reported by Verheye et al.,102 Webster et al.,103
Schmermund et al.,104 Dudek et al.,105 perhaps because a
larger proportion of their patients were taking antiinflam-
matory medications or statins, and in addition, their
thermography techniques do not obstruct flow, whereas
the larger thermistor used earlier by Stefanadis often
“wedges” the lesion and reduces blood flow. It should be
noted that blood flow can potentially attenuate the measured
temperature heterogeneity over the atherosclerotic plaque.
That complete obstruction of blood flow may markedly
increase the degree of detected temperature heterogeneity
and proximal occlusion of the artery by use of a balloon has
26.4 27.6
26.9
25.9
29.2
29.6
28.3
FIGURE 27A.6. Endarterectomized carotid plaques show tempera-
ture heterogeneity (all temperatures are °C).
628 chapter
been suggested as a method to improve the temperature
reading from arterial wall.
Toutouzas et al.106 reported a good correlation between
remodeling index (defined as the ratio of the external elastic
membrane area at the lesion to that at the proximal site
determined by intracoronary ultrasound) and temperature
difference between the atherosclerotic plaque and the healthy
vessel wall in patients with acute coronary syndromes. They
also showed that serum matrix metalloproteinase 9 (MMP-9)
concentration is correlated with temperature difference in
patient’s ACSs.107 Temperature heterogeneity is associated
with vascular remodeling, which is, by itself, associated with
local inflammation in plaque.108
Verheye et al.102 examined the relation of clinical presen-
tation to the number of hot lesions. On average, half of the
patients with stable angina pectoris had a hot lesion, versus
an average of one lesion per patient with unstable angina and
two hot lesions per patients with MI. They also demonstrated
that temperature heterogeneity is determined by plaque com-
position and macrophage mass. They randomized 20 New
Zealand rabbits to receive 6 months of either a normal diet
(n = 10) or a cholesterol-rich (0.3%) diet (n = 10). At 6 months,
10 control rabbits and five hypercholesterolemic rabbits were
euthanized, and the five remaining rabbits were put on a
normal diet for 3 months.109 In the hypercholesterolemic
rabbits, marked temperature heterogeneity (up to 1°C) was
observed at sites of thick plaques with high macrophage
content, but no temperature heterogeneity was seen in
plaques with low macrophage content. Interestingly, in
rabbits who received 3 months of a low-cholesterol diet,
plaque thickness remained unchanged, but the macrophage
content decreased significantly.109
Thermography is currently under evaluation in human
clinical trials in New Zealand, Brazil, Europe, Japan, and the
U.S. Human clinical trials will determine the safety, repro-
ducibility, and clinical utility of this method. If approved by
the U.S. Food and Drug Administration, it may be used to
detect vulnerable plaques and to predict the risk of vulnera-
ble lesions and vulnerable patients. Its combination with
palpography, IB IVUS, OCT, and other techniques is cur-
rently being examined.
Noninvasive Imaging of Vulnerable Plaques
Magnetic Resonance Imaging
High-resolution magnetic resonance imaging (MRI) is a
promising method for noninvasive imaging of vulnerable
plaques. During MRI studies, the patient is subjected to a
high local magnetic field [e.g., 1.5 tesla (T)], which aligns the
protons. A radiofrequency pulse excites these protons, which
in turn emit a signal that can be detected by receiver coils.
Detected signals are influenced by the relaxation times (T1
and T2), proton density, motion and flow, molecular diffu-
sion, magnetization transfer, changes in susceptibility, etc.86
Magnetic resonance imaging of the atherosclerotic
plaques is influenced by the signal intensity, contrast, and
lack of noise.86 Magnetic resonance imaging can differentiate
plaque components based on their biophysical and biochemi-
cal parameters, such as chemical composition and concentra-
27A
tion, water content, physical state, molecular motion, or
diffusion.86 It provides imaging without using ionizing radia-
tion and can be safely repeated sequentially over time to
monitor progression or regression of atherosclerotic lesions.86
It has been used to detect atherosclerotic plaques (and assess
effect of lipid-lowering drugs on plaques) in animal models.
Magnetic resonance imaging has been used with success
to study atherosclerotic plaques in human carotid, aortic,
peripheral, and coronary arterial disease and for in vivo
visualization of arterial thrombi.110 Superficial location and
immobility of carotid arteries have made them especially
suitable targets for MRI studies.111 Magnetic resonance
imaging has been used to assess the effect of lipid-lowering
therapy (statins) in hypercholesterolemic patients. A signifi-
cant regression of atherosclerotic lesions was observed after
12 months of statin therapy.112 Interestingly, a decrease in the
vessel wall area occurred in absence of significant changes
in the lumen area.113,114
Better visualization of the arterial wall may be achieved
by use of preparatory pulses that render the signal from the
blood flow black. This method has been used to study human
carotid artery, aorta, and coronary arterial lumen and wall.115
Magnetic resonance spatial resolution can be improved with
higher field strength magnets (e.g., 3 T), surface coils, intra-
coronary antennae, or superconductivity. Recently, several
groups have reported that plaque macrophages can be imaged
by their uptake of iron-containing nanoparticles.116 Tagging
gadolinium or iron oxide particles with LDL or plaque-
specific antibodies are other opportunities for molecular
imaging of atherosclerosis.
Magnetic resonance imaging is more time-consuming
and expensive than computed tomography, and some
patients are ineligible by virtue of pacemakers or other
embedded metal, but it has extraordinary potential for plaque
characterization.117,118
Computed Tomography Imaging
Autopsy studies have consistently demonstrated that calci-
fication is a common complication of advanced atherosclero-
sis. Multiple clinical studies have demonstrated that this
calcification can be detected by fluoroscopy and more accu-
rately and quantitatively by fast-gated spiral computed
tomography (CT), electron-beam CT (EBCT), or multidetec-
tor CT (MDCT).119 The EBCT machines use a focused elec-
tron beam targeted at two detector rings positioned in a
semicircle fashion underneath the patient. This technique
produces arterial slice images as thin as 3 mm. Electron-
beam CT needs about 30 to 40 slices (during one or two sepa-
rate breath-holds) from the aortic root to the apex of the heart
to measure coronary calcium.86 Multidetector scanners
utilize multiple rows of detectors, which move in a helical
motion around the patient and can image multiple simulta-
neous sections at higher speeds. The radiation dose of EBCT
is less than that of MDCT.
Although EBCT offers a better temporal resolution and
fewer motion artifacts, MDCT has better spatial resolution,
less noise, and higher speed. The first multislice CT scanners
were introduced in the early 1990s and were improved over
time. Newer 64-detector CT scanners can perform 64 slices
per rotation with a resolution of 0.4 mm in only a few seconds
(5 to 13 seconds), even allowing evaluation of patients with
 at h erosclerot ic v u l n er a ble pl aqu es
severe pulmonary disease and congestive heart failure in one
breath-hold. Short duration of scanning also minimizes
motion artifacts. Their high resolution allows visualization
of the entire coronary tree with high accuracy. They can be
used to assess the overall calcium burden, and to detect and
characterize individual atherosclerotic plaques. Moreover,
when used in conjunction with contrast media, MDCT can
assess blood flow, evaluate dimensions of the lumen and
arterial wall, and characterize arterial wall with high resolu-
tion. Coronary calcium assessments by EBCT and MDCT
systems show good correlation.120
Coronary artery calcium (CAC) is a predictor of an
increased risk of coronary heart disease (CHD) events.
Calcium is present in atherosclerotic coronary arteries and
can be quantified quickly and noninvasively with EBCT or
MDCT. Histopathologic studies have shown a close correla-
tion between whole heart, coronary artery, and segmental
coronary atherosclerotic plaque area and EBCT coronary
calcium area. However, coronary calcium below a threshold
value of 130 Hounsfield units may not be detectable by
EBCT.121 The CAC score may be used to estimate the burden
of atherosclerosis in coronary arteries. The role of calcifica-
tion in plaque vulnerability is controversial. Although some
authors have found calcified regions in association with
adverse clinical events,39 others have suggested that plaque
calcification may actually represent stabilized plaques, as
many high-risk plaques often lack calcium.
Nevertheless, a few studies have shown that CAC is an
independent predictor of future CHD events.122–125 Calcium
scoring is increasingly being used in primary or secondary
risk assessment, and it may prove to be useful in identifying
vulnerable plaques and vulnerable patients.126 A high calcium
score is a sensitive but not a specific marker for coronary
stenosis. A recent meta-analysis of four large studies showed
that calcium score is an independent predictor of cardiovas-
cular events with a relative risk of about 2.1 in persons with
low amounts of CAC (i.e., CAC score, 1 to 100) and much
higher relative risks in persons with high CAC scores (>400)
than in those with no evidence of CAC.127
Currently, the primary goal of coronary calcium screen-
ing is to aid in risk stratification of subjects who are at
intermediate risk based on Framingham tables. It is also
assumed that knowledge of CAC score may further encour-
age patients to adhere to their therapeutic regimen.
Low-density lipoprotein lowering with statin drugs can
slow (and sometimes halt or even reverse) the progression of
atherosclerosis measured as an increase in mean calcium-
volume score over a 12-month period.128 However, more data
are needed before concluding that this decrease in CAC
progression will be translated into a reduction in clinical
events.129
Increasing use of calcium scanning has raised some con-
cerns. Multidetector CT delivers considerable radiation, and
although it may be justified in high-risk or symptomatic
patients, it should be used in the general population only
after careful assessment of its risk-benefits ratio. In fact,
false-positive test results may lead to unnecessary anxiety
and interventions. The cost of the calcium scan (approxi-
mately $500 to $1000) is another factor that needs to be kept
in mind in clinical decision making; though it is roughly
half that of radionuclide stress testing, it is usually used in
629
conjunction with, but not replacing, stress testing. Thus the
costs are additive.
In theory, the use of calcium scoring appears to identify
persons with preclinical coronary disease, some of whom are
not identified by careful review of symptoms and physical
examination, stress testing, and laboratory tests including
CRP. It may help select patients for whom statins may
prevent unheralded MI or SCD. It may also identify patients
in need of more dietary advice, and more frequent follow-up
visits. Though these uses of CT are not yet substantiated by
clinical trials, case series attest to the plausibility of these
uses of CT.
Computed tomography angiography (CTA) is easily and
rapidly performed by intravenous injection, and the images
obtained with the 64-slice machines are nearly as good as tra-
ditional but more invasive and more costly arteriograms. One
caveat is that heavily calcified stenoses appear more severe
than they are due to the calcium “blooming” artifact. Another
is that stenoses are judged more severe by CTA because it is
able to identify the true reference diameter, whereas arterio-
grams can underestimate the severity of a stenosis by compar-
ing it to a region with angiographically inapparent disease
(e.g., some patients have no normal areas, only diffuse smooth,
concentric disease mistaken for normal). However, the main
drawback is the inability to perform interventional proce-
dures, which means that some patients must have a second
procedure, which entails more time, cost, dye load, and radia-
tion. Thus, at present, CTA is most often used in the emer-
gency room setting where patients with chest symptoms can
be ruled out for coronary occlusion, pulmonary embolus, and
aortic dissection with a single procedure (albeit one with a
radiation approximately that of 1000 chest x-rays).
As with MR angiography, CT angiography has great
potential as a single comprehensive evaluation of the vulner-
able patient, as follows: First, MDCT should be able to provide
information about the vulnerability of specific plaques;
such plaques are large, remodeled, proximal, located opposite
branch points or in areas that flex, and they retain dye (plaque
“blush”). Although even 64-slice CTA cannot distinguish a
1-mm-thick cap from a 0.1-mm, it may be able to determine
which plaques have a large lipid core. Finally, the new
machines, together with advances in image filtering, may
permit the detection of speckled calcium beneath lipid cores,
which is a feature of high-risk plaques. However, the detailed
evaluation of multiple plaques would prove time-consuming,
and it is not known if such analyses could be automated.
Second, CTA may prove useful—and convenient to both
patient and doctor—in simultaneously evaluating carotid
artery stenosis, aortic plaque and aneurysm, renal artery
stenosis, and iliac stenosis. Detecting these (often unsus-
pected) conditions is useful in its own right and because
some studies suggest that coronary patients with peripheral
disease merit a more aggressive approach.
Third, if the patient has not had a recent echocardiogram,
CTA conveniently provides left and right ventricular size,
shape, regional wall motion, and ejection fraction, left atrial
size and presence of thrombus, valve calcification, and peri-
cardial effusion. Perfusion imaging should soon be possible
as well.
Fourth, MDCT can provide information about pulmo-
nary edema, effusion, infection, embolus, and malignancy.
630 chapter
Lung cancer shares with atherosclerosis such risk factors as
age, smoking, and diet, and thus some patients undergo
bypass surgery and spend several months recuperating only
to have to undergo a procedure for a lung nodule. Such situ-
ations may be avoided by CT screening, which has proven
useful for identifying lung cancer when it is surgically
curable.
Finally, CTA may occasionally detect unexpected disease
in the gallbladder, pancreas, liver, ovary, or kidneys. Careful
clinical trials will be needed to determine whether the fre-
quency and clinical utility of such findings, even with the
apparent convenience and rationale of comprehensive assess-
ment of patient vulnerability, justify the radiation, and offset
other costs.
Treatment of Vulnerable Plaques
Current Therapy
Because there is not yet an accepted way to detect and follow
the course of vulnerable plaques, there is no proven interven-
tion for reducing the risk of plaque rupture, plaque erosion,
or plaque thrombosis per se. However, the risk factors for MI
and angina pectoris are nearly identical in most studies, and
those for SCD are similar; risks of these outcomes have been
reduced, albeit modestly, in most primary and secondary
prevention studies by reducing blood pressure,130–132 choles-
terol levels,133–137 cigarette smoking,138 and adding an aspirin
regimen.49 Some of the benefit is due to a slowing of athero-
genesis and some to a stabilization of vulnerable plaque.
Atherogenesis and vulnerable plaque differ in several respects:
vulnerable plaques are characterized by inflammation, a thin
fibrous cap, a tendency to thrombose, coronary vasoconstric-
tion, calcification, and superficial erosion. These factors are
less closely identified with atherosclerotic progression per se.
Indeed, there is some evidence that the inflammatory process
may have a mixed effect in atherogenesis (the beneficial
effect being the removal of cholesterol from the plaque),
whereas in vulnerable plaques, inflammation is overwhelm-
ingly dangerous. Likewise, exercise probably reduces the risk
of developing vulnerable plaques.
Diet and Dietary Supplements
Diet remains the cornerstone of treatment of cardiovascular
disease because this single approach can reduce hyperten-
sion139,140 (in particular, by reducing intake of salt and increas-
ing that of magnesium and potassium and by reducing
weight) and also in reducing serum glucose and LDL choles-
terol. Other important dietary opportunities, as reviewed by
Hu et al.,141 include the incorporation of more fish in the diet,
which appears to lower the risk of sudden cardiac death
independent of any effect on cholesterol. The substitution of
monounsaturated and polyunsaturated fats for trans fats also
appears to be important.142,143
Other epidemiologic studies suggest that a moderate con-
sumption of alcohol (especially red wine), and of tea rather
than coffee, together with an increased intake of water (pre-
sumably offsetting the atherothrombotic effects of elevated
viscosity) may reduce cardiovascular mortality.144,145 Evi-
27A
dence is likewise suggestive, but not definitive, for the use
of B vitamin supplements (particularly folic acid, B6, and B12)
to lower serum homocysteine levels.146,147 Normalizing
homocysteine, like statins and vitamin C, improves endo-
thelial function, and endothelial dysfunction is a predictor
of clinical events.148
Of particular interest is the Mediterranean diet (or Indo-
Mediterranean diet).149–152 These diets, which are rich in olive
and canola oil, whole grain cereals, fish, and vegetables, have
been shown in randomized trials to reduce the risk of MI
and cardiac death by approximately 50% without altering
LDL and HDL cholesterol levels or body weight. The benefits
begin by 6 months—and by 4 months in the Gruppo Italiano
per lo Studio della Sopravvivenza (GISSI) trial of fish oils.153
Antioxidative, antiinflammatory, and antithrombotic mech-
anisms have been suggested, but in the Lyon Heart Study,
patients were already well treated with standard medications
and the control group was fed a traditional low-fat diet.150
Thus, it is clear that there are factors other than intake of
saturated fat and cholesterol that have an important impact
on cardiovascular outcomes.
As for supplements, vitamins A, E, and C confer no
benefit, though the combination of E and C may offer some
protection as may L-arginine and selenium, though data are
limited. Many patients self-prescribe coenzyme Q10, though
there is no clinical trial that supports this.154–156
Lipid-Lowering Medications
Randomized trials have clearly shown that statins reduce the
risk of MI, cardiac death, and stroke,133–137 and there is evi-
dence that niacin, resins, and fibrates can do the same.157,158
Statins also exert antiinflammatory effects independent of
their effects on lipid levels.159 New drugs that block intesti-
nal fat absorption (e.g., ezetimibe or orlistat) or inhibit other
aspects of lipid metabolism, such as cholesterol esterase
transfer protein (CETP) inhibitors, are entering clinical
trials.
It is important to note that even as the enormous public-
ity and marketing of the statins has not yet resulted in the
majority of patients reaching their LDL goal, the reductions
in mortality do not reach significance until 6 to 12 months
after the drugs are begun. Higher doses may confer an earlier
benefit, as suggested by the Myocardial Ischemia Reduction
with Aggressive Cholesterol Lowering (MIRACL) trial, and
combinations with niacin may yet prove to work faster than
statins alone.160 As statins do not reduce mortality for at least
6 months to 1 year, local interventional therapies may be
needed to “buy time” until statin therapy confers significant
protection.
Apo A-I Milano
Apolipoprotein A-I Milano (apoA-I Milano) is a naturally occurring
mutant of apoA-I, with a cysteine-to-arginine substitution at
position 173. It was first described in 1980 in three members
of an Italian family who had significant hypertriglyceride-
mia with very markedly decreased levels of HDL cholesterol
(7 to 14 mg/dL).161,162 In its carriers, apoA-I Milano is associated
with longevity and freedom from vascular disease despite
markedly reduced HDL and elevated triglyceride levels.163 In
 at h erosclerot ic v u l n er a ble pl aqu es
1989, Badimon, Fuster, and colleagues164 showed that admin-
istration of homologous HDL–very high density lipoprotein
(VHDL) fraction to cholesterol-fed rabbits dramatically inhib-
ited the extent of aortic fatty streaks and lowered lipid depo-
sition in the arterial wall and liver without modifying the
plasma lipid levels.
Ameli and coauthors165 showed that repeated administra-
tion of recombinant apoA-I Milano reduced intimal thickening
and macrophage content after balloon injury in cholesterol-
fed rabbits without changing the arterial total cholesterol
content. Soma and associates166 tested the effect of a recom-
binant disulfide-linked apoA-I Milano on neointimal formation
induced by periarterial manipulation in cholesterol–fed
rabbits. These researchers observed a marked inhibition of
neointimal formation and proliferation of smooth muscle
cells.
Shah and coworkers167 demonstrated that recombinant
apoA-I Milano reduced atherosclerosis progression, plaque lipid
content, and inflammation in apoE-deficient mice on a
high-cholesterol diet. Later, these authors showed that a
single high dose of recombinant apoA-I Milano could rapidly
mobilize tissue cholesterol, reduce plaque lipid by 40% to
50%, and reduce macrophage content by 29% to 36% in
apoE-deficient mice. These findings suggest a strategy for the
rapid stabilization of plaques. Navab and associates168 devel-
oped an oral form of apoA-I mimetic peptides (D-4F) that,
when administered orally to LDL receptor-null mice on a
Western diet decreased the lesions by 79%; when added to
the drinking water of apoE-null mice, this agent reduced the
lesions by approximately 75%.
These series suggest that apoA-I therapy may be used to
stabilize atherosclerotic plaques and induce their regression
by promoting reverse cholesterol transport and removal of
oxidized lipids. Several groups are investigating gene transfer
of apoA-I to induce regression of atherosclerosis.169–172 Nissen
et al.173 recently reported significant regression of coronary
atherosclerosis as measured by IVUS following intravenous
administration of recombinant ApoA-I Milano/phospholipid
complex (ETC-216) in 123 patients. Studies of novel HDL-
raising agents such as torcetrapib are also underway.174
Antiinflammatory Drugs
One of the most exciting developments in the past few years
has been the identification of serum levels of CRP as a marker
of the risk of MI and death in patients hospitalized for angina
or MI and as a (somewhat weaker) predictor years before the
onset of angina or MI.175 In most studies of primary and sec-
ondary prevention, CRP is a slightly better predictor than
LDL cholesterol or even the LDL/HDL ratio.176
Angiotensin-converting enzyme (ACE) inhibitors have
been shown not only to reduce blood pressure and prevent
MI, beginning at about 6 months, but also to have significant
antiinflammatory effects.177,178 Together with the numerous
recent demonstrations that inflammation promotes throm-
bosis, and vice versa, an interplay of factors suggests the
promise of combination therapies. Thus, the next few years
will bring results of clinical trials that will help identify the
specific CRP and cholesterol/HDL goals that may be reached
by a combination of dietary, lipid-lowering, and antiinflam-
matory interventions.
6 31
Because of the side effects of such broad antiinflamma-
tory approaches as corticosteroids and nonsteroidal antiin-
flammatory drugs, and because of the 1-year delay until
statins even begin to reduce mortality, more specific antiin-
flammatory approaches are worth investigating. Examples of
candidate drugs include inhibitors of lipoxygenases, tumor
necrosis factor-α (TNF-α) and its receptor (and related
members of that family), blockers of monocyte chemoattrac-
tant peptide-1 (MCP-1), CD40 and its ligand, intercellular
adhesion molecule-1 (ICAM-1), vascular cell adhesion
molecule-1 (VCAM-1), interleukin-1 (IL-1), interleukin-6 (IL-
6), matrix metalloproteinases 1, 3, 8, 9, and 13, CRP, and, in
particular, nuclear factor κB (NF-κB), whose activation is one
of the most important molecular controls of the inflamma-
tory process.179, 180
Particularly promising are the peroxisome proliferator-
activated receptor (PPAR) agonists, such as the fibrates (which
decrease LDL and triglyceride levels) and glitazones (which
decrease serum glucose), yet each has unique antiinflamma-
tory actions.181
Vaccination and Atherosclerosis
A desirable alternative might be to avoid the antigens incit-
ing the inflammatory response, or remove them, mask them,
or induce tolerance.182,183 However, the science and tech-
niques of antigen masking and of desensitization therapies
remain poorly understood. Antigens that might be avoided
include oxidized LDL cholesterol, as previously discussed.
Other antigens of interest include heat shock proteins (HSP)
60 and 65 and β2-glycoprotein I.184,185
Role of Infections
Candidates include infections, such as Chlamydia pneu-
moniae, herpes simplex viruses, Helicobacter pylori, Porphy-
romonas gingivalis, Mycoplasma pneumoniae, other
infections that induce expression of HSPs (e.g., HSP 65), and
influenza.186 C. pneumoniae has been studied more exten-
sively; however, the results of large human clinical trials
using antibiotics against it have been disappointing.187,188
Because upper respiratory infections precede approxi-
mately one third of AMIs,189 we examined whether vaccina-
tion against influenza was associated with a reduced rate
of MI in persons over 65 years old with chronic coronary
disease. In a multivariate analysis, we found a 66% reduction
in the rate of reinfarction but not in mortality.190 A simulta-
neous study found a similar reduction in the risk of SCD,191
and a subsequent study found a similar reduction in the risk
of stroke.192 A small randomized trial yielded similar find-
ings,193 but one case-control trial has described no associa-
tion of vaccination with cardiovascular events.194 To test the
effect of influenza on atherosclerosis, we inoculated athero-
sclerotic apoE-deficient mice with influenza A; we found a
marked increase in inflammation and thrombosis in plaques,
but not in normal regions of the aorta.195
The association is plausible because of influenza’s asso-
ciation with the winter increase in cardiovascular events,196
the upsurge in cardiovascular events that followed the 1918
Spanish flu pandemic,197 the known effects of inflammation
on inactivation of HDL,198,199 and the fact that acute respira-
632 chapter
tory infections increase fibrinogen, CRP, and (by hemocon-
centration) concentrations of clotting factors. Moreover,
influenza can cause tachycardia, hypoxemia, elevations in
norepinephrine, and other plausible triggers for MI or stroke.
The fact that influenza vaccine is effective and inexpensive
(and backup strategies are available, such as the neuramini-
dase inhibitors and amantadine) suggests that it is important
to confirm or refute the influenza hypothesis.186
Prevention of Thrombosis
The fact that aspirin reduces the risk of MI and death by only
20% to 30% (and that in some 30% to 40% of patients,
aspirin produces little or no improvement in bleeding time
or in in vitro platelet aggregation) led to studies combining
aspirin with ticlopidine or clopidogrel. Adding either drug to
aspirin reduced the risk of acute thrombotic occlusion with
stenting, and clopidogrel reduced the incidence of MI in
patients with unstable angina.200
In the Aspirin and Coumadin After Acute Coronary Syn-
dromes Trial (ASPECT 2) in patients with ACSs, warfarin
titrated to an international normalized ratio (INR) of 3 to 4
and warfarin titrated to 2 to 2.5 plus low-dose aspirin reduced
by 50% the combined incidence of stroke, MI, and death
compared to low-dose aspirin alone.201 Likewise, in the Anti-
thrombotics in the Prevention of Reocclusion In Coronary
Thrombolysis (APRICOT)-2 trial of 308 patients with AMI
treated with thrombolysis, those randomized to warfarin
(INR 2 to 3) plus aspirin had a 14% rate of MI or revascular-
ization over 3 months, versus 36% for aspirin alone.202
In a British study of men with cardiovascular risk factors
but no MI or angina, warfarin—alone or with aspirin—again
reduced the event rate compared to aspirin alone.203 Taking
into consideration that not all the patients are protected by
the current regimens, new combination regimens (with pos-
sibly three drugs) and novel antithrombotics, such as inhibi-
tors of thrombin, tissue factor, or glycoprotein Ib (GPIb),
merit study to confer further protection.
Treatment of Hypertension
The ability to fi nd vulnerable plaques will make it possible
to test the hypothesis that vulnerable patients require lower
blood pressure, e.g., 120/70 mm Hg. As noted earlier, ACE
inhibitors not only reduce blood pressure, stroke risk, and
mortality in congestive heart failure, but also reduce the
risk of reinfarction and of progressive atherosclerosis.204–206
Several mechanisms may contribute, including the antiin-
flammatory action of ACE inhibitors. Related and equally
promising drugs are the angiotensin receptor blockers, which
have the putative benefits of blocking angiotensin-II formed
by the action of tissue chymases and of increasing the stimu-
lation of the type 2 receptor of angiotensin-II.207,208 However,
limited clinical information, to date, suggests that the ben-
efits are similar to those of ACE inhibitors, albeit with a
lower incidence of angioneurotic edema and cough.209
β-adrenergic blockade reduces blood pressure, cardiac
contractility, increases diastolic filling time, and decreases
vulnerability to arrhythmias. It also reduces the risks of
reinfarction and of mortality in congestive heart failure. The
mechanism(s) by which beta-blockers reduce the risk of
27A
infarction are not clear, but may simply relate to the reduced
number of heartbeats and the reduced rate of pressure rise in
the coronary arteries.210
The recently released Antihypertensive and Lipid Lower-
ing Treatment to Prevent Heart Attack Trial (ALLHAT) sug-
gested that the benefits of diuretics are essentially equal to
that of ACE inhibitors and beta-blockers, but the caveat is
that most ALLHAT patients did not have coronary athero-
sclerosis. Thus, the multiple demonstrated benefits of ACE
inhibitors and beta-blockers in patients with known coro-
nary disease should not be ignored.210,211
Inhibition of Neovascularization
Inhibition of neovascularization is another potential method
for stabilizing plaques and reducing plaque growth. Folk-
man’s lab212 used recombinant murine angiogenesis inhibi-
tors (endostatin and TNP-470) in apolipoprotein E–deficient
(apoE−/−) mice and showed that these drugs significantly
reduce plaque progression (by 85% and 70%, respectively)
without affecting cholesterol levels.213
Local and Regional Therapies
Stenting, clopidogrel, and GPIIb/IIIa inhibitors reduce the
incidence of acute complications with angioplasty. New
drug-eluting stents, in particular, have been shown to mark-
edly reduce restenosis rates. Together with the recent recog-
nition that percutaneous coronary intervention (PCI) serves
mainly to reduce angina and increase walking distance some
20% to 30%, whereas most MIs and coronary deaths are pre-
cipitated by thrombosis of a plaque less than 50% diameter
stenosis (DS), and that most patients with MI have a second
or even a third vulnerable lesion, interventional cardiologists
are now planning trials of stenting for hot plaques.
Despite their cost, drug-eluting stents are particularly
attractive for treatment of vulnerable plaques because mac-
rophage content has repeatedly been shown to predispose
to restenosis.214 Moreover, Stefanadis et al.100 found that
warmer lesions post–percutaneous transluminal coronary
angioplasty (PTCA) had a higher rate of subsequent events.
Interventionalists have also noted that plaque vulnerability
could help decide whether to intervene on a 50% to 70% DS
lesion, or influence stent selection. For example, if a 20%
stenosis that is 10 mm downstream of the ischemia-causing
culprit is hot or otherwise vulnerable, the interventionalist
may select a stent that is long enough to treat both lesions.
Balloon Angioplasty with Drug-Eluting Stents
Balloon angioplasty has been used in humans since 1977, and
the advent of coronary stenting in 1986 led to a marked
reduction in the postangioplasty restenosis rate. Further
improvement has been achieved with stents coated with
antiproliferative drugs (such as sirolimus and paclitaxel),
which can potentially abolish in-stent restenosis. The
concept of local drug delivery via coated stents offers both
the biologic and the mechanical means of preventing such
restenosis. Several drugs are being used for this purpose.
Paclitaxel- and sirolimus-eluting stents have been studied
extensively with major success in minimizing the risk of
in-stent restenosis.215–222 Newer stent designs and new molec-
 at h erosclerot ic v u l n er a ble pl aqu es
ular and cellular stents including those covered with stem
cells are under development and may confer major improve-
ments in the field.
The potential benefit of stenting hemodynamically
nonsignificant but vulnerable (e.g., hot, remodeled) plaques
remains to be investigated in randomized clinical trials.
Several drugs with different mechanisms of action (antiprolif-
erative, anticoagulant, antiinflammatory, gene-transferring,
etc.) are being investigated for use in these stents. Better char-
acterization and classification of each lesion with new detec-
tion techniques will help investigators decide which coated
stent is best suited for treating a specific lesion.
Use of antiproliferative drugs in oral form after stent
implantation is another promising therapy for preventing
restenosis. Farb and coworkers223 used oral everolimus (a
macrolide of the same family as sirolimus) to inhibit in-stent
neointimal growth in the iliac arteries of rabbits. This drug
reduced in-stent neointimal growth significantly (42% to
46%). The safety and efficacy of such treatment in humans
remains to be proven.223
Photodynamic Therapy
Photodynamic therapy (PDT) has been used in treatment of
cancer lesions and has been evaluated for focal treatment of
atherosclerosis and prevention of restenosis.224,225 Motexafin
lutetium (MLu, Antrin) has been used most in atherosclero-
sis research because of its tendency to accumulate in plaques.
Pilot studies have used motexafin lutetium and endovascular
illumination and resulted in a reduction of plaque volume in
animal models, presumably due to apoptosis of macrophages
and smooth muscle cells.226 Other new agents are being
developed to be used in photodynamic therapy of vulnerable
plaques.
Thermal Stabilization
We have shown in ex vivo and animal studies that
gentle local heating of plaques (up to 43°C for 15 minutes) is
capable of reducing macrophages density by induction of
apoptosis and downregulating proinflammatory genes.227
Gentle heating (increasing temperature from 37° to 40°C)
markedly reduces formation of the crystals in the macro-
phages and promotes the apoptotic effects of oxysterols on
macrophages.228
Avoiding “Triggers”
Muller and colleagues229 pioneered the concept of “triggers”:
events that precipitate plaque rupture, erosion, or thrombosis.
Thus, exercise increases the risk of MI up to 50-fold during
and immediately afterward (even though exercise may reduce
risk in the long term).230 Thus, exercise in deconditioned
patients with angina—and especially recent MI—should
be gradual, and supervised if possible. Patients should be
instructed to keep warm, and to avoid cocaine, decongestants,
large meals, infection, and dehydration. Family members can
help to reduce psychological stresses, as can a program of
meditation, counseling, or pastoral support. To date, antide-
pressant medications have not reduced the risk of MI, perhaps
because most of them stimulate not only serotonergic, but
633
also the adrenergic systems.231–233 Recently, these drugs have
been associated with an increased risk of SCD.234
In summary, vulnerable plaques represent a wide variety
of anatomic variations of atherosclerosis, reflecting multiple
genetic and environmental risk factors. A correspondingly
wide variety of medical and surgical treatments—some
current and others in development—are likely to achieve
major reductions in morbidity and mortality caused by vul-
nerable plaques.
Summary
During the past two decades, we have witnessed considerable
progress in understanding the pathogenesis of atherosclerosis
and vulnerable plaques. Multiple methods are being investi-
gated for detection of vulnerable plaques. A combination of
several detection techniques may be used to screen and
detect lesions invasively or noninvasively. This can lead to
development of more efficient methods to prevent and control
coronary heart disease. A comprehensive preventive and
therapeutic approach would considerably reduce the risk of
fatal and nonfatal heart attacks.
A major goal in preventive care and treatment of CHD
patients is to identify patients who are vulnerable to acute
coronary thrombosis.38 These “vulnerable patients” are
likely to have a high atherosclerotic burden, high-risk/
vulnerable plaques, or thrombogenic blood. Traditional and
newly identified risk factors235 and imaging methods, both
invasive and noninvasive,41 are likely to be of increasing
utility in identifying such patients and guiding therapy.38
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 2 Biomarkers of
7 Inflammation as
B Surrogate Markers
in Detection of
Vulnerable Plaques and
Vulnerable Patients
Mohammad Madjid, Samuel Ward Casscells, and
James T. Willerson

High-Sensitivity C-Reactive Protein . . . . . . . . . . . . . . . . 642 Serum Amyloid A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646

Leukocyte Count . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643 CD40 Ligand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
Lipoprotein-Associated Phospholipase A 2 . . . . . . . . . . . . 644 Proinflammatory Cytokines . . . . . . . . . . . . . . . . . . . . . . 646
Myeloperoxidase. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 645 Adhesion Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647
Pregnancy-Associated Plasma Protein-A . . . . . . . . . . . . . 645 Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648

Key Points • Elevated serum amyloid A at hospital admission in patients

• C-reactive protein (CRP) activates endothelial cells to
express adhesion molecules, VCAM and ICAM, and
Monocyte Chemotactic Protein, and CRP decreases the
availability of nitric oxide. Thus, it is a proinflammatory
substance and its serum level is also a predictor of future
vascular events.
• White blood cell counts are independent predictors of
cardiovascular events.
• Lipoprotein-associated phospholipase A 2 (Lp-PLA 2) may
have both proinflammatory and antiinflammatory effects.
High Lp-PLA 2 levels predict future cardiovascular
events.
• Myeloperoxidase is proinflammatory and its serum level
is a predictor of prognosis of cardiovascular events in
patients.
• In troponin-negative acute coronary syndrome (ACS)
patients, elevated pregnancy-associated plasma protein-A
is an independent predictor of adverse outcome during 6
months of follow-up.
with unstable angina predicts a poorer prognosis.
• CD40 and CD40 ligand levels predict prognosis in
patients with ACS.
• The primary proinflammatory cytokines are interleukin-
1 and -6 and tumor necrosis factor-α. Increased serum
levels of the proinflammatory cytokines are associated
with a poorer prognosis, development of congestive
heart failure (CHF), and of progressive atherosclerosis.
Increased serum levels of interleukin-10 are associated
with a better prognosis in patients with coronary artery
disease (CAD).
Traditional risk factors, such as those included in the Fram-
ingham risk tables, fail to predict all patients at risk of
cardiovascular events. Therefore, an extensive search is
under way to find markers that can identify patients at risk
of adverse cardiovascular events. As a general rule, new risk
predictors need to be biologically plausible, measurable,
repeatable, and show strong and graded relation to the disease.
Accuracy and precision of the related laboratory tests and

6 41
6 42 chapter
low or modest variability in the clinical setting are also
necessary.1 In the past decade, several biomarkers have been
identified that can be used for prediction of future risk of
events, prognosis after interventions, monitoring therapy,
and risk stratification for the purpose of clinical decision
making.2
Atherosclerosis is an inflammatory disease characterized
by multifocal lesions and systemic elevations of a number of
acute-phase proteins, cytokines, and cell adhesion molecules,
including but not limited to, high sensitivity C-reactive
protein (hsCRP),3 white blood cells,4 lipoprotein-associated
phospholipase A 2 (Lp-PLA 2),5 myeloperoxidase (MPO),6
pregnancy-associated plasma protein-A,7 serum amyloid A
(SAA),8 tumor necrosis factor-α (TNF-α),9 interleukin-6 (IL-
6),10,11 soluble intercellular adhesion molecule-1 (sICAM-1),12
sP-selectin,13 and CD40 and CD40 ligand.14 These markers
have been studied for the prediction of coronary events in
apparently healthy men and women, as well as among
patients with stable angina, acute coronary syndromes (ACS),
and in secondary prevention.3 The list of inflammatory
markers used for this purpose is growing rapidly. This chapter
discusses several of the markers that have generated enough
evidence to support their clinical use, and briefly discusses
some of the emerging biomarkers.
High-Sensitivity C-Reactive Protein
C-reactive protein is an acute-phase reactant and its levels
increase many fold, nonspecifically, after injury, inflamma-
tion, or infection. It activates the classic complement pathway
and possesses proatherogenic and proinflammatory proper-
ties.15 It activates endothelial cells to express the adhesion
molecules intercellular adhesion molecule-1 (ICAM-1), vas-
cular cell adhesion molecule-1 (VCAM-1), selectins, and the
chemokine monocyte chemotactic protein-1, and decreases
the expression and bioavailability of endothelial nitric oxide
synthase in human endothelial cells.15,16 It is produced by the
liver in response to a rise in IL-6 levels. Aortic smooth muscle
cells and adipocytes also produce CRP. In the absence of
inflammation, CRP levels are usually less than 1 μg/mL,
whereas in the presence of infections, autoimmune diseases,
or malignancy, they can rise to as high as 100 μg/mL or even
more. Most of CRP’s predictive power resides in the range
between 1 to 5 μg/mL. Serum CRP levels higher than 15 μg/
mL suggest the presence of an infection or other systemic
inflammatory process and require a repeat measurement
weeks to months later.
Multiple prospective cohort studies in different popula-
tions have shown that high-sensitivity C-Reactive Protein
(hsCRP) is a reliable marker of systemic inflammation and a
strong predictor of future myocardial infarction (MI) and
stroke. The hsCRP level is a predictor of both short-term (a
few years) and long-term risk (up to 20 years).17 Multiple
studies have shown that CRP determination can be of value
in primary and secondary prevention in men and women,
and in the young and the elderly.18,19 The large cohort studies
that have demonstrated this predictive role include the
MONICA (MONItoring trends and determinants in CArdio-
vascular disease) study of the Augsburg Center in Germany,20
the Atherosclerosis Risk in Communities Study,21 the
27 B
Women’s Health Study,22 the Honolulu Heart Study,23 and the
National Health and Nutrition Examination Survey
(NHANES) study, which have shown similar, consistent
results in this regard.2 In general, there is a reproducible,
dose-dependent relationship between hsCRP levels and the
risk of incident coronary heart disease (CHD), sudden death,
and peripheral arterial disease.2 hsCRP can predict recurrent
MI in acute coronary syndromes,24,25 estimate the risk of
restenosis after percutaneous coronary intervention (PCI),26
and predict prognosis and recurrent events in patients with
stroke27 and peripheral arterial disease.28
Several meta-analyses of prospective population-based
studies have shown an increase in relative risk for major
coronary events for patients at the upper tertile versus the
lowest tertile of hsCRP (Fig. 27B.1). The initial estimates for
the odds of major coronary events in subjects with high
hsCRP were approximately 1.9 [95% confidence interval (CI)
1.5 to 2.3].29 However, more recent studies have suggested a
relative risk of 1.45 (95% CI 1.25 vs. 1.68) after adjusting for
other risk factors.30,31
C-reactive protein has a well-standardized assay that is
widely available at this time. It has a long-term stability
during storage and a long half-life, and it lacks diurnal varia-
tion and age- and sex-dependence. These attributes, coupled
with its strong predictive power, have helped it become a part
of routine clinical practice in many settings.32 hsCRP testing
is currently used to identify apparently healthy men and
women at risk of developing cardiovascular events (Fig.
27B.2).15
hsCRP is widely ordered (at the discretion of the physi-
cian) along with lipid profiles in patients judged by global
risk assessment to be at intermediate CHD risk (10% to 20%
risk in 10 years). It is also widely used in subjects free of
cardiovascular disease (CVD). hsCRP may potentially help
direct further evaluation and therapy in the primary preven-
tion of CVD; however, the benefits of such an approach
remain to be proven. Knowledge of hsCRP levels may help
motivate patients to improve their lifestyle behaviors.1
Statins have been shown to reduce CRP levels by 25% to
50%.33–35 Studies are under way to investigate the effect of
statins in reducing risk in patients with high CRP levels and
Danesh (2000)
Ridker (1997)
Koenig (1999)
Kuller (1996)
Lowe (1999)
Tracy (1997)
Tracy (1997)
Witherell (1999)
Ridker (1998)
Agewall (1998)
Roivainen (2000)
Overall 2.0 (95% Cl 12.6 to 2.5)
0.1 1 10
Relative risk for CHD
FIGURE 27B.1. C-reactive protein (CRP) and coronary heart disease
(CHD). Relative risk top vs. bottom tertile. Prospective—persons
without cardiovascular disease (CVD) at baseline.
 biom a r k e r s of i n f l a m m at ion a s su r rog at e m a r k e r s 643

CRP Level TABLE 27B.1. Patient characteristics and conditions associated

with increased or decreased levels of hsCRP
mg/mL Interpretation Increased levels Decreased levels

Elevated blood pressure

Elevated body mass index Moderate alcohol
Repeat test in 1 month. consumption
Exclude other processes. Cigarette smoking Increased activity/endurance
exercise
Metabolic syndrome/diabetes Weight loss
10 mellitus
Low high-density lipoprotein Medications
(HDL)/high triglycerides
Estrogen/progestogen hormone use Statins
High risk
Chronic infections (gingivitis, Fibrates
bronchitis)
Chronic inflammation Niacin
3 (rheumatoid arthritis) Aspirin
Intermediate risk
1
Low risk
Leukocyte Count
FIGURE 27B.2. Interpretation of CRP level.
Inflammatory cells play a critical role in atherosclerosis.
Therefore, it is not surprising that white blood cell (WBC)
low low-density lipoprotein (LDL) levels.36 In a study by count is an independent risk factor for incident cardiovascu-
Nissen and colleagues,37 using intravascular ultrasound for lar events in apparently healthy individuals without CVD,
assessing plaque burden, after adjustment for the reduction a risk factor for recurrent cardiovascular events in CHD
in blood lipid levels, the decrease in CRP levels was indepen- patients, and a prognostic marker of future events in ACS
dently and significantly correlated with the rate of disease patients.4 White blood cells may exert their deleterious
progression. In fact, patients with greater reductions in both effects through several mechanisms summarized in Table
LDL cholesterol and CRP had significantly slower rates of 27B.2.
progression of their atherosclerotic lesions. Another study Leukocyte count has been correlated with CHD since the
using statins for reducing the risk of recurrent MI or death early 1920s.43 Several large, prospective studies in CHD-free
from coronary causes in patients with acute coronary syn- populations have shown a consistent and positive correlation
dromes showed that patients with lower CRP levels after between leukocyte count and risk of CHD (Fig. 27B.3),44–47
statin therapy had better clinical outcomes than those with even after adjustment for other risk factors.48–50 The predic-
higher CRP levels, regardless of the final level of LDL cho- tive value of high WBC is especially robust in smokers.4 In
lesterol.38 Losing weight and controlling diabetes can also subjects with angiographically documented coronary artery
lower CRP levels (Table 27B.1).2 Serial hsCRP testing is not stenosis, both WBC and neutrophil count correlated with the
recommended for monitoring the effects of treatment.1 number and the extent, severity, and location of coronary
Current guidelines discourage use of hsCRP in application stenosis and patient survival.51,52 Other studies have shown
of secondary prevention measures, but the authors recom-
mend periodic measurements of serum CRP along with
lipids.1
hsCRP is correlated with body weight and is raised in the
TABLE 27B.2. Possible mechanisms of action of leukocytes in
metabolic syndrome. Adipose tissues produce CRP, and coronary heart disease
weight loss reduces the hsCRP levels. These findings have
Endothelial cell injury caused by proteolytic enzymes
led some authors to suggest that hsCRP may be a marker for
obesity and insulin resistance.39,40 Another limitation of CRP Vessel plugging
is its nonspecificity for vascular inflammation and the fact Decreased perfusion
that its predictive power is at least partially affected by the Abnormal leukocyte aggregation
obesity level. hsCRP loses some of its predictive power when Effects on blood flow
adjustments for other risk factors are made in multivariate Increased expression of monocyte tissue factors
analyses. In fact, some recent studies have cast doubt on the Activation of coagulation system
ability of hsCRP to add additional prognostic information in Association with atherosclerotic risk factors
the presence of traditional risk factors.31 Another limitation Electrical instability
of hsCRP is its moderate, within-individual variability.41,42
Increased thrombus formation in coronary heart disease (CHD)
Currently, in a manner similar to cholesterol, two separate
Involvement in hematologic stress syndrome
measurements of hsCRP (i.e., 2 weeks apart and then aver-
Increased leukocyte adhesion in coronary artery disease (CAD)
aged) are recommended to classify a subject’s risk level.
644 chapter
CHD incidence
Zalokar et al (1981)
BRHS (1992)
MRFIT I (1992)
MRFIT II (1992)
Gillum et al (1993) males
Gillum et al (1993) females
Weijenberg et al (1996)
Folsom et al (1997) males
Folsom et al (1997) females
Lee et al (2001)
Aronow et al (2003)
Manttari et al (1992)
CHD mortality
Grimm et al (1985)
Gillum et al (1993)
Brown et al (2001)
Lee et al (2001), Afric. Americans
Lee et al (2001), Whites
Weijenberg et al (1996)
Ali et al (2001)
0 1 2 3 4 5
a strong effect of leukocyte count on prognosis of patients
with CHD after an MI event. In the first Persantine-Aspirin
Reinfarction Study (PARIS-1), after adjustment for other risk
factors, including smoking, baseline leukocyte count was
strongly associated with recurrent coronary events and total
mortality after an MI event.53 Leukocyte count is also a pre-
dictor of prognosis in MI patients54,55 and an independent
predictor of in-hospital, 6-week, and 1-year mortality in acute
MI (AMI) patients.4,56
In addition, a high leukocyte count is a risk factor
for increased mortality in patients with unstable angina
pectoris57,58 and unstable angina or non-ST elevation MI
(NSTEMI).59,60 In the latter patients, high baseline leukocyte
counts have been associated with poorer myocardial reperfu-
sion, more extensive coronary artery disease (CAD), and
higher 6-month mortality.60 The same study also found WBC
count and CRP to be independent, additive predictors of the
6-month mortality.60
The Hiroshima and Nagasaki Adult Health Study in a
large population of asymptomatic subjects showed that total
leukocyte count could predict the incidence of CHD.61 More-
over, high eosinophil, neutrophil, and monocyte (but not
lymphocyte) counts were independent predictors of events.61
Such an effect was observed for monocyte counts in the Paris
Prospective Study II and for neutrophil and eosinophil counts
in a United Kingdom study.62,63 When combined with the
widely available and inexpensive leukocyte count, CRP may
yield additional information about risk and prognosis for
patients with unstable angina or MI.60
Leukocyte count is safe, reliable, inexpensive, easy to
interpret, and routinely ordered in inpatient and outpatient
settings. In fact, its combination with other inflammatory
markers (such as hsCRP) may act synergistically to predict
cardiovascular events. A recent report from the Women’s
Health Initiative Observational Study in 72,242 postmeno-
pausal CVD-free women aged 50 to 79 years showed that a
WBC count greater than 6.7 × 109 cells/L was an independent
predictor of CVD events and all-cause mortality. Moreover,
in logistic regression analyses of the CHD risk, high hsCRP
and high WBC had an additive effect, and having high values
27 B
FIGURE 27B.3. Point estimate and 95%
confidence intervals for odds of CHD
events associated with high leukocyte
counts. For more detail, please see Madjid
M. et al. Leukocyte count and coronary
heart disease: implications for risk
assessment. J Am Coll Cardiol. 2004
6 7 8 16;44(10):1945–56.
of both markers was associated with an almost sevenfold
elevation of risk.64
Lipoprotein-Associated Phospholipase A2
Lipoprotein-associated phospholipase A 2 (Lp-PLA 2), also
known as platelet-activating factor acetylhydrolase (PAF-
AH), is an enzyme that hydrolyzes oxidized phospholipids
resulting in production of proinflammatory lysophosphati-
dylcholine (lysoPC) and oxidized nonesterified fatty acids
(NEFAs).5 On the other hand, hydrolysis of platelet-activating
factor and other phospholipids has antiinflammatory effects.
Therefore, Lp-PLA 2 can have both proinflammatory and anti-
inflammatory actions.
Lp-PLA 2 is produced by inflammatory cells and co-travels
primarily (70–80%) with circulating LDL, and its enzyme
activity is higher in small, dense LDL.65 Lp-PLA 2 levels are
lower in menopausal women than in men, with levels
increasing with age.5
In human atherosclerotic plaques, Lp-PLA 2 is both
produced locally by inflammatory cells (macrophages, T
cells, mast cells) and is possibly internalized with LDL from
circulation. An autopsy study showed that in coronary
plaques, positive Lp-PLA 2 immunostaining is particularly
marked in macrophage-rich areas within thin-cap
fibroatheromas.5
Several studies have shown that high Lp-PLA 2 levels
(measured as its mass or activity) predict future cardiovascu-
lar events. In most studies, the attributable risk for develop-
ment of coronary events, stroke, or death remains statistically
significant even after full adjustment for traditional risk
factors.66–70 The strength of association varies and is generally
modest (hazard ratios < 2), which is typical of common risk
factors (Fig. 27B.4).5 Because of different sources of produc-
tion and metabolic pathways, there is no correlation between
CRP and Lp-PLA 2, though they have additive value in pre-
dicting cardiovascular risk.68,70
In a case–cohort analysis of the West of Scotland Coro-
nary Prevention Study (WOSCOPS), CRP, WBC, and fibrino-
 biom a r k e r s of i n f l a m m at ion a s su r rog at e m a r k e r s
Risk ratios for CHD based on Lp-PLA2 levels
All LDL concentrations 1.0 1.5 2.5
310 420
LDL <130 mg/dL 1.0 2.2 3.5
310 420
LDL ≥130 mg/dL 3.15 3.7
350 460
300 320 340 360 380 400 420 440 460
LP-PLA2 ng/mL
FIGURE 27B.4. Risk ratios for CHD based on lipoprotein-associ-
ated phospholipase A 2 (Lp-PLA 2) levels.
gen levels were strong predictors of the risk of coronary
events, but the association of these variables with risk was
markedly attenuated in multivariate models. After adjust-
ment for traditional risk factors and hsCRP, high baseline
Lp-PLA 2 levels were still strongly associated with increased
risk for CHD events.71 In a case–control analysis from the
Women’s Health Study, baseline Lp-PLA 2 levels were higher
in women who later developed cardiovascular events.
However, this association lost its significance after adjust-
ment for traditional risk factors and hsCRP.67
In a prospective, case cohort study in apparently healthy,
middle-aged men and women followed for 6 years in the Ath-
erosclerosis Risk in Communities (ARIC) study, both Lp-
PLA 2 and CRP were associated with incident CHD after
adjustment for age, sex, and race with a hazard ratio of 1.78 for
the highest tertile of Lp-PLA 2 and 2.53 for the highest category
of CRP versus the lowest categories.68 However, in a multi-
variate model adjusting for several risk factors, including LDL
cholesterol, the association of Lp-PLA 2 with CHD was attenu-
ated and not statistically significant. In individuals with LDL
measurements <130 mg/dL, Lp-PLA 2 and CRP were still both
significantly and independently associated with CHD even
after full adjustment for other risk factors.68
A more recent report from the MONICA Augsburg study
showed that, after 14 years of follow-up, elevated levels of
Lp-PLA 2 are predictive of future coronary events in appar-
ently healthy middle-aged men with moderately elevated
total cholesterol, independent of CRP.69
In the Rotterdam Study, after adjustment for traditional
risk factors, WBC, and CRP, Lp-PLA 2 activity was a strong
predictor of both coronary heart disease and ischemic
stroke.70 Lp-PLA 2 levels have been correlated with the extent
of angiographic CAD on univariate, but not multivariate,
analysis.72 In the same population, higher Lp-PLA 2 levels
were associated with a greater risk of incident cardiovascular
events, even after adjusting for other risk factors and CRP.72
Treatment with statins or fenofibrate decreases Lp-PLA 2
activity by 20% to 30% without an effect on synthesis and
secretion of Lp-PLA 2 by macrophages.73,74 Currently, several
potent Lp-PLA 2 inhibitors are being evaluated for lowering
Lp-PLA 2 activity in plasma and tissues.75 Oral forms of these
645
inhibitors of Lp-PLA 2 have been able to reduce >95% of the
circulating enzyme activity.5 If proved safe and effective,
these agents may find a place in stabilizing vulnerable
plaques.
Myeloperoxidase
Polymorphonuclear neutrophils (PMNs) play a critical role in
myocardial cell injury and undergo degranulation within the
coronary circulation in ACS.26,76 A major product of PMN
5.1 activation is myeloperoxidase, a hemoprotein with micro-
bicidal activity. Myeloperoxidase (MPO) also has potent
proatherogenic properties, such as the ability to oxidize LDL
cholesterol, activating metalloproteinases, and catalytically
consuming endothelium-derived nitric oxide, hence impair-
ing its vasodilatory and antiinflammatory functions.77 Serum
level of MPO is a predictor of prognosis of cardiovascular
events in patients.
In a case-control study of patients with and without angi-
ographically determined CAD, leukocyte and blood MPO,
both levels were significantly greater in patients with CAD
than in controls.6 Even after adjusting for traditional risk
factors and WBC counts, MPO levels were significantly and
strongly associated with the presence of CAD.6
In patients with ACS enrolled in the c7E3 Anti-Platelet
Therapy in Unstable Refractory Angina (CAPTURE) trial,
patients with elevated MPO levels (>350 μg/L) experienced a
markedly increased cardiac risk on 6-month follow-up, par-
ticularly in patients with troponin T levels below 0.01 μg/L.77
In a multivariate model, including other biochemical markers,
troponin T, CRP, vascular endothelial growth factor (VEGF),
soluble CD40 ligand, and MPO were all independent predic-
tors of the patients’ 6-month outcome.77
In a study of 604 sequential patients presenting to the
emergency department with chest pain, baseline plasma
myeloperoxidase levels predicted the risk of MI, even in
patients with negative troponin T tests.78 The initial myelo-
peroxidase levels also predicted the risk of major adverse
cardiac events within 30 days and 6 months after presenta-
tion, even in absence of myocardial necrosis.78
Pregnancy-Associated Plasma Protein-A
Pregnancy-associated plasma protein-A (PAPP-A) is a zinc-
binding matrix metalloproteinase that is abundantly
expressed in plaque cells and extracellular matrix of eroded
and ruptured plaques.7 It has been suggested to be a marker
of plaque destabilization. Circulating PAPP-A levels have
been observed to be significantly higher in patients with
unstable angina or AMI than in patients with stable angina
and controls.7
A later study in patients with chronic stable angina found
that patients with complex coronary stenoses had a signifi-
cantly higher PAPP-A and PAPP-A/proMBP ratio than those
without complex lesions [the proform of eosinophil major
basic protein (proMBP) is the endogenous inhibitor of PAPP-
A].79 In asymptomatic male subjects whose carotid intima-
media thickness (IMT) and lesion status were evaluated by
noninvasive ultrasonography, the presence of hyperlipidemia
646 chapter
and hyperechoic or isoechoic and echogenic lesions was asso-
ciated with significantly higher PAPP-A levels.80
In troponin-negative hospitalized ACS patients, elevated
PAPP-A is an independent predictor of adverse outcome
during 6 months of follow-up.81 In a sub-study of the
CAPTURE trial, elevated PAPP-A levels (>12.6 mIU/L), in
patients with ACS indicated an increased risk of death or MI
at 30 days and 6 months, even in patients with negative tro-
ponin T results.82
Serum Amyloid A
Serum amyloid A (SAA) is a family of proteins that is syn-
thesized in the liver and plays a significant role in the acute-
phase response.76 In response to infections and stresses, SAA
is secreted as the predominant apolipoprotein on plasma
high-density lipoprotein (HDL) particles, replacing apolipo-
protein A-I. Serum amyloid A maintains the reverse choles-
terol transport system. Moreover, SAA is present in
atherosclerotic lesions, and cells in the artery walls are able
to express SAA.83 Several studies have suggested an associa-
tion between SAA levels and cardiovascular disease.84 Ele-
vated SAA on hospital admission in patients with unstable
angina is a predictor of poor prognosis.85 In the TIMI11A
study, high baseline SAA predicted a higher incidence of
early death for hospitalized unstable angina and non-Q MI
patients, even with a negative rapid assay for cTnT.86
The National Heart, Lung, and Blood Institute–
sponsored Women’s Ischemia Syndrome Evaluation (WISE)
study evaluated women referred for coronary angiography
for suspected myocardial ischemia and showed that, after
adjusting for conventional risk factors, SAA levels are
still independently and moderately associated with angio-
graphic CAD and highly predictive of 3-year cardiovascular
events.8
Serum amyloid A has also been shown to be associated
with a higher rate of recurrent coronary events in stable
patients who have had an acute MI87,88 and to predict poor
outcome in patients with unstable angina.89 High-dose ator-
vastatin has been shown to reduce the elevated levels of SAA
and CRP (but not IL-6).90
CD40 Ligand
CD40 ligand (CD40L also called CD154) is a trimeric trans-
membrane protein of the tumor necrosis factor family and,
in conjunction with its receptor CD40, plays a major role
in vascular inflammation. Several types of immune cells
express CD40 and CD40 ligand and both are present in
human atherosclerotic plaques.91 CD40 signaling in plate-
lets, monocytes, endothelial cells, and smooth muscle cells
promotes a large number of proatherogenic and prothrom-
botic functions. CD40L is present both in a membrane-bound
form and in a soluble form in plasma (sCD40L). More
than 95% of the circulating CD40L is derived from platelets.
In healthy, middle-aged women, baseline sCD40L levels can
predict subsequent development of MI, stroke, or cardiovas-
cular death.14 The relative risk of developing future cardio-
vascular events in women with CD40L levels above the 95th
27 B
percentile distribution (>3.71 ng/mL) has been reported to be
more than three times.14
Patients with unstable angina have significantly raised
serum levels of sCD40L when compared with patients with
stable angina and controls.92 T cells in patients with unstable
angina had enhanced surface expression of CD40L and
increased release of sCD40L on anti-CD3/anti-CD28 stimu-
lation in vitro.92 In a large study on patients with acute coro-
nary syndromes, sCD40L levels indicated a significantly
increased risk of death or nonfatal MI during 6 months of
follow-up.93 In subjects presenting with chest pain, an ele-
vated sCD40L level identified patients with acute coronary
syndromes who were at high risk for death or nonfatal MI.93
The increased risk in patients with elevated sCD40L can be
reduced by treatment with abciximab.93
In the OPUS-TIMI16 trial, patients who developed death,
MI, or congestive heart failure (CHF) within 10 months of
the study had significantly higher baseline plasma sCD40L
levels than controls, after adjustment for other risk predic-
tors and levels of troponin (cTnI) and CRP.94
In subjects with an acute coronary syndrome enrolled in
the Myocardial Ischemia Reduction with Aggressive Choles-
terol Lowering (MIRACL) study, those with high sCD40L
levels (>90th percentile) were at increased risk of a recurrent
cardiovascular event.95 This risk increase was abolished by
atorvastatin, though its effect on sCD40L levels was not
significant.95 Plasma levels of sCD40L are higher in diabetic
patients and intensive multifactorial risk management can
reduce the elevated levels.96 In patients with successful
balloon angioplasty, plasma levels of sCD40L can predict
restenosis.97,98
Proinflammatory Cytokines
The main proinflammatory cytokines are IL-1 and IL-6 and
TNF-α. TNF-α is produced by the endothelial cells, smooth
muscle cells, and macrophages, and plays a major role by
inducing the synthesis of the other cytokines. IL-1 and IL-6
are multifunctional cytokines with extensive humoral and
cellular immune effects. IL-6 is a major mediator of the
acute-phase response and the primary determinant of CRP
production.99
Multiple studies have implied that proinflammatory
cytokines play important roles in atherogenesis, and their
circulating levels can predict cardiovascular events. In the
Health, Aging, and Body Composition (Health ABC) Study,
2,225 participants 70 to 79 years old, without baseline car-
diovascular disease, were followed for 3.6 years for incidence
of CHD, stroke, and CHF events.100 High IL-6 levels were
significantly associated with all outcomes (CHD events,
stroke, and CHF events).100 TNF-α showed significant
associations with CHD and CHF events, whereas CRP was
significantly associated with CHF events.100 In a long-term
study in healthy men, baseline levels of IL-6 predicted MI
incidence.11
In apparently healthy postmenopausal women studied
in the Women’s Health Initiative, median baseline levels of
CRP and IL-6 were independent predictors of incident CHD.101
Use of hormone replacement therapy was associated with
significantly elevated median CRP levels, but did not increase
 biom a r k e r s of i n f l a m m at ion a s su r rog at e m a r k e r s
IL-6 levels.101 In asymptomatic elderly subjects enrolled in
the Framingham Study, high serum IL-6 and CRP levels and
increased production of TNF-α by the peripheral blood mono-
nuclear cells were associated with future risk of developing
CHF.102 Subjects with elevated levels of all three biomarkers
were at the highest risk of developing CHF.102 In the Choles-
terol and Recurrent Events (CARE) trial, high TNF-α levels
were predictive of recurrent nonfatal MI or a fatal cardiovas-
cular event.9 In fact, the excess risk of recurrent coronary
events after MI was predominantly seen among those with
the highest levels of TNF-α.9
The effects of TNF-α are mediated by two receptors (TNF-
R1 and TNF-R2), which circulate in soluble forms (sTNF-R1
and sTNF-R2, respectively). These can be measured with
greater accuracy and reliability than TNF-α itself.103 The
soluble receptors may promote inflammation in the absence
of free TNF ligand. In disease-free women participating in
the Nurses’ Health Study and men participating in the Health
Professionals Follow-Up Study, high levels of IL-6 and CRP
were significantly associated with an increased risk of CHD
in both sexes, whereas high levels of soluble TNF-α receptors
were predictors of CHD only among women. However, after
adjustment for lipid and nonlipid factors, these associations
were all attenuated and only CRP levels remained signifi-
cantly associated with development of CHD.103
Interleukin-18 plays a central role in the inflammatory
cascade and in the processes of innate and acquired immuni-
ties. IL-18 induces interferon-γ (IFN-γ) production in T
lymphocytes and natural killer cells and acts in synergy
with IL-12 to promote the development of T helper 1 (Th-1)
responses.104 Increased local expression of IL-18 in human
atherosclerotic plaque has been reported.105 Serum IL-18 level
is a strong independent predictor of cardiovascular death in
patients with coronary artery disease (with either stable or
unstable angina).104 In the Prospective Epidemiological Study
of Myocardial Infarction (PRIME) study, baseline level of IL-
18 was an independent predictor of coronary events in
healthy, middle-aged European men.106
Interestingly, low levels of the antiinflammatory cyto-
kine IL-10 is an important prognostic determinant in patients
with acute coronary syndromes.107 In a sub-study of The
CAPTURE trial, patients with high IL-10 levels (>3.5 pg/mL)
had a lower risk of death and nonfatal MI on 6 months after
admission compared with patients with elevated IL-10
levels.107 The predictive value of IL-10 was independent of
myocardial necrosis, but had significant interaction with
CRP levels. Patients with both high CRP and IL-10 serum
levels had less risk than patients with high CRP but with
low IL-10 levels.107 This suggests that the balance between
proinflammatory and antiinflammatory markers may be a
major determinant of patients’ prognosis.
Adhesion Molecules
The adhesion molecules permit rolling of monocytes and
lymphocytes on the endothelium and firm attachment and
migration of the blood cells into the arterial wall.108 Adher-
ence of circulating leukocytes to the endothelial cells and
their entry into the arterial wall depend on a cascade of
events mediated by a family of cellular adhesion molecules
6 47
expressed on the surface of endothelial cells. These mole-
cules, which can be found on different cell types present in
the arterial wall, include VCAM-1, ICAM-1, endothelial
leukocyte adhesion molecule (ELAM-1), P-selectin, and E-
selectin.108 VCAM-1 plays a critical role in monocyte
adherence to endothelial cells under flow conditions and
ICAM-1 ligands include CD11a/CD18 (LFA-1) and CD11b/
CD18 (Mac-1), which are present on monocytes, lympho-
cytes, and neutrophils.109 Atherosclerotic plaques demon-
strate increased expression of ICAM-1 and VCAM-1.
Membrane-bound forms of these adhesion molecules are dif-
ficult to measure; however, their soluble forms can be mea-
sured in the serum or plasma, and they indicate the expression
of membrane-bound adhesion molecules.
In apparently healthy women participating in the
Women’s Health Study, mean levels of soluble P-selectin
were significantly higher at baseline among women who
subsequently experienced cardiovascular events compared
with those who did not.13 In a subset of subjects from the
Atherosclerosis Risk in Communities (ARIC) study, baseline
levels of VCAM-1 were not significantly different among the
patients with incident CHD, those with carotid artery ath-
erosclerosis (CAA), and control subjects.110 Patients with
CHD or CAA had higher levels of E-selectin and ICAM-1
compared with the control subjects. The relationship of
ICAM-1 and E-selectin with CHD and CAA was independent
of other known CHD risk factors.110
In healthy men enrolled in the Physicians’ Health Study,
there was a significant association between increasing base-
line concentration of sICAM-1 and risk of future MI, even
after adjustment for lipid and nonlipid risk factors.111 In
apparently healthy postmenopausal women, sICAM-1, along
with CRP, SAA, IL-6, and homocysteine, were predictors of
cardiovascular events on follow-up. However, in multivariate
analyses, hsCRP was the only inflammatory plasma markers
that could independently predict future events.112 In a pro-
spective study of asymptomatic men who were monitored
for 16 years, ICAM-1 was a predictor of CHD. However, its
association lost significance after adjustments for some
classic coronary risk factors and indicators of socioeconomic
status.113 After similar adjustments, VCAM-1, E-selectin, and
P-selectin did not add much predictive information to that
provided by established risk factors.113
In the Epidemiological Study of Myocardial Infarction in
apparently healthy middle-aged men, plasma ICAM-1 was an
independent predictor of the risk for MI, coronary death, and
also for angina pectoris. Subjects with high CRP had
increased coronary risk only if ICAM-1 was high. An ele-
vated level of VCAM-1 was not associated with any risk of
future acute coronary event or angina pectoris.114
In a prospective, nested case-control study in patients
with CHD enrolled in a secondary prevention trial, baseline
serum concentrations of sICAM-1 could significantly predict
future coronary events even after multivariate adjustment
for traditional risk factors.12 In healthy male participants in
the Physicians’ Health Study, there was no association
between sVCAM-1 levels and the risk of future MI.115 In
contrast, in patients with documented CAD, higher levels of
sVCAM-1, sICAM-1, and sE-selectin were associated with
increased risk of future death from cardiovascular causes.116
In a multivariate model, sVCAM-1 was still a predictor of
648 chapter
fatal events even after simultaneously controlling for sICAM-
1, sE-selectin, and CRP.12
In apparently healthy middle-aged men participating in
the Physician’s Health Study, baseline levels of sICAM-1
could predict subsequent development of symptomatic
peripheral arterial disease (PAD).117 After additional adjust-
ment for lipid and nonlipid risk factors, including CRP, ele-
vated sICAM-1 remained significantly associated with
subsequent PAD.117
Serum sICAM-1 levels can be used to noninvasively
assess risk of transplant CAD, posttransplant ischemic
events, and cardiac graft failure. Cardiac allograft recipients
with high serum sICAM-1 levels have greater risk of CAD
and graft failure.118
Implications
In the past decade, we have witnessed a growing interest in
the role of inflammation in atherosclerosis and a surge in the
use of blood levels of markers of inflammation in order to
predict the risk of cardiovascular events. hsCRP is widely
used by physicians for CHD prediction and Lp-PLA 2 has
received approval from the Food and Drug Administration as
a test to predict coronary events and stroke. However, a large
number of new biomarkers are currently being studied and
the search is on to find more novel risk markers.
Although a large body of evidence suggests a positive
association between these inflammatory markers and car-
diovascular risk, the clinical utility of measuring these
biomarkers depends on multiple factors. The ideal risk
marker needs to have several attributes as follows: It has
to have consistent and strong association with cardiovascu-
lar events. Its predictive power needs to be independent
from the established risk factors; in other words, its measure-
ment has to improve our ability to predict cardiovascular
risk. Either the same single test or different tests may be
used in acute and chronic coronary disease states. From a
practical point of view, the ideal test has to have a widely
available standardized assay and its distribution in the
general population has to be well defined. Its predictive
ability needs to be generalizable to various patient popula-
tions at an acceptable cost.
The current approach of measuring only one or two
markers may not be sufficient to accurately identify high-
risk subjects. Measuring several biomarkers at the same time
(for example, measuring proinflammatory and antiinflam-
matory biomarkers at the same time) may yield better predic-
tive values. Proteomic approaches may be especially helpful
in this regard. We need to know if lowering the biomarkers
may lead to a decreased risk of coronary events. Several
medications, such as statins, acetylsalicylic acid (ASA), anti-
biotics (i.e., azithromycin), and weight loss have been shown
to decrease levels of CRP and a few other biomarkers.
However, the absolute reduction in CRP level is very small
with these methods. Specific therapies for reducing the levels
of inflammatory markers will be of special interest as a pre-
ventive measure for cardiovascular disease. This approach
will be more effective if the drugs can inhibit those markers
that may have direct proatherogenic effects rather than being
a simple marker of inflammation.
27 B
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 2 Global Differences in
8 Atherosclerosis
Philip A. Poole-Wilson
Size of the Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Changing Pattern of Disease Around the World . . . . . .
Country Differences in Atherosclerosis . . . . . . . . . . . . .
Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Key Points
• Cardiovascular disease causes one third of the deaths in
the world.
• Eighty percent of these deaths are in developing
countries.
• In developed countries death from infectious diseases
has diminished as death from cardiovascular disease has
increased.
• The proportion of cardiovascular deaths due to coronary
heart disease and stroke varies between countries.
• The risk factors for cardiovascular diseases are known.
• Deaths can be largely accounted for by nine risk
factors.
• These risk factors are common across the world regard-
less of geography, ethnicity, and gender.
• The origins of many risk factors relate to social, eco-
nomic, fiscal, and political circumstances.
• Global institutions allocate insufficient funds to the pre-
vention of cardiovascular disease.
• Informing the public and patients will put pressure on
politicians to respond to the increasing global attrition of
cardiovascular disease.
The consequences of atherosclerosis are grouped under the
broad phrase “cardiovascular diseases,” which is made up of
coronary heart disease, cerebrovascular disease, and other
circulatory disorders. These afflictions include the many
manifestations of coronary heart disease, such as myocardial
infarction, acute coronary syndromes, and heart failure, and
the consequences of peripheral disease, such as stroke,
peripheral vascular disease, aortic disease, and renal failure.
Myocardial infarction and stroke have become the major
global causes of death and disability around the world.1–5
Much is now known about the natural history and patho-
physiology of atherosclerosis. The disorder begins in child-
hood and the lesions in the arterial vasculature develop over
many decades.6 The clinical sequelae appear in middle age
or later life. Cardiovascular disorders are becoming more
653 Prevention of Coronary Heart Disease Around
654 the World. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656
655 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657
655
common and dominate patterns of disease in most countries
primarily because of the epidemiologic transition from com-
municable (infectious disease) to noncommunicable disease
(chronic diseases) as the major cause of death and disability
around the world.7,8 With the decline of infectious diseases,
particularly in the young, life expectancy, the global popula-
tion, and the proportion of elderly persons in most countries
has increased. In 1950, the global population was 2.5 billion.
In 2000, it was 6.0 billion, and it is estimated to reach 9.0
billion by 2050. These demographic changes are the second
major cause of the increase in the impact of cardiovascular
disease.
Size of the Problem
The size of the problem around the world is difficult to esti-
mate. Whereas reliable figures may be available in developed
countries, in many parts of the world, there is not sufficient
organizational capacity to obtain accurate figures. The diag-
nosis may be used to explain deaths to the satisfaction of
grieving relatives with little attention to accuracy. In many
countries, coronary artery disease is a socially acceptable
cause of death. Without postmortem evidence, the diagnosis
may be in error. Equally, it may be overlooked particularly
in patients dying suddenly where often the diagnosis is in
fact acute myocardial ischemia. A further difficulty can arise
in some countries because health authorities have no interest
in coronary artery disease, regarding it as a disease of the
elderly, a pleasant way to die, a personal responsibility, a
disease of affluence, and a problem limited to the male
gender. All five of these beliefs and attitudes are serious
misconceptions and untrue.
The consequences of atherosclerosis in causing cardio-
vascular deaths have been estimated by the World Health
Organization (WHO) (Table 28.1).9 In 2002, the world popula-
tion was 6.22 billion. The total number of deaths was 57.0
million (0.9%). Cardiovascular deaths occurred in 16.7
653
654 chapter 28

TABLE 28.1. Global causes of death Percentage 65 years or older

Population 6,224,000,000 30
Total deaths per year 57,027,000 (0.9%) 2000
Cardiovascular deaths 16,665,000 (31%)
43% coronary heart disease 2050
33% stroke 20
78% not in high-income
countries
52% in women
AIDS 2,821,000
Tuberculosis 1,605,000 10
Malaria 1,222,000 (mostly in Africa)

million (29% of the total deaths). The greater number of
these deaths (52%) occurred in women. Of those, 43% were
due to coronary artery disease and 33% to cerebrovascular
disease, and 78% were not in high income or developed
countries. Hypertensive heart disease10 caused 0.9 million
(5%) deaths, rheumatic heart disease11,12 0.33 million (2.0%)
deaths, and inflammatory heart disease 0.40 million (2.4%)
deaths. By contrast, AIDS accounted for 2.82 million deaths,
tuberculosis 1.61 million, and malaria 1.22 million. The
deaths from malaria were mostly in Africa and many in
children.
The burden of disease can be assessed by calculating dis-
ability-adjusted lost years (DALYs). In 2002, cardiovascular
disease accounted for 9.9% of lost years, whereas HIV/AIDS
accounted for 5.8%, tuberculosis 2.4%, and malaria 3.0%.
Changing Pattern of Disease Around
the World
The 20th century saw a most remarkable increase in public
health. Life expectancy measured in years accrued is possibly
the crudest but simplest measure of public health. Over the
last century, life expectancy in what are now developed coun-
tries increased from about 40 years to almost 80 years (Fig.
28.1).13 In general, women have a life expectancy 1 or 2 years
greater than men, and that greater longevity has been main-
tained as life expectancy has increased. The large increase in
life expectancy has been brought about partly as a result of
0
Europe North Oceania Asia Latin Near Sub-
America America East Saharan
Caribbean North Africa
Africa
FIGURE 28.2. Persons over the age of 65 years projected to 2050 in
different regions of the world.
medical treatments, but also as a consequence of social and
hygienic change reducing the impact of infectious diseases.
One consequence is that the proportion of elderly persons in
populations is changing rapidly and will do so for the next
several decades (Fig. 28.2). Such an alteration in the demog-
raphy of society has major implications for economic and
social change in many countries. A second consequence is
that in developed countries there has been a major switch in
the causes of death. The pattern of disease whereby infections
were the dominant causes of death has been replaced by
chronic diseases, and notably atherosclerosis, as the primary
cause. That epidemiologic transition in health is common
around the world. However, in poorer countries noncommu-
nicable diseases continue to be the dominant cause of death
(Fig. 28.3).14 Those countries can be expected to change their
pattern of disease as public health improves.
It is a common belief that poverty and economic prosper-
ity are closely linked to health, but it is not so (Fig. 28.4).15
Among countries with a high life expectancy, there is con-
siderable variation in income per capita. Among countries
with a low income per capita, there is a large difference in
life expectancy. The precise reasons are many and complex,

100
% Of total deaths in group
90
90
80
Women 80
Life expectancy (y)

70
70 Communicable
60 60
Men diseases
50 50 Noncommunicable
40 40 diseases
30 30 Injuries
20 20
10 10
0
0
1500 1600 1700 1800 1900 2000 Global World Global
FIGURE 28.1. Expectation of life over centuries in England and poorest 20% average richest 20%
Wales. FIGURE 28.3. The burden of disease among the global poor.14
 globa l differ ences in at h erosclerosis
Life expectancy (years)
80
1990
70
1960
60 About 1930
About 1900
50
40
30
0 5000 10000 15000 20000 25000
Income per capita (normalized to U.S. dollars)
FIGURE 28.4. Life expectancy by income and historical period.15
but what is clear is that the relation between low income and
health is not linear. The macroeconomic impact of HIV/
AIDS has been investigated extensively; less is known about
the consequences of chronic disease and cardiovascular
disease.16 In younger persons, death from HIV/AIDS just
exceeds cardiovascular disease taken as a whole (Fig. 28.5).9
Heart disease and cerebrovascular disease together are the
sources of the greatest proportion of disease burden in men
and women (Fig. 28.6).9 Loss of persons from society or inca-
pacity of contributory and talented individuals in the age
range 35 to 70 years leads to social, economic, and political
instability.16
Predictions have been made with regard to how the
causes of death will alter over the next two decades (Fig.
28.7).1 Heart and lung disease remain the leading causes of
deaths and of disability. The position in 2020 is projected to
be little different from that in 1990. A major factor is the
change in the demography of populations with respect to age
(Fig. 28.2). In those between the age of 15 and 59 (Fig. 28.5),9
the most common cause of death globally is HIV/AIDS, but
that is equaled by deaths from ischemic heart disease and
cerebrovascular disease. In those over the age of 60, the
sequelae of atherosclerosis are by far the major causes of
death.
655
Country Differences in Atherosclerosis
The proportion of persons in countries who die from the
consequence of atherosclerosis varies. For example, in the
United States and the United Kingdom (Fig. 28.8), coronary
heart disease is the most common manifestation of athero-
sclerosis, whereas in other countries, such as Japan, stroke is
more common. In China, stroke is more common than coro-
nary heart disease, but the pattern is changing and is expected
to change even further as the population moves from rural
communities to towns. Urbanization17 leads to alterations of
lifestyle with a changed diet, reduction of exercise, and
increase in diabetes and obesity. In the towns and cities of
China, coronary heart disease is becoming more common.
A common misconception is that atherosclerosis is a disease
of affluent and developing countries; that is simply falla-
cious. Seventy-eight percent of deaths from coronary heart
disease occur in developing countries. Even in low-income
regions such as sub-Saharan Africa, where AIDS ravages
populations, the probability of dying from a chronic disease
(noncommunicable disease) is higher than in established
market economies.4 The reasons for this apparent paradox
are unclear, but include all the known risk factors and the
possibility that poor nutrition and illness in childhood are
linked to early atherosclerosis. The attributable causes of
death in developing countries are shown in Figure 28.9 for
low- and high-income countries.9
Risk Factors
The so-called risk factors for coronary heart disease are
well known.18,19 These risk factors appear to be similar
across all countries regardless of gender, geography or ethnic-
ity.19 Variation in the prevalence of heart disease among
countries can be largely explained on the basis of the degree
to which any particular risk is present. One study19 claims
that nine risk factors can account for 90% of cardiovascular
events. Furthermore, these risk factors are the same risk
factors that are related to cancer, diabetes, and respiratory
diseases. The consequence for public health policy is that the
modification of risk factors may bring greater benefit to a
country than the treatment of specific diseases. The attribut-

15−59 years 60 years and over

2279 HIV/AIDS 5823 Ischemic heart disease

1331 Ischemic heart disease 4692 Cerebrovascular disease
1037 Tuberculosis 2399 COPD
811 Road traffic accidents 1398 Lower respiratory infection
783 Cerebrovascular disease 929 Trachea, bronchitis,lung cancer
672 Self-inflicted injuries 754 Diabetes mellitus
475 Violence 735 Hypertensive heart diease
382 Cirrhosis of the liver 606 Stomach cancer
352 Lower respiratory infections 496 Tuberculosis
343 COPD 478 Colon and rectal cancers
FIGURE 28.5. Leading causes of mortality in adults,
2002.9 COPD, chronic obstructive pulmonary disease. (Deaths 000)
656 chapter 28

Males Females

9.2 Heart disease 8.4 Unipolar depressive disorder

6.9 HIV/AIDS 7.3 HIV/AIDS
6.9 Cerebrovascular disease 6.8 Maternal conditions
4.3 Tuberculosis 5.3 Ischemic heart disease
4.2 COPD 5.2 Cerebrovascular disease
3.8 Unipolar depressive disorders 3.2 Cataracts
3.6 Hearing loss, adult onset 2.8 Hearing loss, adult onset
3.1 Motor vehicle accidents 2.8 COPD
2.8 Cataracts 2.6 Tuberculosis
2.5 Alcohol use disorders 2.0 Osteoarthritis
FIGURE 28.6. Leading causes of disease burden [dis-
ability-adjusted lost years (DALYs)]. Persons aged 15 and
(DALYs) over, worldwide, 2002.9

able mortality is shown in Table 28.2.9 In developed coun-
tries, the recent fall in events relating to coronary heart
disease has been associated with both advances in medical
treatment and reduction of risk factors in almost equal
proportions.20,21
Risk factors such as smoking, poor diet, obesity, and lack
of exercise have been quantitated in many countries of the
world, although the accuracy of some estimates is question-
able. What is less clear is the issue of what is the underlying
cause of these risk factors. Many are related to agricultural
policy and food availability. Social deprivation is closely
linked to coronary heart disease.22–25 Climate change, fiscal
policy particularly in relation to tobacco, industrialization,
and urbanization are associated with risk factors and an
increase in coronary heart disease. Thus, the origins of the
increase in atherosclerosis and differences in prevalence and
incidence among countries may be explained more by social
circumstances within a country than by specific conven-
tional risk factors. It is for this reason that the idea of car-
diovascular disease as a personal responsibility is a myth.
The understanding of the impact of stress and social depriva-
tion and how these are linked to the development of coronary
artery disease is currently a matter of considerable research.
Certainly major stresses, such as earthquakes and natural
disasters, are associated with an increase in deaths from
heart disease. On the other hand, in selected wars, possibly
due to the impact of diet, coronary heart disease has
decreased. Social deprivation leads to depression and bio-
chemical changes within the body that promote the develop-
ment of atherosclerosis.
Prevention of Coronary Heart Disease Around
the World
For many years, organizations have sought to prevent the
development of coronary heart disease in the many countries
of the world. The World Health Organization (WHO) in its
constitution states that health is a state of complete physical,
mental, and social well-being and not merely the absence of
disease or infirmity. In the declaration of Alma Ata in 1978,
it is further stated that the existing gross inequality in the
health status of the people, particularly between developed
and developing countries, is politically, socially, and eco-
nomically unacceptable, and it is therefore of common
concern to all countries. Others have spoken of the moral
principles underlying the care of others.26–28 However, it is
only recently that this problem has been approached more
directly. The Framework Convention on Tobacco Control
adopted at the 56th World Health Assembly in 2003 has had
considerable impact around the world, not only in encourag-
ing countries to introduce legislation, but also in changing
the mood and minds of the public to regard smoking as the
loathsome habit it is. Equally, the Global Strategy on Diet,
Physical Activity, and Health, which was adopted at the 57th
World Health Assembly in 2004, may have the same conse-
quence. Informing the public and politicians of the size and
nature of the problem may have greater consequences overall
than many other approaches.
Those responsible for intervening are many, but too often
groups of experts claim this problem to be their own. The
greatest need is for more cooperation among experts. Epide-

Ischemic heart disease 1 1 Ischemic heart disease U.S.

Cerebrovascular disease 2 2 Cerebrovascular disease
Lower respiratory infections 3 3 COPD
Diarrheal diseases 4 4 Lower respiratory infections U.K. CHD
Perinatal period 5 5 Trachea, bronchus, and lung Stroke
COPD 6 6 Motor vehicle accidents
Tuberculosis 7 7 Tuberculosis Japan Other CVD
Measles 8 8 Stomach cancer
Motor vehicle accidents 9 9 HIV Other
Trachea, bronchus, and lung 10 10 Self-inflicted injuries China (rural)
Malaria 11 11 Diarrheal diseases
Self-inflicted injuries 12 12 Cirrhosis of the liver
Cirrhosis of the liver 13 13 Liver cancer China (urban)
Stomach cancer 14 14 Violence
Diabetes mellitus 15 15 War 0 500 1000 1500
16 16
20 19 Annual mortality per 100,000 males 35–74 years
21 27
30 29 FIGURE 28.8. Causes of death in China, Japan, U.K., and U.S. WHO
FIGURE 28.7. Rank order of deaths in the world 1990–2020.1 statistics.
 globa l differ ences in at h erosclerosis 657
Cardiovascular diseases
Malignant neoplasms
Injuries
Respiratory infections High mortality
Respiratory diseases Low mortality
HIV/AIDS
Perinatal conditions
Diarrheal diseases
Tuberculosis
Digestive diseases
Childhood diseases
Malaria
Diabetes mellitus
Genitourinary system disease
Neuropsychiatric disorders
Maternal conditions
FIGURE 28.9. Deaths attributable to 16 leading causes: 0 2000 4000 6000 8000 10,000 12,000
developing countries, 2001.9 Deaths (000)

miologists, health economists, the media, and politicians
need to demonstrate a more active role. Nurses, health
workers, and primary physicians can influence the public
and patients and their families. Hospital physicians, cardiol-
ogists, and university scholars must emphasize the impor-
tance of the prevention of disease rather than the cure of the
acutely ill. There is a role for medically qualified persons,
but a greater role in prevention for those who work in profes-
sions closely allied to medicine. Perhaps the greatest respon-
sibility resides with political leaders who need to consider
the implications for coronary heart disease when making
political decisions on socioeconomic factors in a country and
on fiscal matters. Reducing multiple risk factors will not
bring about total equity around the world in terms of healthy
life expectancy, but it will reduce substantially the current
differences in equality.29 The reduction in the costs of drugs
as they come off patent will make them more available to
the global population. International collective action,30
engagement of developed countries,31 action by civil society,32
and above all, involvement of the public and patients are
essential for a successful program of prevention.
The preventive approach to heart disease is undervalued
and underused around the world. This is partly because of a
lack of knowledge and partly because of the desire of physi-
cians to treat the acutely sick. Gains from prevention are not
immediately evident so that the elation associated with
bringing about an immediate impact on a patient’s condition
is absent. Some commercial interests may obstruct policy
change. Until recently, the media have focused more on
glamorous advances in medical care than on changes that
would lead to prevention.
The burden of noncommunicable diseases and particu-
larly atherosclerosis in developing countries outweighs com-
municable diseases. That fact is only just being widely
appreciated and was referred to as the double burden requir-
ing a double response by the WHO Health Report in 2003.9
It was proposed that a comprehensive health care system was
required that integrated the prevention and control of both
communicable and noncommunicable diseases. Sadly, that
is not yet happening. There is at present insufficient coordi-
nation among health specialists, politicians, health bodies,
and nongovernmental organizations. The Millennium
Project with its development goals,33 the World Bank, the
Global Fund,34 the Commission for Africa,35 and the more
recent WHO reports are largely silent with regard to cardio-
vascular disease; a change is needed. The World Heart
Federation36 and other nongovernmental organizations have
put forward principles to be adopted so as to promote suc-
cessful policies on prevention.37
Summary
Heart disease and stroke are a global challenge. The diseases
are common and becoming more common. The problem
exists regardless of ethnicity, gender, or geography. The

TABLE 28.2. Attributable mortality by risk factor (%) 9

Developing countries

Developed countries Low mortality High mortality

Blood pressure 22 Blood pressure 13.8 Underweight 13

Tobacco 18 Tobacco 7.9 Unsafe sex 10.1
Cholesterol 16 Alcohol 5.3 Blood pressure 7.4
Overweight 10.5 Cholesterol 5.3 Unsafe water 5.8
Few fruit & veg. 7.5 Few fruit & veg. 4.9 Cholesterol 5.3
Physical inactivity 6.3 Overweight 4.8 Tobacco 4.6
Alcohol 4.2 Indoor smoke 3.5 Indoor smoke 3.9
Urban air poll. 1.1 Physical inactivity 3.0 Few fruit & veg. 3.6
Carcinogens 0.5 Urban air poll. 2.7 Zinc deficiency 2.9
Lead exposure 0.6 Underweight 1.8 Vit. A deficiency 2.8
658 chapter
causes are known and prevention is possible by applying
existing scientific knowledge. A strong international effort
will encourage country-led initiatives, but perhaps the key
to success is to inform better the public and patients so that
political leaders react in a manner the enhances the health
of the people of the world.
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 2 Coronary Artery Disease:
9 Regulation of Coronary
Blood Flow
Robert J. Bache
Determinants of Myocardial Oxygen Consumption . . .
Epicardial Coronary Arteries . . . . . . . . . . . . . . . . . . . . . .
Coronary Resistance Vessels . . . . . . . . . . . . . . . . . . . . . .
Endothelium-Dependent Vasodilation . . . . . . . . . . . . . . .
Over a wide range of activity, coronary blood flow is closely
matched to myocardial metabolic requirements to maintain
a consistently high level of oxygen extraction by the heart.
Even during resting conditions 70% to 80% of the oxygen
perfusing the coronary capillaries is extracted by the myocar-
dium, so there is little ability to increase oxygen uptake by
means of increasing oxygen extraction.1 For this reason,
increases of oxygen demands during exercise or other stress
must be met by proportionate increases in coronary flow.
Close coupling of coronary blood flow to cardiac work is
further mandated by the strongly oxidative nature of energy
production by the heart. More than 95% of the adenosine tri-
phosphate (ATP) utilized by the myocardium is produced
through oxidative phosphorylation, which requires a continu-
ous supply of oxygen to the mitochondria.2 Since the ATP pool
of the heart turns over four to five times per minute, failure of
ATP production to equal ATP consumption results in loss of
contractile function within a few seconds. Reductions of coro-
nary blood flow by as little as 10% to 20% result in contractile
dysfunction and depletion of high-energy phosphates.3,4 These
considerations imply that the myocardium functions near the
brink of ischemia, and emphasizes the importance of the
mechanisms by which coronary vasomotor tone is adjusted in
response to beat-to-beat changes of myocardial energy
demands. Ischemia occurs when diseased coronary vessels
are unable to deliver sufficient arterial inflow to meet myocar-
dial metabolic demands. When coronary flow is limited by an
arterial stenosis, myocardial oxygen demands play a decisive
role in setting the threshold for ischemia.
659 Transmural Distribution of Myocardial Blood Flow . . . 663
660 Coronary Collateral Circulation . . . . . . . . . . . . . . . . . . . 663
661 Coronary Steal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664
662 Left Ventricular Hypertrophy . . . . . . . . . . . . . . . . . . . . . . 664
Determinants of Myocardial
Oxygen Consumption
Approximately 85% of the ATP produced in the heart is uti-
lized to support contractile activity, so that indices of cardiac
pump function can be used to estimate myocardial oxygen
demands. Furthermore, therapies that decrease the response
of contractile work during exercise can prevent the develop-
ment of ischemia in myocardial regions in which flow reserve
is limited by a coronary stenosis. The hemodynamic vari-
ables that determine myocardial energy consumption (Table
29.1) include the following:
Systolic Wall Tension
Force produced by the contracting myocardium to generate
pressure is expressed in terms of wall tension. Systolic wall
tension is directly proportional to left ventricular systolic
pressure. Since wall tension is expressed as force per unit
cross-sectional area, it is directly proportional to left ven-
tricular cavity diameter and inversely proportional to wall
thickness. Since wall tension cannot be directly measured,
systolic arterial pressure is commonly used as a surrogate for
systolic wall tension. Because the effects of left ventricular
cavity diameter and wall thickness are neglected, the rela-
tionship between systolic arterial pressure and myocardial
oxygen consumption is imprecise. However, changes in
659
660 chapter
TABLE 29.1. Determinants of myocardial oxygen consumption
Systolic wall stress
Left ventricle (LV) systolic pressure
LV diameter
Wall thickness
Contractility
Heart rate
systolic wall stress are directly proportional to changes in
systolic blood pressure and are predictive of changes in
oxygen consumption during exercise.
Contractility
Myocardial contractility describes the rate of tension devel-
opment during cardiac contraction. An increase in contrac-
tility causes an increase in the rate of pressure development
and an increase in the velocity of shortening of the contract-
ing myocardium. The first-time derivative of left ventricular
pressure during isovolumic contraction (dP/dtmax) is used to
estimate myocardial contractility. This variable changes in
parallel with contractility, but is also influenced by both left
ventricular preload (end-diastolic pressure) and afterload (sys-
tolic pressure). Direct determination of this index of contrac-
tility requires high-fidelity measurements of left ventricular
systolic pressure in the catheterization laboratory.
Heart Rate
Heart rate is a summing factor for the energy cost of cardiac
contraction. Since systolic wall tension and contractility are
computed on a per beat basis, changes in heart rate bear a
strong relationship to changes in myocardial oxygen uptake.
Furthermore, heart rate directly influences contractility, so
that increases of heart rate during exercise or other stress
result in increased contractility.
Rate-Pressure Product
The product of heart rate and systolic arterial pressure (rate-
pressure product) is a convenient index for estimating changes
in myocardial oxygen demands. Proportional changes in
heart rate or systolic pressure have equal effects on myocar-
dial oxygen consumption.5 The rate-pressure product is espe-
cially useful for estimating the cardiac workload during
exercise testing.
Epicardial Coronary Arteries
The epicardial arteries form a network of vessels that arbo-
rize over the surface of the heart and give off branches that
penetrate into the myocardium. Normal epicardial arteries
are true conduit vessels that contribute little to total coro-
nary vascular resistance. The epicardial arteries are richly
innervated with sympathetic nerve fibers, and coronary
artery smooth muscle cells contain both α-adrenoceptors
that mediate vasoconstriction as well as β-receptors that
29
cause vasodilation. In the normal heart, exercise results in
endothelium-dependent vasodilation of the epicardial arter-
ies, which is mediated by nitric oxide, so that blockade of
nitric oxide production prevents normal coronary artery
vasodilation during exercise.6,7 Endothelial dysfunction
resulting from hyperlipidemia, hypertension, or atheroscle-
rosis blunts or abolishes the normal epicardial artery dilation
during exercise.8
Autopsy studies of patients with atherosclerotic disease
have demonstrated that approximately 75% of coronary ath-
eromas are eccentric in location, leaving part of the vessel
wall uninvolved. The existence of a relatively uninvolved
segment explains the observation that coronary stenoses
often do not behave as fixed narrowings, but have some
degree of compliance and are able to undergo active vasomo-
tion.9,10 The intraarterial distending pressure within a
stenosis opposes the vasomotor tone and elasticity of the
arterial wall, which act to constrict the vessel. Compliant
stenoses can interact with the distal resistance vessels as the
result of hydrodynamic changes in the stenotic segment.
Thus, when exercise results in vasodilation of the distal
resistance vessels, the increased blood velocity (kinetic
energy) within the stenotic segment causes a proportionate
decrease in pressure (potential energy) acting to distend the
stenosis. As the distending pressure in the stenosis decreases
with increasing flow, the arterial wall elasticity and vasocon-
strictor tone act to collapse the stenosis and increase stenosis
severity.11 This effect is augmented by endothelial dysfunc-
tion in the atherosclerotic coronary circulation, since the
normal flow-mediated vasodilator response is absent.9,12 When
a stenosis is severe, the effects of increasing blood velocity
within the stenosis can be sufficient to cause a paradoxical
decrease in blood flow in response to resistance vessel dila-
tors such as adenosine or dipyridamole. In addition, a compli-
ant segment of arterial wall at the site of a stenosis can
undergo active vasoconstriction in response to sympathetic
nervous system activation or agonists such as ergonovine,
serotonin, or thromboxane. Sympathetic vasoconstriction is
augmented in the atherosclerotic coronary circulation, since
adrenergic stimulation causes endothelial release of nitric
oxide, which opposes vasoconstriction in normal coronary
vessels but is lost in atherosclerotic vessels (Table 29.2).13
TABLE 29.2. Relative potency of vasodilators on epicardial
coronary arteries and coronary arterioles in normal subjects (n)
and in patients with coronary risk factors or minimal coronary
disease and endothelial dysfunction (Dys)
Epicardial artery Coronary arterioles
n Dys n Dys
Acetylcholine ++ Constrict + Constrict
Nitrates ++++ ++++ + +
Adenosine + ↔ ++++ ++++
Dipyridamole + ↔ +++ +++
Serotonin Constrict Constrict +++ +++
Nifedipine + ↔ ++ ++
Verapamil + ↔ + +
Exercise + ↔ +++ +++
 corona ry a rt e ry dise a se : r egu l at ion of corona ry bl ood f l ow
Isometric exercise causes greater activation of the sympa-
thetic nervous system than dynamic exercise; consequently,
the tendency toward constriction of stenotic coronary artery
segments is more prominent with isometric exercise than
with dynamic exercise.10
Coronary Resistance Vessels
The principal resistance to blood flow resides in coronary
microvessels smaller than 400 μm in diameter. Coronary
resistance vessels can be divided functionally into two sepa-
rate segments: arterioles and resistance arteries. Coronary
arterioles less than 100 μm in diameter mediate metabolic
vasoregulation and autoregulation, by which blood flow is
adjusted in response to myocardial demands and is main-
tained constant over a range of perfusion pressures. Coronary
resistance arteries 100 to 300 μm in diameter account for as
much as 40% of total coronary resistance but do not partici-
pate in metabolic flow regulation.14 Because of important
differences in the responses of the coronary arterioles and
the resistance arteries, these vascular segments are discussed
separately.
Coronary Arterioles
Regulation of blood flow in response to changing myocardial
needs occurs at the level of the coronary arterioles. Coupling
of arteriolar vasomotor tone to myocardial metabolic
demands appears to involve ATP-sensitive potassium chan-
nels (K+ATP) in coronary vascular smooth muscle cells.15,16
Opening of K+ATP channels results in outward flux of potas-
sium, thereby causing an increase of membrane potential in
the smooth muscle cell. This hyperpolarization causes
voltage-dependent calcium channels to close; the resultant
decreased influx of calcium produces relaxation of the vas-
cular smooth muscle (vasodilation).15 Pharmacologic inhibi-
tion of K+ATP channel opening has been demonstrated to
impair coronary autoregulation, metabolic vasoregulation,
and ischemic vasodilation.15,16 These channels open in
response to decreases of intracellular ATP or increases of
ADP. Such alterations of high-energy phosphates occur
during ischemia, but cannot account for coronary vasodila-
tion that occurs during physiologic increases of myocardial
oxygen demands during exercise or other stress. Although
the factors that regulate vascular K+ATP channel activity
during physiologic conditions are uncertain, the critical
importance of this channel is demonstrated by the finding
that mice with genetic deletion of coronary K+ATP channels
are vulnerable to myocardial ischemia and sudden death.17
Adenosine has been suggested as a mediator of metabolic
coronary vasodilation.18 When cardiac work is increased, the
rate of ATP utilization by the contractile apparatus tran-
siently exceeds the rate of resynthesis of ATP, resulting in
an increase of free adenosine diphosphate (ADP). The cyto-
solic enzyme adenylate kinase can then act on two molecules
of ADP to form one molecule each of ATP and adenosine
monophosphate (AMP). The AMP released by this reaction
can be catabolized to adenosine, which can be transported
out of the myocyte into the interstitial fluid. In the intersti-
tial fluid, adenosine engages receptors on the coronary
6 61
smooth muscle cell membrane to cause vasodilation.18 Ade-
nosine can be taken up by the myocardial myocytes for
reincorporation into the adenine nucleotide pool or can be
deaminated to inosine, which has little vasodilator activity.
These reactions occur very quickly, so that the half-life of
adenosine is only a few seconds. The vasodilator effect of
adenosine can be inhibited by methyl xanthines such as
theophylline, which act as adenosine receptor blockers. Ade-
nosine receptor blockade does not interfere with the normal
increase in myocardial blood flow during exercise or other
increases of oxygen demands, implying that adenosine is not
a principal mediator of normal metabolic vasoregulation.19
However, adenosine production increases markedly during
ischemia and does contribute to vasodilation of coronary
resistance vessels in ischemic myocardial regions.20 Other
metabolic perturbations that occur during ischemia, includ-
ing accumulation of hydrogen ion and lactate, can also cause
coronary vasodilation, but these changes are not likely to
contribute to regulation of arteriolar tone during physiologic
conditions. Decreases of arterial oxygen tension and increases
of carbon dioxide tension exert vasodilator effects on coro-
nary resistance vessels, with evidence for a synergistic inter-
action between them.21 Oxygen diffusion out of the coronary
microvessels occurs so rapidly that oxygen tension in arteri-
oles and even small arteries is lower than in aortic blood,
suggesting a direct role for oxygen in the local regulation of
blood flow.22
Myogenic Mechanisms
Myogenic automaticity refers to the intrinsic property of
smooth muscle to respond to stretch with a counteracting
increase in contractile force. Thus, an increase in intralumi-
nal distending pressure causes the vascular smooth muscle
to contract, whereas a decrease in pressure results in vasodi-
lation. Myogenic activity is an intrinsic property of coronary
arterioles and is not altered by endothelial denudation.23
Myogenic responses to changes of intraluminal pressure are
more prominent in arterioles from the subepicardium than
from the subendocardium of the left ventricle, suggesting
that intrinsic differences in responsiveness could contribute
to the lesser ability to autoregulate in the subendocardium.24
Although myogenic activity can be demonstrated in isolated
coronary arterioles, the contribution of myogenic mecha-
nisms to regulation of blood flow in the intact heart is likely
of less importance than metabolic or endothelium-mediated
responses.
Resistance Arteries
Small arteries (100 to 300 μm in diameter) contribute up to
40% of total coronary resistance but, unlike the arterioles,
these vessels are not responsive to the metabolic state of the
myocardium.25 However, when increased cardiac activity
results in metabolic vasodilation of the coronary arterioles,
the resultant increase of blood flow causes shear-mediated
endothelium-dependent dilation of the resistance arteries.
Loss of flow-mediated vasodilatation of the resistance arter-
ies in patients in whom hyperlipidemia, atherosclerosis, or
hypertension has resulted in endothelial dysfunction can
impair vasodilator reserve even in the absence of occlusive
662 chapter 29

coronary artery disease. This is supported by the finding that Agonist

vasodilator reserve measured with positron emission tomog-
raphy is impaired in patients with hyperlipidemia but with Ca2+
angiographically normal coronary arteries, and that this Endothelial
abnormality can be corrected by lipid-lowering therapy.25,26 cell Shear
Ca2+ 2+ stress
Ca
2+ Akt
Penetrating Arteries Ca2+ Ca calmodulin
Cyclooxygenase eNOS P AA P-450
Intramyocardial arteries can be divided into two classes: AA L-arg EDHF
class A arteries arborize soon after entering the myocardium PGI2 NO
and supply principally the outer two thirds of the left ven- ONOO– O2– K+
tricular wall; and class B arteries penetrate deep into the EDHF
PGI2 NO
myocardium before arborizing to supply blood to the suben- Smooth muscle
docardium.27 The class B vessels are also called penetrating cell Adenylyl Guanylyl
arteries. The potential influence of the penetrating arteries cAMP cyclase cyclase
K+
on blood flow is documented by the finding that pressure in
hyperpolarization
arterioles in the subendocardium is less than in subepicar- K+ hyperpolarization cGMP GTP
dial arterioles, indicating that a significant pressure loss 2+
Ca Relaxation Ca2+
occurs across the penetrating arteries.23 Furthermore, vaso-
motor activity of the penetrating arteries can selectively K+
influence blood flow to the subendocardium. Vasodilation of FIGURE 29.1. Endothelium-dependent vasodilator mechanisms.
Agonists such as acetylcholine, bradykinin, or histamine engage
the penetrating arteries appears to be a mechanism by which
specific receptors on endothelial cells that increase cytosolic
nitroglycerin can augment blood flow to the subendocar- calcium. Calmodulin binds the calcium, and the calcium-calmodu-
dium in ischemic myocardial regions.28 lin complex activates eNOS to catalyze the conversion of L-arginine
(L-arg) to produce nitric oxide (NO). The increased cytosolic calcium
also activates cyclooxygenase to augment production of prostacyclin
(PGI 2) from arachidonic acid (AA). Shear stress acts open calcium
Endothelium-Dependent Vasodilation channels but also activates Akt, which phosphorylates eNOS to
cause a sustained increase of enzyme activity. Mechanisms respon-
sible for production of endothelium-dependent hyperpolarizing
Nitric Oxide factor (EDHF) are currently unclear, but may result from P-450
acting on arachidonic acid. NO produced in endothelial cells dif-
The importance of the vascular endothelium in mediating
fuses to the underlying smooth muscle to activate guanylyl cyclase,
vasodilator responses was first demonstrated by Furchgott thereby increasing cytosolic cyclic guanosine monophosphate
and Zawadski,29 who observed that acetylcholine caused (cGMP) levels, which produce relaxation by decreasing cytosolic
relaxation of isolated coronary artery rings when the endo- calcium as well as by decreasing calcium sensitivity of the
thelium was intact, but produced contraction when the endo- contractile proteins. Increased superoxide (O2 –) production in the
atherosclerotic coronary circulation consumes NO to produce per-
thelium was removed. Subsequent studies demonstrated that oxynitrite (ONOO –), thereby decreasing NO bioavailability and
a number of agonists including acetylcholine, bradykinin, causing endothelial dysfunction.
histamine, and thrombin cause coronary vasodilation indi-
rectly by engaging specific receptors on the endothelium that
trigger the release of one or more endothelium-derived relax-
ing factors (EDRFs).30 The principal mediator of this vasodila- by cytokines or inflammatory mediators, and which is not
tion is nitric oxide (NO), which is produced when the regulated by the intracellular calcium content (Fig 29.1).
constitutive endothelial cell enzyme nitric oxide synthase Endothelium-dependent NO-mediated coronary vasodi-
(eNOS) acts on arginine to produce citrulline with liberation lation is impaired in the setting of hyperlipidemia or athero-
of NO. Enzyme nitric oxide synthase is a calcium-calmodu- sclerosis. Impairment of NO-dependent vasodilation appears
lin–dependent P-450 enzyme; agonists that produce endothe- to result in part from increased oxygen free radical produc-
lium-dependent NO-mediated vasodilation generally act by tion in the atherosclerotic vessel, which quenches NO,
causing increases of intracellular calcium to activate the thereby attenuating its biologic actions.33,34 There is some
enzyme.31 Alternatively, eNOS can be activated by serine evidence that arginine administration can improve endothe-
phosphorylation, thereby causing sustained increases of NO lium-dependent vasodilator mechanisms. Since intracellular
production. Nitric oxide produced by eNOS can diffuse to arginine is present in excess, arginine deficiency is unlikely
the vascular smooth muscle and activate guanylate cyclase; to directly limit NO production. However, circulating argi-
the resultant increase in cyclic guanosine monophosphate nine analogues, such as asymmetric dimethylarginine, have
(cGMP) causes relaxation of the vascular smooth muscle. been identified that can act as endogenous competitive
The shear force produced by blood flowing over the endothe- inhibitors of arginine.35 Increased levels of these endogenous
lial cells can also activate eNOS; in this way dilation of the eNOS inhibitors are found in patients with coronary disease,
epicardial arteries is coordinated with the increased flow congestive heart failure, and renal failure, and may con-
produced by metabolic dilation of the coronary resistance tribute to endothelial dysfunction in these conditions.
vessels during exercise.6,31–33 Enzyme nitric oxide synthase is Arginine administration could potentially exert a beneficial
distinct from inducible nitric oxide synthase (iNOS), which effect by competition with these endogenous inhibitors of
is not present in normal coronary vessels but can be induced NO synthase.
 corona ry a rt e ry dise a se : r egu l at ion of corona ry bl ood f l ow
Prostacyclin
Prostacyclin is a coronary vasodilator and potent inhibitor
of platelet aggregation that is produced from arachidonic acid
by vascular endothelial cells. Prostacyclin is synthesized by
the enzyme cyclooxygenase so that nonsteroidal antiinflam-
matory agents that inhibit cyclooxygenase can decrease pros-
tacyclin production.36 The rate-limiting step for prostacyclin
synthesis appears to be the availability of arachidonic acid
mobilized from membrane phospholipids by phospholipase
A 2. Basal prostacyclin production in the coronary circulation
is insufficient to be detectable using current technology.36
Prostacyclin is released in response to agonists that interact
with specific endothelial cell surface receptors including bra-
dykinin, histamine, and thrombin, as well as by increased
endothelial shear forces that cause release of calcium from
intracellular stores, thereby activating phospholipase A 2.37
Production of prostacyclin in response to these stimuli is
transient even when the agonist is continuously present.
Most evidence suggests that prostacyclin functions princi-
pally as an antiplatelet and antithrombotic molecule with
only a modest influence on coronary vasomotor activity in
the normal heart.
Hyperpolarizing Factor
Studies in isolated coronary vessels have demonstrated that
the vasodilator response to acetylcholine and certain other
endothelium-dependent agonists cannot be fully accounted
for by NO or prostacyclin. These agents cause hyperpolariza-
tion of the vascular smooth muscle cell membrane by opening
of calcium-activated potassium channels; membrane hyper-
polarization decreases calcium influx, thereby resulting in
vasodilation.38 The mediators of this effect have been termed
endothelium-dependent hyperpolarizing factors (EDHFs);
current evidence suggests that they are cytochrome P-450–
dependent metabolites of arachidonic acid. The extent to
which EDHF contributes to regulation of coronary blood
flow during physiologic conditions is unknown.
Transmural Distribution of Myocardial
Blood Flow
In the normal heart blood flow to the subendocardium is
maintained 20% to 40% higher than flow to the subepicar-
dium, reflecting greater systolic tension development and
greater oxygen utilization in the subendocardium.39 Mainte-
nance of this perfusion gradient favoring the subendocar-
dium requires active vasomotion of the coronary resistance
vessels. During systole the contracting myocardium com-
presses the thin-walled microvessels within the wall of the
left ventricle; the interaction between the extravascular
forces acting to collapse the vessels and the intravascular
distending pressure that resists collapse of the vessels is
termed the vascular waterfall.40 In a vascular waterfall, the
outflow pressure that impedes flow is not the venous pres-
sure, but rather results from the compressing force acting on
the intramural vessels. Since extravascular compressive
forces increase from epicardium to endocardium, impedance
to blood flow is greatest in the subendocardium. To compen-
663
sate for underperfusion of the subendocardium during systole,
during diastole vasomotor tone of the resistance vessels is
maintained lower in the subendocardium than in the sub-
epicardium. As a result, vasodilator reserve is lower in the
subendocardium than in the subepicardium.
In response to an arterial stenosis, the coronary resis-
tance vessels undergo vasodilation to compensate for the
additional resistance caused by the stenosis. The need for
this vasodilation during basal conditions compromises the
ability for further dilation to increase blood flow during
exercise or other stress.41 A stenosis that is sufficiently severe
to elicit near maximal vasodilation of the resistance vessels
is termed a critical stenosis, inasmuch as an increase in
myocardial metabolic demand cannot be met by an increase
in blood flow, so that ischemia results. When a coronary
stenosis limits blood flow below the metabolic demands of
the myocardium, the limited arterial inflow is preferentially
redistributed to the outer myocardial layers, so that hypoper-
fusion and ischemia are most severe in the subendocardium.
This redistribution of blood flow away from the subendocar-
dium initially occurs because vasodilator reserve is least in
the subendocardium. In addition, ischemic vasodilation of
the coronary resistance vessels can result in a marked
pressure drop across a stenosis; because of the decreased
distal coronary pressure, the intramural vessels are less
able to resist the compressing effects of the extravascular
forces. Since intramyocardial pressure is highest in the sub-
endocardium, impedance to blood flow is greatest in this
region. Increases of left ventricular diastolic pressure will
further augment the extravascular compressive forces and
amplify the redistribution of blood flow away from the
subendocardium.
Coronary Collateral Circulation
Normal human hearts possess a rudimentary network of
intercoronary collateral anastomoses 20 to 300 μm in diam-
eter.42 These intrinsic collateral vessels are generally insuf-
ficient to limit myocardial injury during acute coronary
occlusion, but form a scaffold for the development of an effec-
tive collateral circulation in response to occlusive coronary
artery disease.42 If a coronary occlusion occurs gradually,
sufficient time for collateral vessel development can prevent
myocardial infarction, despite total coronary occlusion. Col-
lateral vessel development is stimulated by hemodynami-
cally significant coronary artery stenoses. High-grade
coronary stenotic lesions are required to stimulate growth of
well-developed collateral vessels. A stenosis causing less
than 80% luminal narrowing is rarely associated with well-
developed collaterals, whereas stenoses causing 95% narrow-
ing are almost always associated with good collateral filling.43
The rate of collateral development has been studied in
patients hospitalized for acute myocardial infarction. Sequen-
tial coronary angiograms demonstrated that approximately
50% of patients developed an effective collateral circulation
within 2 weeks and approximately two thirds by 2 months
after acute coronary occlusion.44 It is unclear whether col-
lateral vessel growth proceeds at a similar rate in patients
with high-grade coronary stenotic lesions and recurrent isch-
emia but without tissue necrosis.
664 chapter
Collateral vessel development can occur by sprouting of
new vessels (angiogenesis) or by growth and remodeling of
the rudimentary intercoronary anastomoses that exist in
normal hearts (arteriogenesis).45 Angiogenesis predominates
in regions adjacent to infarcted myocardium, likely as the
result of growth factors released from necrotic myocytes and
recruited inflammatory cells. In contrast, collateral vessel
growth in response to a coronary stenosis in the absence of
infarct occurs principally through arteriogenesis.46 It appears
that increased flow (endothelial shear) initiates growth of the
collateral vessels. In the normal heart there is little flow in
the rudimentary collateral vessels, since blood pressure in
adjacent coronary arteries is equal. However, when a coro-
nary stenosis causes a decrease in distal coronary pressure,
blood from the adjacent arteries flows through the rudimen-
tary collateral vessels into the lower pressure vessel. The
resultant endothelial shear causes expression of adhesion
molecules that attract monocytes46 that release growth
factors that exert mitogenic effects on endothelial and smooth
muscle cells. Administration of growth factors (basic fibro-
blast growth factor, vascular endothelial growth factor) have
been shown to accelerate collateral vessel growth in experi-
mental animals subjected to coronary occlusion, but clinical
trials of growth factor treatment in patients with ischemic
heart disease have not produced beneficial effects.47,48
Although marked collateral vessel growth can occur in
response to coronary artery occlusion, vasodilator reserve is
not normal in regions perfused by collateral vessels. Thus,
developed collateral vessels can provide adequate arterial
inflow to meet myocardial needs during resting conditions,
but the ability to augment flow in response to exercise or
other stress is less than in normally perfused myocardial
regions.49 Furthermore, occlusive disease in the donor arter-
ies from which collateral vessels originate can impair the
ability to increase blood flow. Well-developed collateral
vessels have a well-organized muscular media and are respon-
sive to vasodilator and vasoconstrictor stimuli; as a result,
collateral vessels can undergo vasomotor activity.50 Vasocon-
striction of collateral vessels can worsen hypoperfusion of a
collateral-dependent region of myocardium and lower the
threshold for ischemia during exercise.51 Nitroglycerin is a
potent collateral vessel dilator that has been demonstrated
to improve exercise tolerance in patients with single-
vessel coronary occlusion and a region of viable collateral-
dependent myocardium.51
Coronary Steal
Coronary steal occurs when coronary vasodilation causes an
increase of blood flow in one myocardial region but a paradoxi-
cal decrease in flow in an adjacent region.52 This can occur
when adjacent collateral-dependent and normally perfused
myocardial regions derive their blood supply from a common
stenotic coronary artery. The stenosis in the common feeding
artery is critical in the development of coronary steal, because
it causes a pressure drop that varies with the flow rate and
thereby determines the perfusion pressure at the origin of the
collateral vessels. During basal conditions the arterioles in
the collateralized region must maintain sufficient vasodila-
tion to compensate for the resistance of the collateral vessels;
29
consequently, part of their vasodilator reserve is utilized even
during basal conditions. In response to an increase of myocar-
dial oxygen demands (exercise) or a pharmacologic small-
vessel dilator (e.g., adenosine or dipyridamole), the resistance
vessels in both the normally perfused and collateral-
dependent regions dilate. Since vasodilator reserve is greater
in the normal zone than in the collateral zone, flow will
increase preferentially in the normal zone. When a stenosis
exists in a common artery that supplies both the normal and
collateral zones, the increased flow rate will magnify the pres-
sure drop across the narrowing and cause a decrease in distal
coronary pressure. If the fall in distal perfusion pressure
exceeds the ability of the resistance vessels in the collateral
zone to dilate, then an absolute decrease in flow into the col-
lateral zone will occur.53 Drugs that cause dilation of coronary
resistance vessels such as adenosine or dipyridamole have the
potential to cause coronary steal, while agents such as nitro-
glycerin that act to dilate collateral vessels and proximal
coronary arteries (including compliant stenotic segments)
oppose the development of steal.
Left Ventricular Hypertrophy
Left ventricular hypertrophy (LVH) is associated with struc-
tural and functional abnormalities of the coronary circula-
tion that can increase the vulnerability to ischemia during
exercise or other stress. In patients with hypertension, LVH
confers an increased risk for development of angina pectoris,
congestive heart failure, and sudden death.54 Furthermore, a
coronary stenosis that limits arterial inflow during exercise
causes more severe subendocardial hypoperfusion in animals
with LVH than in animals without hypertrophy.55 Acute
coronary occlusion results in infarction of a greater fraction
of the myocardial region at risk and a higher incidence of
sudden death in animals with LVH than in normal animals.56
Epicardial coronary artery lumen diameter is increased in
LVH, but this is less than expected for the increase in myo-
cardial mass.57 Maximum coronary flow rates per gram of
myocardium are impaired in the hypertrophied heart. This
impairment of coronary vasodilator reserve results from
both failure of the coronary vessels to grow in proportion to
the increased myocardial mass, as well as because of increased
extravascular forces in the hypertrophied heart that act to
compress the intramural coronary microvasculature.58 The
effects of the increased extravascular forces in the hypertro-
phied heart are most prominent in the subendocardium, so
that exercise can result in transmural redistribution of blood
flow away from the subendocardium even in the absence of
atherosclerotic coronary artery disease. In patients with
severe pressure overload LVH, especially that resulting from
aortic stenosis, the abnormalities of coronary perfusion can
be sufficient to result in exertional angina pectoris even in
the absence of occlusive coronary artery disease.
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artery occlusion in human subjects. J Am Coll Cardiol 1989;
13:297–303.
44. Schwartz H, Leiboff RH, Bren GB, et al. Temporal evolution of
the human coronary collateral circulation after myocardial
infarction. J Am Coll Cardiol 1984;4:1088–1093.
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45. Helisch A, Schaper W. Arteriogenesis: the development
and growth of collateral arteries. Microcirculation 2003;10:
83–97.
46. Schaper W, Ito WD. Molecular mechanisms of coronary col-
lateral vessel growth. Circ Res 1996;79:911–919.
47. Rosinberg A, Khan TA, Sellke FW, Laham RJ. Therapeutic
angiogenesis for myocardial ischemia. Expert Rev Cardiovasc
Ther 2004;2:271–283.
48. Scheinowitz M. therapeutic myocardial angiogenesis: past,
present and future. Mol Cell Biochem 2004;264:75–83.
49. Bache RJ, Schwartz JS. Myocardial blood flow during exercise
after gradual coronary occlusion in the dog. Am J Physiol 1983;
245(Heart Circ Physiol 14):131–138.
50. Foreman BW, Dai XZ, Bache RJ. Vasoconstriction of canine
coronary collateral vessels with vasopressin limits blood flow
to collateral-dependent myocardium during exercise. Circ Res
1991;69:657–664.
51. Pupita G, Maseri A, Kaski JC, et al. Myocardial
ischemia caused by distal coronary-artery constriction
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52. Bache RJ, Duncker DJ. Coronary steal. ACC Curr J Rev 1994;
3:9–12.
29
53. Kaufmann PA, Mandinov L, Seiler C, Hess OM. Impact of
exercise-induced coronary vasomotion on anti-ischemic
therapy. Coron Artery Dis 2000;11:363–369.
54. Koren MJ, Devereaux RB, Casale PN, Savage DD, Laragh JH.
Relation of left ventricular mass of geometry to morbidity and
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55. Bache RJ, Wright L, Laxson DL, Dai X. Effect of a coronary
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56. Dellsperger KC, Clothier JL, Koyanagi S, Inou T, Marcus ML.
Effects of coronary artery occlusion in animals with hyperten-
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Circ Physiol 38):H271–H281.
 3 Coronary Heart
0 Disease Syndromes:
Pathophysiology and
Clinical Recognition
James T. Willerson, Attilio Maseri,
and Paul W. Armstrong
Stable Angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668
Variant Angina (“Prinzmetal’s Angina”). . . . . . . . . . . . . 670
Unstable Angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672
Key Points
• Atherosclerotic plaque fissuring or ulceration generally
cause the development of the acute coronary artery
disease syndromes.
• Vulnerable or “unstable” atherosclerotic plaques have
temperature and pH heterogeneity, thin fibrous caps,
inflammatory cells primarily macrophages, and activated
T cells on their surface, and an adjacent lipid pool. Some
patients have multiple unstable atherosclerotic plaques
simultaneously.
• Several serum markers when elevated help identify
patients at increased risk for future vascular events,
including C-reactive protein (CRP), CD40SL, pregnancy-
associated protein, serum amyloid protein (SAP), brain
natriuretic peptide (BNP), vascular cell adhesion mole-
cule (VCAM), intracellular adhesion molecule (ICAM),
and interleukin-6.
• Unstable angina and non-ST segment elevation myocar-
dial infarction (NSTEMI) are associated with atheroscle-
rotic plaque fissuring or ulceration, adherence of platelets
at the same sites, the accumulation of thromboxane
A 2, serotonin, adenosine diphosphate (ADP), thrombin,
tissue factor, oxygen-derived free radicals, and endothelin
promoting growth of the thrombus and dynamic vaso-
constriction with transient (unstable angina or NSTEMI)
Vulnerable or Unstable Atherosclerotic Plaque . . . . . . . 672
Acute Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . 677
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
or permanent coronary artery occlusion (ST segment
elevation MI, STEMI).
• The functional absence or diminished effect of nitric
oxide (NO), tissue-type plasminogen activator (t-PA),
and prostacyclin at sites of vascular injury contributes
to dynamic thrombosis, vasoconstriction, fibroprolifera-
tion, and inflammation at sites of coronary artery athero-
sclerosis and plaque fissuring and ulceration.
• Unstable angina, NSTEMI, and STEMI represent a con-
tinuum of thrombosis and vasoconstriction in that
unstable angina is often caused by transient and
recurrent coronary artery thrombosis and vasoconstric-
tion, NSTEMI by slightly more prolonged but still
usually transient thrombosis and vasoconstriction or
subtotal coronary artery occlusion, and STEMI by
prolonged and usually permanent coronary artery
occlusion.
• Power failure complications of MIs occur in patients
with ≥40% irreversible damage to the left ventricle (LV)
and include cardiogenic shock, medically refractory con-
gestive heart failure (CHF), and medically refractory
arrhythmias.
• Even with relatively small MIs, mechanical problems,
such as acute mitral regurgitation (MR), ventricular
septal defects (VSDs), and ventricular aneurysms may
lead to shock and CHF.
6 67
668 chapter 30

TABLE 30.1. Coronary heart disease syndromes

Stable angina pectoris
Unstable angina pectoris
Variant angina (“Prinzmetal’s angina”)
Acute myocardial infarction
Non-Q wave or non-ST elevation (usually nontransmural infarcts)
Q wave or ST elevation (usually transmural myocardial infarcts)

Stable Angina

Pathophysiology
The coronary heart disease syndromes are listed in
Table 30.1.
Angina pectoris is the clinical term used to describe
chest discomfort resulting from a relative oxygen deficiency
in heart muscle. Heberden1 named this entity when he
identified a “disorder of the breast marked with strong and
peculiar symptoms and considerable for the kind of danger
belonging to it” associated with a “strangling and anxiety,”
which he suggested should be called “angina pectoris.” This
description was enlarged on by Herrick2 in 1912. Angina is
usually described by the patient as a left precordial tightness
or ache provoked by exercise or emotion and relieved by rest.
Many patients deny they have pain, but when questioned
closely, they identify chest tightness, chest pressure, or ache
associated with effort, emotion, and/or cold exposure. Angina
occurs when oxygen demand exceeds supply.3–7 Most indi-
viduals with angina have underlying atherosclerotic coro-
nary artery disease (CAD) (Figs. 30.1 and 30.2).
However, angina may also develop in some patients with
ventricular hypertrophy, left ventricular (LV) outflow obstruc-
FIGURE 30.2. Typical narrowing and occlusion of the coronary
artery by atherosclerosis in patients with unstable angina and MI.
In many other patients, the severity of the left anterior descending
coronary artery stenosis is less than that demonstrated in this right
anterior oblique projection of the left coronary artery by coronary
arteriography.
tion, severe aortic valvular regurgitation or stenosis, cardio-
myopathy, or dilated ventricle(s) in whom severe coronary
artery stenoses are not present. The explanation for angina
when CAD is not present is that even normal coronary arter-
ies may not adequately supply hypertrophied, dilated, or
failing heart muscle with oxygen. On occasion, limited coro-
nary vasodilator reserve may explain angina, especially in
some patients with severe ventricular hypertrophy associ-
ated with LV outflow obstruction, including valvular aortic

A
FIGURE 30.1. (A) A typical atherosclerotic plaque in which plaque
has ruptured, leading to the development of coronary artery throm-
bosis. Such a patient may or may not have had angina at effort before
the plaque rupture and thrombosis, and may have abruptly devel-
oped severe chest pain and a myocardial infarction (MI) with plaque
rupture and coronary artery thrombosis. (B) The neointimal prolif-
eration occurring with restenosis after coronary artery angioplasty,
leading to coronary artery luminal diameter narrowing and the
need for some additional revascularization procedure is shown.
Patients who develop coronary heart disease after cardiac transplan-
tation also demonstrate this same alteration in their coronary arter-
ies (i.e., neointimal proliferation). Native atheromas have substantial
fibroproliferative alterations as well.
 corona ry h e a rt dise a se sy n drom e s
stenosis and hypertrophic obstructive cardiomyopathy, and
in patients with poorly controlled systemic arterial hyper-
tension.8,9 Coronary artery vasoconstriction occurring with
exercise or stress may also be a contributing factor.10,11 Most
humans without coronary heart disease or ventricular hyper-
trophy do not develop angina with effort or stress, probably
because the heart is protected from an important imbalance
between oxygen supply and demand by other factors that
limit physical activity, such as dyspnea and fatigue.
The predisposing pathologic alteration in coronary arter-
ies responsible for angina is atherosclerosis, atherothrombo-
sclerosis, and neointimal fibrous proliferation (Fig. 30.3; see
also Figs. 30.1 and 30.2). The term atherothrombosclerosis
describes the relative importance of each of its components,
including atherosclerosis, thrombosis, and fibrosclerosis, in
the development of the process that has long been called
atherosclerosis, but in fact often includes evidence of throm-
bosis in the progressive atherosclerotic plaque. Embolic ath-
erosclerotic debris and platelet aggregates may contribute to
distal coronary artery occlusion and limitation of coronary
flow reserve (Fig. 30.3). Severe narrowing of the lumen of
the coronary artery results in a decreased ability to deliver
oxygen, especially when oxygen demand in the heart is
increased, as with increases in heart rate, contractile state,
or myocardial wall tension, or a combination of these.3–7
Therefore, stable and relatively predictable angina may
develop during exercise, cold exposure, or emotional stress
or after eating a large meal. Angina may also occur because
of extracardiac influences. In particular, severe anemia or
carbon monoxide exposure reduces the amount of oxygen
delivered to the heart and may result in angina under condi-
tions that would otherwise be well tolerated. Increases in
systemic arterial pressure and consequent dilatation of the
heart may result in angina. Increases in heart rate or con-
tractile state, as with hyperthyroidism, pheochromocytoma,
and exogenous administration or release of catecholamines,
may also lead to angina. Cold exposure decreases oxygen
delivery by causing coronary artery vasoconstriction and
increases systemic blood pressure, ventricular wall tension,
and oxygen demand.
Physical Examination/Bedside Findings
The findings on physical examination in the patient with
stable angina pectoris are highly variable. Sometimes, there
are no localizing or suggestive physical findings. Alterna-
tively, associated risk factors, such as systemic arterial
hypertension, hyperlipidemia, valvular heart disease, heart
failure, or peripheral atherosclerosis may result in a specific
physical finding, such as elevated blood pressure, a promi-
nent fourth heart sound (S4), an accentuated aortic closure
sound, a paradoxically split second heart sound (S2) [systemic
arterial hypertension, during an episode of angina or with
left bundle branch block (LBBB)], reduced peripheral pulse
(i.e., carotid, femoral, or lower extremity pulse with or
without bruit over the artery), murmur of aortic stenosis or
mitral insufficiency (the most commonly associated valvular
heart diseases with CAD), or a third heart sound (S3) with
heart failure or rapid filling of the ventricle, such as occurs
with moderately severe and severe aortic or mitral insuffi-
ciency. The patient with coronary heart disease and stable
angina may or may not have an enlarged heart, frequent
669
t-PA
PGI2 –
PGI2 +
EDRF
EDRF
Platelet aggregation
Platelet
Mechanical attachment at site
obstruction of endothelial
cell injury
Vasoconstriction
Transient platelet
aggregation
Release of mediators
Thromboxane A2
Serotonin
Mechanical
Adenosine diphosphate
obstruction
Thrombin
Platelet-activating factor
Vasoconstriction
Oxygen-derived
free radicals
Tissue factor
Endothelin
FIGURE 30.3. Schematic diagram suggests probable mechanisms
responsible for the conversion from chronic coronary heart disease
to acute coronary artery disease syndromes. In this scheme, endo-
thelial injury, generally at sites of atherosclerotic plaques and usually
plaque ulceration or fissuring, is associated with platelet adhesion
and aggregation and the release and activation of selected mediators,
including thromboxane A 2, serotonin, adenosine diphosphate, plate-
let-activating factor, thrombin, oxygen-derived free radicals, and
endothelin. Local accumulation of thromboxane A 2, serotonin,
platelet-activating factor, thrombin, adenosine diphosphate, and
tissue factor promotes platelet aggregation. Thromboxane A 2, sero-
tonin, thrombin, and platelet activating factor are vasoconstrictors
at sites of endothelial injury. Therefore, the conversion from chronic
stable to acute unstable coronary heart disease syndromes is usually
associated with endothelial injury, platelet aggregation, accumula-
tion of platelet and other cell-derived mediators, further platelet
aggregation, and vasoconstriction, with consequent dynamic nar-
rowing of the coronary artery lumen. In addition to atherosclerotic
plaque fissuring or ulceration, other reasons for endothelial injury
include flow shear stress, hypertension, immune complex deposition
and complement activation, infection, and mechanical injury to the
endothelium as it occurs with coronary artery angioplasty, stents,
and after heart transplantation. Injured endothelial cells have
reduced amounts of the normally present vasoprotective substances
that when present prevent thrombosis, vasoconstriction, and inflam-
mation, nitric oxide (NO), tissue-type plasminogen activator (t-PA),
and prostacyclin (PGI 2).
or complex ventricular premature beats, S4, murmur of
mitral insufficiency, S3 moist rales, and peripheral vascular
disease.
The electrocardiogram (ECG) may be normal, but it often
shows ST-T-wave changes, usually ST depression and T-wave
flattening or inversion during angina. On occasion, ST-T-
wave depression or inverted T waves persist for weeks or
longer, presumably reflecting chronic ischemia. The ECG
67 0 chapter
may also show ventricular ectopic beats or evidence of a prior
Q wave myocardial infarction (MI). An echocardiogram may
be normal at rest or may show regional or global wall motion
abnormalities, including reduced left ventricular ejection
fraction or increased LV dimensions (“ischemic cardiomyopa-
thy”), consistent with myocardial ischemia or infarction, or
mitral insufficiency. Chest x-ray may show a normal-sized or
enlarged heart with or without heart failure. On occasion, the
patient has coronary artery calcification on the chest x-ray.
Rapid-speed computed tomography (CT) [or electron
beam CT (EBCT)] often identifies coronary artery calcifica-
tion. Several studies12–16 have shown that coronary calcium
assessment using fluoroscopy or EBCT imaging has a sensi-
tivity for significant angiographic stenoses comparable with
that of exercise tests when used in symptomatic patients, but
the specificity is lower. Symptomatic patients with coronary
calcium have at least a fourfold increased risk of death or
infarction compared with those with no calcification. The
fluoroscopic finding of at least one calcified coronary artery
or the EBCT identification of a coronary calcium score
exceeding 100 has been shown to be predictive of the pres-
ence of advanced coronary plaque and stenosis. In general,
greater degrees of calcification in coronary arteries are con-
sistent with greater amounts of atherosclerotic plaque and
more advanced coronary luminal diameter narrowing. An
advantage of an assessment of coronary artery calcium is
that it can be done irrespective of the patient’s ability to
exercise and regardless of the presence or absence of resting
electrocardiographic abnormalities. However, a valuable
finding in the symptomatic patient is a negative EBCT study
for coronary calcium. The negative predictive value of such
a calcium scan for significant stenosis of a major coronary
artery is greater than 90%. Thus, EBCT scanning might be
an appropriate first test in individuals with atypical cardiac
symptoms in whom the likelihood for ischemic disease is
considered to be small by the responsible physician. Patients
with a zero or very low calcium score (i.e., <10) may generally
be reassured and further testing directed at noncardiac eti-
ologies of chest pain. On the other hand, if the calcium score
is consistent with moderate or severe atherosclerotic plaque
development, additional cardiac evaluation, including stress
testing ideally with perfusion or functional evaluation, may
be indicated. We must keep in mind individual variation,
however, and even in the absence of coronary artery calcifi-
cation, one may have coronary heart disease as the cause of
one’s chest pain. We do not recommend routine screening of
patients for coronary calcification.
Asymptomatic individuals differ from symptomatic
patients in that the risk of subsequent morbid events is rela-
tively small. Data are not conclusive regarding the ability of
coronary calcification in asymptomatic individuals to predict
short-term coronary artery risks.12 Figure 30.4 demonstrates,
however, that prevalence/risk relationships decrease with
age. Although serious overprediction may occur in the young,
overprediction is only moderate in the elderly. It should be
stressed, however, that extensive coronary artery calcifica-
tion does not necessarily indicate the presence of a signifi-
cant coronary artery stenosis, and some patients with very
advanced coronary calcium scores have no significant coro-
nary artery stenosis or functional abnormality on stress
perfusion or LV functional analysis.
30
12 100%
Ca prevalence/event risk 90%
Ca prevalence/event risk ratio
10
Ca prevalence; event risk
80%
8
70%
Ca prevalence 60%
6 50%
40%
4 30%
10-Year
event risk 20%
2
10%
0 0%
25 35 45 55 65 75
Age (years)
FIGURE 30.4. Coronary artery calcium (Ca) prevalence, 10-year
event risk, and prevalence/risk ratio in asymptomatic men. Event
risk and calcium prevalence are plotted against the right axis, and
prevalence/risk ratio is plotted against the left axis. Prevalence/risk
curve decreases with age, demonstrating serious overprediction in
the young and moderate overprediction in the elderly.
Hemodynamic monitoring typically shows increases in
mean pulmonary capillary wedge pressure during angina
pectoris. With the onset of myocardial ischemia, the initial
hemodynamic change in the left ventricle is a decrease in
myocardial compliance and an increase in stiffness. This
results in a sharp increase in mean pulmonary capillary
wedge pressure during angina, with a return to baseline as the
angina resolves. The change in compliance is followed by ST-
T wave changes on the ECG, a decline in regional systolic
wall thickening, and finally, the development of chest pain,
with this entire sequence occurring within a few seconds.
Variant Angina (“Prinzmetal’s Angina”)
Patients with variant angina pectoris (“Prinzmetal’s angina”)
have angina at rest, often in the early morning hours, associ-
ated with ST-segment elevation on the ECG and the presence
of coronary artery spasm that causes focal obliteration of a
coronary artery lumen (Fig. 30.5).17,18
In the early descriptions of typical angina, Latham19 and
Osler20 suggested that this entity was due to periodic spasm
of a large coronary artery. Subsequently, however, clinical
studies with anatomic correlations suggested that fixed ath-
erosclerotic CAD was responsible for typical angina and MI.
In 1959, Prinzmetal and coworkers21 revived interest in
coronary arterial spasm when they described a group of indi-
viduals with “variant angina.” The clinical features of this
syndrome are distinctly different from those of typical
angina.17,21–48 First, the patients described by Prinzmetal and
coworkers usually had chest pain at rest rather than with
physical exertion or emotional stimulation. Second, the epi-
sodes of pain tended to recur at roughly the same time(s) each
day, often during the early morning hours, awakening the
patient from sleep. Third, the patient with variant angina
usually had ST-segment elevation on the ECG recorded during
chest pain (Fig. 30.5). Fourth, the episodes of chest pain were
sometimes accompanied by atrioventricular block or ven-
 corona ry h e a rt dise a se sy n drom e s 671
firmed the existence of this syndrome and have shown the
presence of coronary artery spasm at sites of fixed coronary
A Arterial spasm
artery stenosis and in regions of the coronary vasculature
where no obvious stenosis exists. In patients with clinically
active coronary artery spasm, variant angina can often be
induced by ergonovine maleate.33–43 Other maneuvers that
ST segment have been used to produce coronary artery spasm in suscep-
elevation
tible patients include hyperventilation with the administra-
tion of an alkaline buffer, cold pressor testing, and the
administration of methacholine, a parasympathomimetic
agent, acetylcholine, or serotonin.38,41–48 We have speculated
that endothelial or adventitial injury, often in association
with coronary artery stenosis, leads to the accumulation of
platelets and white blood cells, mononuclear cells, including
Normalization mast cells, and T cells, and the release of humoral mediators,
of ECG including serotonin, thromboxane A 2, prostaglandin D2,
thrombin, leukotrienes, platelet-activating factor, endothe-
B After nitroglycerin lin, or histamine, which singly or in combination may cause
coronary artery spasm (see Figs. 30.3 and 30.5).49–58 Exposure
of tissue factor59 and accumulation of local inhibitors of
A B thrombolysis, such as the endogenous inhibitor of tissue
Channel 1 plasminogen activator (PAI-1),60 and activation of procoagu-
lant factors, such as factors X and Xa (Fig. 30.6),61 may also

Channel 2

Baseline recording Just before chest pain

XII
C D TF
VII VIIa PK
Channel 1 XI HK
HK
XIIa
IX
Ca2+
VIIa/TF XIa
Channel 2

IXa
During chest pain With pain relidf Ca2+
PL
VIIIa VIII
FIGURE 30.5. Top: (Inset A) Focal obliteration of the coronary
artery lumen caused by coronary artery spasm at a spot marked by X Xa
the arrows. (Inset B) The associated ST-segment elevation that
occurs with coronary artery spasm (A–D) Continuous 24–hour
Holter recording in a patient with coronary artery spasm before
chest pain (A,B), as chest pain begins (B), during chest pain (C), and Ca2+ Va V
with pain relief (D). The T wave prominence and ST-segment eleva- PL
tion that occur with coronary artery spasm are demonstrated.
Bottom: (D) Resolution of the coronary artery spasm after adminis- PL Th
tration of nitroglycerin. (Inset) Normalization of the electrocardio-
gram (ECG).
Fibrinogen Fibrin
monomer

tricular ectopic activity, and occasionally, the patients had Fibrin

transient ventricular tachycardia. Finally, the chest polymer
discomfort of variant angina was quickly relieved by nitro- XIIIa XIII
glycerin, after which the ST-segment elevation resolved. Cross-linked
Prinzmetal’s patients did not undergo selective coronary arte- fibrin
riography, but Prinzmetal and coworkers hypothesized that polymer
patients with variant angina had severe proximal stenoses of FIGURE 30.6. Schematic representation of the role of tissue factor
(TF), factors IX, X, XI, XII, and VIII in the formation of thrombin
one or more large coronary arteries in which spasm occurred (Th) and the subsequent role of thrombin in the formation of fibrin.
periodically. Since the original description of variant angina HK, high-molecular-weight; PK, prekallikrein; PL, phospholipids;
by Prinzmetal and coworkers, many observers21–32 have con- PT, prothrombin.
67 2 chapter 30

contribute to the development of thrombosis. This is espe-

cially likely to be true when endothelial injury decreases Subendocardium
vascular concentrations of the endogenous inhibitors of
inflammation, thrombosis, and vasoconstriction, nitric
oxide, tissue plasminogen activator, and/or prostacyclin (see
Fig. 30.3).53–55 It also seems highly likely that the endothe- Subepicardium
lium-derived vasoconstrictor, endothelin, is responsible for
coronary artery constriction or spasm in some patients (Fig.
30.3).53–55 Local plaque and systemic increases in catechol-
amine concentrations also contribute to the development of Left ventricle
plaque thrombosis and vasoconstriction.

Unstable Angina

Pathophysiology
Angina occurring in a crescendo pattern, with limited physi-
cal activity or at rest, is known as unstable angina. The chest
discomfort is typically milder than that occurring with
acute MI, being described as recurrent chest or epigastric
“tightness” or “pressure” and as usually “not severe” in
character. Typically, the episodes of angina last less than 30
minutes; they may or may not be associated with nausea. On
occasion, however, unstable angina is associated with more
severe and prolonged chest pain or nausea, making its clini-
cal differentiation from acute MI at the bedside difficult. In
these situations, serial ECGs and measurement of serum
creatine kinase (CK) and its relatively specific cardiac isoen-
zyme, CK-MB, and of troponin I or T are needed to distin-
guish unstable angina from acute MI. While unstable angina
and non-ST segment elevation myocardial infarction
(NSTEMI) both lead to ST segment flattening or depression
and T-wave flattening or inversion (Fig. 30.7), increases in
troponin I or T or of CK-MB identify the presence of myo-
cardial necrosis.
Unstable angina is usually caused by a primary decrease
in coronary blood flow and myocardial oxygen delivery
occurring as a consequence of atherosclerotic plaque fissur-
ing or ulceration.59–70 The atherosclerotic plaque fissuring or
ulceration is followed by platelet adhesion and aggregation
at the site of plaque disruption and transient thrombosis or
subtotal coronary artery occlusion with dynamic vasocon-
striction. Platelet adhesion occurs by platelet attachment to
exposed collagen and to von Willebrand binding sites largely
through platelet glycoprotein Ib receptors. Thrombosis and
vasoconstriction are promoted by the local accumulation of
powerful promoters of platelet aggregation and vasoconstric-
tion at these same sites, including thromboxane A 2, sero-
tonin, adenosine diphosphate, platelet-activating factor (PAF),
thrombin, oxygen-derived free radicals, tissue factor, and
endothelin (see Fig. 30.3).49–58 All but endothelin promote
thrombosis. Thromboxane A 2, serotonin, PAF, and thrombin
are also vasoconstrictors. Endothelin is a powerful vasocon-
strictor. There is also a loss of the endogenous inhibitors of
thrombosis and vasoconstriction, nitric oxide (NO), tissue-
type plasminogen activator (t-PA), and prostacyclin at sites
of vascular injury (Fig. 30.3).65–70
Unstable angina may also occur in the individual with a
severe coronary artery stenosis or partially occluded coro-
nary artery when myocardial oxygen demand is increased
Subendocardial
A (non-Q-wave) myocardial infarction
R
P P
R
T
T
Electrocardiographic changes
of (non-Q-wave) myocardial infarction
B
FIGURE 30.7. (A) Schematic diagram shows the location of
myocardial necrosis with non-ST segment elevation myocardial
infarction (NSTEMI) and a representation of the typical electrocar-
diographic changes. (B) Typical electrocardiogram (ECG) in a patient
with acute NSTEMI. With these infarcts, the ECG is unable to
provide specific evidence of the presence of the infarct but ST-
segment depression of varying magnitude and T-wave abnormali-
ties, usually T-wave flattening or inversion, often develop. The only
evolution of the electrocardiographic abnormalities is a return to
the normal pattern.
by intense emotion, tachycardia, or systemic hypertension.
Alternatively, unstable angina may occur as a result of a
reduction in myocardial blood flow associated with severe
and progressive coronary artery atherosclerosis or dynamic
coronary artery constriction associated with coronary artery
spasm.17,18
Vulnerable or Unstable Atherosclerotic Plaque
Pathophysiology
Figure 30.8 demonstrates the characteristics of the “vulner-
able” unstable atherosclerotic plaque herein defined as one
likely to ulcerate or fissure or otherwise promote platelet
adherence and aggregation and vasoactive mediator accumu-
lation leading to the development of thrombosis, dynamic
 corona ry h e a rt dise a se sy n drom e s 67 3

Relative cell density

12 vs delta T (Celsius)

10

Relative cell density

Macrophages Degradation 8
of collagen
in fibrous 6
cap
Protease 4
release
VCAM
Integrin 2
receptors

Oxidized LDL 0
0 1 2 3 4 5
Delta T (C)
A
FIGURE 30.9. Relationship between temperature heterogeneity and
Anatomy of 30% of fatal myocardial infarctions: Erosion inflammatory cell presence in human carotid plaques removed at
carotid endarterectomy.

vasoconstriction, and fibroproliferation. The morphologic

characteristics of the unstable plaque include a thin fibrous
cap, the presence of inflammatory cells on or beneath the
atherosclerotic plaque surface, and an adjacent lipid core.
Casscells et al.71 have shown that such plaques in the human
carotid artery have temperature heterogeneity with tempera-
tures varying by 0.2° to 2°C in that part of the plaque where
the inflammation exists (Fig. 30.9). More recently, others
have confirmed these observations and shown the same tem-
perature heterogeneity in vivo in human coronary arteries in
patients with unstable angina and acute MI (Fig. 30.10).72 In
B
vivo studies have shown that the temperature heterogeneity
Anatomy of 60% of fatal myocardial infarctions: Rupture is more commonly in the 0.15° to 1°C range in the vulnerable
atherosclerotic plaque. Maseri, Borst, and others73–75
have suggested that unstable atherosclerotic plaques may
develop as part of widespread inflammation and that a sub-
stantial number of patients have multiple unstable plaques
simultaneously.
Endothelium
Thrombus
Macrophages
Thin fibrous cap
Difference from background temperature (°C)

Cholesterol,
Diffuse intimal thickening old hemorrhage,
(dense collagen, sparse cell debris, 3
smooth muscle cells) calcium
2.5

C 1.5
FIGURE 30.8. (A) Potential mechanisms responsible for athero-
1
sclerotic plaque fissuring and ulceration. Oxidized low-density lipo-
protein (LDL) within the atherosclerotic plaque promotes the
upregulation of vascular cell adhesion molecule (VCAM) and other 0.5
integrins, resulting in the recruitment of inflammatory cells, pri-
marily monocytes-derived macrophages but including activated T 0
cells and mast cells; subsequent protease release from the mononu- Controls Stable angina Unstable Acute
clear cells; and degradation of collagen in the fibrous cap, leading to angina myocardial
its fissuring and ulceration. (B) Atherosclerotic plaque fissuring, infarction
leading to platelet adhesion and aggregation and thrombosis. (C)
Atherosclerotic plaque ulceration and thrombosis. FIGURE 30.10. Increased temperature of infarct-related plaques in
patients with unstable angina and with acute MI compared with
controls and with patients with stable angina.
674 chapter 30

12.0 Group 1 Group 2A Group 2B 39.4 mg/dL

11.0 Group 1 Group 2A Group 2B

Serum amyloid a protein (mg/dL)

30.0
C-Reactive protein (mg/dL) 10.0 27.5
9.0 25.0
8.0 22.5
7.0 20.0
6.0 17.5
5.0 15.0
4.0 12.5
10.0
3.0
7.5
2.0
5.0
1.0 2.5
0.3 0.3
Adm. Peak Adm. Peak Adm. Peak Adm. Peak
A value value B value value
FIGURE 30.11. Plasma levels of C-reactive protein (A) and serum value for serum amyloid A protein, which exceeded the values on
amyloid A protein (B) in patients with stable angina (group 1), in the scale, is shown numerically and joined by a dashed line to the
patients with unstable angina and levels of C-reactive protein corresponding value on admission. The level of C-reactive protein
<0.3 mg/dL on admission (Adm.) (group 2A), and in patients with is <0.3 mg/dL horizontal line in A) in 90% of normal subjects. The
unstable angina and levels of C-reactive protein ≥0.3 mg/dL on median normal level of serum amyloid A protein is 0.3 mg/dL
admission (group 2B). Circles, urgent coronary artery bypass or (dashed horizontal line in B); 96% of normal subjects have levels of
angioplasty; squares, cardiac death or MI. In one patient, the peak serum amyloid A protein <1.0 mg/dL.

Several studies have shown that patients with unstable A 6

6
angina, NSTEMI, and ST segment elevation MI (STEMI) with
elevated serum C-reactive protein (CRP) levels at hospital dis- p = .014
30-day mortality relative risk

5
charge, elevations in serum troponin I or T at hospital admis-
sion, or increases in serum interleukin-6 concentrations or of 4 3.5
multiple biomarkers during their hospital admission have an
increased risk of future coronary events, presumably reflecting 3
the importance of inflammation in the instability of their
unstable atherosclerotic plaques (Figs. 30.11 to 30.16).76–86,96 2 1.8
Increases in troponin I and T identify myocardial necrosis 1
and possibly more extensive plaque instability, longer duration 1
of platelet-derived thrombosis and vasoconstriction, and n = 67 n = 150 n = 155 n = 78
0
0 1 2 3

No. of elevated cardiac biomarkers

B
0.25
Probability of death wihin 30 days

14 13
p = .0001
30-day mortality relative risk

0.20 12

10
0.15
8
0.10 5.7
6

0.05 4
2.1
2 1
0.00
0 0.1 0.5 1 2 5 10 15 n = 504 n = 717 n = 324 n = 90
0
Troponin T (ng/mL) 0 1 2 3

FIGURE 30.12. Probability of death within 30 days according to No. of elevated cardiac biomarkers
the serum troponin T level at hospital admission. Dots represent FIGURE 30.13. Relative 30-day mortality risks in OPUS-TIMI 16
simple estimates of mortality derived from ranges of the troponin (A) and TACTICS-TIMI 18 (B) in patients stratified by the number
T level that contained at least 70 patients. of elevated cardiac biomarkers.
 corona ry h e a rt dise a se sy n drom e s 675

Relative risk of future cardiovascular events

Mortality at 42 days (% of patients)
8 7.5 8
7
6.0 7
6
6
5
4 3.4 3.7 5
3 4
2 1.7 3
1.0
1 2
831 174 148 134 50 67
0
0 to <0.4 0.4 to <1.0 1.0 to <2.0 2.0 to <5.0 5.0 to <9.0 ≥9.0 1
Cardiac troponin I (ng/mL) 0
Risk ratio 95% <0.5 0.5−1.0 1.0−2.0 2.0−3.0 3.0−4.0 4.0−5.0 5.0−10.0 10.0−20.0 >20
1.0 1.8 3.5 3.9 6.2 7.8
confidence _ 0.5−6.7 1.2−10.6 1.3−11.7 1.7−22.3 2.6−23.0
interval
“Low risk” “Moderate risk” “High risk”
FIGURE 30.14. The mortality incidence at 42 days in patients
HsCRP (mg/l)
admitted to the hospital with unstable angina or NSTEMI (non-Q-
wave MI) based on their initial cardiac troponin serum levels (nano- FIGURE 30.15. Relative risks of future cardiovascular events across
grams per milligram). The number of patients in each category is a full clinical range of high-sensitivity C-reactive protein (hsCRP)
shown within each black bar. values. Black bars represent crude relative risks; gray bars, risk
adjusted for FRS.

sometimes platelet emboli and occlusive disease of distal arter- predict the development of future coronary events, even in
ies (Figs. 30.12 and 30.13).78–86 Table 30.2 lists other biomarkers otherwise apparently healthy individuals. Figure 30.11 dem-
that have been shown to be predictive of future cardiovascular onstrates that for patients with unstable angina and NSTEMIs
events (Figs. 30.14 and 30.15).87–95 with CRP values of 0.3 mg/dL or higher, there is an increased
It has also been shown by Sabatine et al.96 that elevations risk of future coronary events, including urgent coronary
in serum troponin, CRP, and brain natriuretic peptide (BNP) artery bypass surgery or angioplasty, cardiac death, or MI.
each provide unique prognostic information in patients with Similar data have been provided for patients who have ele-
acute coronary syndrome (ACS). A relatively simple multi- vated serum fibrinogen values at hospital discharge.83
marker strategy that categorizes patients with ACS based on Several groups have shown the importance of increases
the number of elevated biomarkers at admission allows risk in serum levels of troponin I as prognostic factors indicative
stratification over a range of short- and long-term major of increased future risk for patients with ACS. Antman and
cardiac events (Fig. 30.13).96 colleagues,78 in a multicenter study of 1404 symptomatic
Berk and coworkers81 were among the first to demon- patients, found a relation between mortality at 42 days and
strate an increase in CRP in patients with acute coronary the serum cardiac troponin I levels at patient admission to
heart disease syndromes. Subsequently, several studies, the hospital (Fig. 30.14). The mortality rate at 42 days was
including those by Maseri and colleagues, demonstrated a significantly higher in the 573 patients with cardiac troponin
poorer prognosis in patients with unstable angina who had I levels of 0.4 ng/mL and greater than in the 831 patients
increased serum CRP and serum amyloid-A protein values.82 with cardiac troponin I levels less than 0.4 ng/mL. For each
Ridker and associates85 (Fig. 30.16) and Koenig and increase of 1 ng/mL in the cardiac troponin I level, there was
coworkers80 demonstrated that increases in serum CRP an associated significant increase in the risk ratio for death,

Framingham 10-year risk <10% Framingham 10-year risk 10% to 20%

5 5

4 4
Relative risk

Relative risk

3 3

2 2

1 1

FIGURE 30.16. Relative risks of future cardio- 0 0

vascular events among those with calculated <0.5 0.5-<1.0 1.0-<3.0 3.0-<10.0 ≥10.0 <0.5 0.5-<1.0 1.0-<3.0 3.0-<10.0 ≥10.0
10-year Framingham risks <10% (left) and
between 10% and 20% (right). hsCRP (mg/L) hsCRP (mg/L)
676 chapter
TABLE 30.2. Biomarkers to predict prognosis in patients with
unstable angina and non-ST segment elevation myocardial
infarction (NSTEMI)
C-reactive protein
Brain natriuretic peptide (BNP)
CD40L and CD40
Myeloperoxidase
Pregnancy-associated protein
Serum amyloid protein
Vascular cell adhesion molecule (VCAM)
Intercellular adhesion molecule (ICAM)
Interleukin-6
Asymmetric dimethylarginine
Troponins
Phospholipase A 2
after adjustment for baseline characteristics that were inde-
pendently predictive of mortality, including ST-segment
depression and age 65 years or older. Similar data have been
provided for serum values of troponin T in patients with
unstable coronary heart disease. Lindahl and associates77
found that the risk of cardiac events in these patients
increased with increasing maximal levels of troponin T
obtained in the initial 24 hours after admission. The lowest
quartile (<0.06 μg/L) constituted a low-risk group, the second
quartile (0.06 to 0.18 μg/L) an intermediate group, and the
third highest quartile (≥0.18 μg/L) a relatively high-risk group
with 4.3%, 10.5%, and 16% risk of either MI or cardiac death,
or both, respectively. Biasucci and coworkers86 demonstrated
an increased risk for future coronary events in patients whose
serum interleukin-6 increased during hospital admission.
Other serum markers that when elevated are associated with
future vascular and myocardial events include CD40L,
CD40, serum amyloid protein (SAP), pregnancy-associated
protein, vascular cell adhesion molecule (VCAM), intercel-
lular adhesion molecule (ICAM), and BNP (Table 30.2).96a
Stability of an atherosclerotic plaque depends largely on
the structural integrity of its fibrous cap, which is composed
primarily of extracellular matrix components rich in colla-
gen. Available evidence supports a role for the release of
matrix-degrading enzymes, that is, matrix metalloprotein-
ases (MMPs) in the catabolism of the structural macromole-
cules causing a dissolution of the fibrous cap of the plaque.97–103
The MMP family includes at least 19 structurally related,
zincdependent enzymes that function at physiologic pH in
the extracellular space. In addition, membrane-type (MT)
metalloproteinases have been identified that have the desig-
nations MT1-MMP through MT4-MMP.
The MMPs have been broadly classified into three main
groups on the basis of substrate specificity. They include the
collagenases (MMP-1, -8, and -13) that degrade intact fibrillar
collagens. The gelatinases (MMP-2 and -9) hydrolyze the
denatured collagen fibril and basement membrane collagen
type IV. The stromelysins (MMP-3, -7, -10, and -11) have broad
substrate specificity. For some of the remaining MMPs,
substrate specificity has not yet been identified.
Regulation of MMPs occurs at three levels: (1) control of
the rate of gene transcription; (2) conversion of the inactive
translational product, and inactive zymogen precursor, to the
30
active form; and (3) inactivation by a family of endogenous
inhibitors known as tissue inhibitors of metalloproteinases
(TIMPs).
Human peripheral blood monocytes produce little MMP,
but differentiation into macrophages yields higher levels of
MMP-9.97–103 Secretion of MMP-9 from macrophages can be
induced by tumor necrosis factor-α, interleukin-1β, and
CD40. Expression of collagenase (MMP-1) and stromelysin
(MMP-3) in macrophages is regulated by certain bacterial
products, including lipopolysaccharide (endotoxin) and yeast
zymosan. Activated T lymphocytes may cause collagenase
and stromelysin expression in the human monocytes-derived
macrophages.
The MMPs are secreted from cells as inactive zymogens
and require activation in the extracellular milieu before they
are capable of degrading extracellular matrix molecules.
Macrophage-derived reactive oxygen species activate MMP-2
and MMP-9 and thrombin activates MMP-2. The MMPs
themselves, once processed from the zymogen to active form,
can trigger activation of other members of the MMP family.
Mast cells within atheroma may release serine proteinases
that activate MMPs.
The endogenous inhibitors known as TIMPs help regu-
late MMP activity under normal circumstances. Four TIMPs
have been described thus far. They exhibit sequence homol-
ogy and share domains of identical protein structures that
consist of highly conserved N-terminal regions believed to
be critical for inhibition of the enzyme.
The balance between MMP activities and their inhibi-
tion by TIMPs is important in the maintenance of homeo-
stasis for the extracellular matrix. Excessive MMP activity
occurs in a number of disease states, including metastatic
cancer, rheumatoid arthritis, and glomerulosclerosis. There
is evidence that MMPs play a role in accelerated connective
tissue turnover associated with degenerative diseases of
vessels, including aortic aneurysms and vein graft stenoses,
as well as migration of smooth muscle cells from the media
to the intima after arterial injury.
Several of the MMPs and TIMPs have been found in
atherosclerotic plaques,97–103 including MMP-1 (collagenase),
MMP-9 (gelatinase B), and stromelysin-1 (MMP-3). Each of
these has been found in the fibrous cap, the atherosclerotic
lesions’ shoulders, and the base of the lipid core. MMP-7
(matrilysin) is found primarily in macrophages overlying
the lipid core. A high expression of MMPs has also been
detected in lipid-laden macrophages in experimental animal
lesions.
Similarly, constitutive expression of TIMP-1 and -2 has
been described in both normal and diseased arteries and
TIMP-3 has been found in atheromas. Thus, the spatial dis-
tribution of selected TIMPs within atheromas correlates
with that described for MMP expression. Most of the MMPs
and TIMPs in atheromas are in macrophages, thereby iden-
tifying the macrophage as most likely a key participant in
the regulation of the balance between synthesis and degrada-
tion of extracellular matrix macromolecules in the athero-
sclerotic plaque.
Available evidence suggests a probable role for metallo-
proteinase release in excess of TIMP presence leading to
degradation of collagen in the fibrous cap and the subsequent
fissuring and ulceration that predisposes to unstable angina
and acute MI (see Fig. 30.8). The proposed scheme includes
 corona ry h e a rt dise a se sy n drom e s
the oxidation of low-density lipoprotein (LDL) within the
plaque and the chemoattractant influence of oxidized LDL
and other oxidation products to promote the expression of
selected adhesion molecules, including VCAM and ICAM
and the subsequent recruitment of monocyte-derived
macrophages, activated T lymphocytes, and mast cells
within the plaque. The release of selected MMPs in excess
of their TIMP concentrations locally degrades plaque colla-
gen within the fibrous cap and leads to fissuring and ulcer-
ation of the atherosclerotic plaque. One anticipates future
clinical trials with inhibitors of selected MMPs, but the
redundancy within the system, that is, the number of MMPs
and other proteases within plaques that are nonmetalloen-
zymes, may make effective inhibition of these plaque-
degrading enzymes difficult. Other approaches to inhibiting
inflammation and the recruitment of monocytes-derived
macrophages that may be protective of atherosclerotic
plaques include inhibiting macrophage homing to unstable
atherosclerotic plaques using inhibitors of VCAM and
ICAM104 or of antioxidants; inhibitors of selected cytokines,
especially tumor necrosis factor-α; nitric oxide donors;
inhibitors of nuclear factor κB (NF-κB); and marked lipid
lowering with the use of medications capable of providing
marked reductions in serum cholesterol and LDL, most espe-
cially statins.
Acute Myocardial Infarction
Acute MI occurs when there are severe reductions in coro-
nary blood flow and myocardial oxygen delivery for more
than 20 minutes. The infarct begins on the inner wall or
subendocardium of the heart and is confined there in the
first 30 minutes to 2 hours (Fig. 30.7; non-Q wave or NSTEMI);
these are generally subendocardial infarcts. If the coronary
artery thrombosis is transient or does not cause complete
coronary artery occlusion, the infarct usually remains largely
confined to the subendocardium (or mid-wall of the heart)
and a non-Q wave or NSTEMI develops. However, if the coro-
nary artery occlusion is sustained for longer periods, the
myocardial necrosis progresses vertically outward toward
the epicardium in the next 2 to 3 hours [“Q wave” or ST
elevation infarct (STEMI)] (Fig. 30.17).
Herrick2 described acute MI caused by coronary artery
thrombosis in 1912. Subsequently, the role of coronary artery
thrombosis in causing MI was debated77 until studies by
DeWood and colleagues105 demonstrated by coronary arteri-
ography that coronary artery thrombosis is virtually always
the cause of acute Q wave or STEMIs. Buja and Willerson106
confirmed the association between thrombosis of the infarct-
related coronary artery and the development of acute Q wave
or STEMI by detailed clinicopathologic correlations. Ninety
percent or more of STEMIs have prolonged occlusive coro-
nary artery thrombosis in the infarct-related coronary
artery.105–107
As noted above, STEMIs are usually caused by persistent
thrombotic occlusion of a coronary artery resulting in sus-
tained reductions in coronary blood flow and myocardial
oxygen availability. Occasionally, increases in myocardial
oxygen demand above the ability of a stenotic coronary
artery to delivery oxygen cause MI, often NSTEMI. Such
67 7
increases in oxygen demand occur in some patients with
CAD who have severe systemic arterial hypertension, sus-
tained tachycardia, or both. Alternatively, sustained reduc-
tions in myocardial oxygen delivery associated with severe
systemic arterial hypotension may lead to MI, again usually
NSTEMI. Approximately 30% of patients with NSTEMI
have an occlusive thrombus in the infarct-related
artery.106,108,109 Nevertheless, in most patients with NSTEMI,
transient coronary artery occlusion, initiated by platelet
aggregation and with associated vasoconstriction most prob-
ably lasting more than 30 minutes and up to 2 hours, is
present (see Figs. 30.3 and 30.7).
Local accumulation of endothelin causes marked
vasoconstriction; serotonin, adenosine diphosphate, throm-
bin, and endothelin are mitogens, and they likely contribute
to subsequent local fibroproliferation with increases in
the neointima, further narrowing the lumen of the endo-
thelium-injured coronary artery.110 In 30% (or more) of
patients with unstable angina and NSTEMIs, there is a
rapid anatomic progression in the severity of the coronary
luminal diameter narrowing, most likely associated
with the inclusion of organized thrombus within the
plaque and the fibroproliferation that follows plaque fissur-
ing and ulceration.110 Reductions in fibrinolytic capability
at sites of vascular endothelial injury associated with
decreases in vascular tissue concentrations of prostacyclin,
tissue plasminogen activating factor, and nitric oxide
undoubtedly contribute to coronary artery thrombosis,
vasoconstriction, and fibroproliferation at these same sites
(see Fig. 30.3).33–35
We have suggested that unstable angina, NSTEMI, and
STEMI represent a continuum pathophysiologically.53–55 The
process begins with coronary endothelial injury, usually
atherosclerotic plaque ulceration or fissuring. The degree of
coronary artery stenosis where plaque ulceration or fissuring
occurs may be mild or severe. Approximately half of the
coronary stenoses where plaque fissuring or ulceration
occurs are sites of less than 50% luminal diameter nar-
rowing.111 We have suggested that when the platelet-fibrin
thrombus and associated severe vasoconstriction persist for
periods of less than 20 minutes and often recur, the clinical
syndrome of unstable angina develops.53–55 However,
when the reduction in coronary blood flow and oxygen
delivery to the heart is more prolonged, lasting 30 minutes
to 1 to 2 hours, a NSTEMI occurs. When the period of
inadequate myocardial oxygen delivery persists for more
than 2 hours, STEMI results (see Fig. 30.3).53–55 When unsta-
ble angina and acute MI are viewed in this manner, it is
easy to appreciate that patients with unstable angina and
NSTEMI have “aborted” Q wave MIs, and therefore, they
remain at risk for new infarction and its consequences
in the ensuing 6 weeks.106,108,112–115 The risk for renewed
unstable angina and MI persists until the endothelial injury
is repaired. Other causes of endothelial injury may also lead
to this same sequence of events, including endothelial injury
associated with systemic arterial hypertension, flow shear
stress, smoking, diabetes, infection, aging, immune complex
deposition, substance abuse (e.g., cocaine), and the placement
of a coronary artery catheter into a coronary artery, espe-
cially with the interventional procedures of percutaneous
transluminal coronary angioplasty (PTCA) and stent
placement.53–55
67 8 chapter 30

A Subendocardium B

Subepicardium P R T P R T

Left ventricle

P R T P R T

R R
P Q T P Q T
Electrocardiographic stages identify
Transmural (Q-wave) transmural (Q-wave) myocardial infarction
myocardial infarction

C 02002

I V1 V2

V2 V1
II

V3 V3r
III

aVR V4 V4r

aVL V5 V5r

aVF V6
FIGURE 30.17. (A) Schematic diagram of the topographic location
of myocardial necrosis with STEMI and the associated electrocar-
diographic changes. (B) The sequential electrocardiographic altera-
tions that document the development of a STEMI or Q-wave infarct,
beginning with T-wave prominence (top), followed by hyperacute
ST-segment elevation (middle), T-wave inversion, and the develop-
ment of a significant Q wave (0.04 seconds in duration) (bottom). (C)
Atrial rhythm, rate 50 beats/min, Q waves in leads II, III, aVF and
V6r
400 msec
V6 indicating conduction delay in the inferolateral wall, ST eleva-
tion in leads II, III, aVF and 4–6, consistent with inferolateral infarc-
tion infarction and right ventricular involvement. As shown by the
right precordial leads, showing prominent ST segment elevation
(V4r–V6r). ST depression in lead I suggests right coronary artery
occlusion. Note also ST depression in leads aVR and aVL typical of
acute inferior wall infarction.

Fissuring and ulceration of the plaque often (but not
always) occur in the asymmetric portion or “shoulder region”
with a thin fibrous cap that is lipid laden. Inflammation at
sites of thin fibrous plaques with adjacent lipid cores best
predicts the vulnerable atherosclerotic plaque and one likely
to fissure or ulcerate.59–69 Inflammation is characterized in
the unstable plaque by the accumulation of monocyte-derived
macrophages, activated T cells, and mast cells. Most likely,
proteases released from the infiltrating mononuclear cells
contribute to thinning of the fibrous cap through their deg-
radation of collagen and subsequent atherosclerotic plaque
fissuring and ulceration (Fig. 30.8).53,55,68,97–103,110–122
Physical Examination/Bedside Findings
The patient with unstable angina and NSTEMI and STEMI
typically appears concerned. There may be no localizing
finding or the patient may have an audible S4, cardiac enlarge-
ment, congestive heart failure (CHF), acute mitral insuf-
ficiency, acute ventricular septal defect, or evidence of
peripheral vascular disease.
The rest ECG between episodes of unstable angina may
be normal or may show the same ST-T wave changes or prior
MI found in patients with stable angina. However, often the
ECG demonstrates ST-T wave changes during angina, usually
 corona ry h e a rt dise a se sy n drom e s
ST depression or T-wave flattening or inversion in patients
with unstable angina and NSTEMI, reflecting alterations in
myocardial perfusion of the “culprit” artery. Similar ECG
changes occur in patients with unstable angina and NSTEMI,
making it impossible to distinguish them electrocardio-
graphically. On occasion, episodes of unstable angina and the
development of NSTEMI are not associated with ST-T wave
changes on the ECG, but this is unusual.
Echocardiographic findings are highly variable, but they
may include reversible or fixed reductions in regional wall
motion or global LV function abnormalities depending on
the reversibility of ischemia, the presence of MI, and its size.
In some patients, reductions in regional wall motion occur
with episodes of rest angina and resolve as the angina
resolves.
The chest x-ray also shows great variability in findings
from a normal-sized heart to cardiomegaly with CHF. Hemo-
dynamic findings are similar to those during angina in the
patient with stable angina, that is, one expects to see an
increase in mean pulmonary capillary wedge and left ven-
tricular end-diastolic pressures that are dynamic and resolve
as the angina disappears. Patients with angina may also
develop transient mitral insufficiency secondary to mitral
valve papillary muscle dysfunction.
Coronary artery spasm leads to abrupt and dynamic
decreases in myocardial oxygen delivery (Fig. 30.5).17,18 With
a primary decrease in coronary blood flow, there is no asso-
ciation between the development of angina and exertion, and
the majority of anginal episodes occur at limited activity and
rest. These patients usually have little or no change in heart
rate or blood pressure before the onset of pain. The pain
occurs first and may be followed later by increased blood
pressure or heart rate.
In the patient with unstable angina, continuous electro-
cardiographic monitoring often documents transient ST-
segment change immediately before the onset of chest pain,
either ST-segment elevation indicating transmural ischemia
as a consequence of spasm in a major epicardial coronary
artery or platelet-initiated transient coronary artery throm-
bosis (see Figs. 30.3 and 30.5) or ST-segment depression.123–125
Most commonly, however, the patient with unstable angina
has ST-segment depression when subendocardial ischemia
develops. In some individuals, ST-segment alterations occur
in the absence of chest pain; this is referred to as silent isch-
emia.125 Silent ischemia has the same prognosis as painful
episodes of ischemia (see Chapter 31).123–125
Clinical Recognition
History
The history is of utmost importance in the recognition of
acute MI.1,2,126 Typically, the patient complains of severe
chest or epigastric pain that lasts until analgesic medication
is administered, usually 30 minutes or longer. The pain is
often described as being retrosternal or left precordial, as a
“heaviness,” “tightness,” or “like a weight on my chest,” and
is often associated with nausea and diaphoresis. It may
radiate to the back, neck, jaw, or left arm, particularly down
its ulnar aspect. Occasionally, the pain exists only in the
67 9
back, jaw, left arm, or neck. The pain is usually described as
the most severe the individual has ever experienced. It gradu-
ally builds in severity, reaches a peak, and then recedes.
Some patients with acute MIs have unstable angina for hours
to days before their infarcts. It should be emphasized,
however, that 10% to 20% of patients with diabetes
mellitus who have MIs have “silent” (i.e., painless) ones.127–129
Silent MIs also occur in patients who develop CAD (trans-
plant vasculopathy) after cardiac transplantation, occasion-
ally in individuals with neuromyopathic abnormalities, and
in some seemingly otherwise normal subjects. One should
have a high index of suspicion in the patient who presents
with new CHF, ventricular arrhythmias, hypotension, heart
murmur of mitral insufficiency, systemic embolic events, or
is resuscitated from sudden death, especially in the diabetic
patient. Serial serum measurements of CK, CK-MB, and tro-
ponin I or T and serial ECGs should be obtained in such
patients.
Physical Examination
Patients with small MIs, particularly NSTEMIs, often have
no detectable abnormality on physical examination. At the
other extreme, patients with extensive damage to the left
ventricle, usually those with anterior STEMIs with ≥40%
irreversible injury of the LV mass, often develop “power-
failure” complications of their infarcts, including cardio-
genic shock, severe LV failure, or medically refractory
arrhythmias (Fig. 30.18).130–134
Inspection and Palpation
The findings on physical examination in patients with acute
MI depend primarily on the extent of the myocardial damage.
Most patients are in obvious discomfort and diaphoretic.
Those with extensive myocardial damage develop a reduc-
tion in systemic arterial blood pressure, ranging from mild
to severe, including the development of cardiogenic shock.
Cardiogenic shock is defined as hypotension resulting from
extensive myocardial damage coexisting with evidence that
the reduced blood pressure is inadequate for normal systemic
perfusion, so that cool skin, mental confusion, and oliguria
are usually present. Patients with extensive LV myocardial
necrosis may also have an alternating pulse force (pulsus
alternans) (Fig. 30.19) and frequent premature ventricular
beats.
If second- or third-degree (complete) atrioventricular
block with sinus rhythm is present, the patient will have
intermittent “cannon” A waves in the jugular venous pulse
(Fig. 30.20). Patients with atrial fibrillation do not have an
A wave in the jugular venous pulse but instead have an
irregularly irregular pulse. Those with important tricuspid
insufficiency have prominent V waves in their jugular venous
pulse (Fig. 30.21). Patients with right ventricular (RV) failure
have an increased jugular venous pressure, and they may
have hepatomegaly, right upper quadrant tenderness when
acute hepatic congestion develops, ascites if the RV failure is
severe, and peripheral or sacral edema.
With acute STEMI, a precordial “ectopic impulse” may
sometimes be palpated over the left precordium, typically
along the lower left sternal border or between the left sternal
border and the apex. This impulse is caused by an increase
680 chapter 30

Group B Group A
90
PCG-AA
80
Recent
Old 1 2 1 2
70 PCG-MA
Myocardial Loss (%)

60
50 Carotid
40
30
ECG
20
10
FIGURE 30.19. Heart sounds (top), carotid pulse tracing (middle),
0 and electrocardiogram (ECG) (bottom). Pulsus alternans is shown
Without Cardiogenic Shock During Life Cardiogenic Shock During Life as the alternating height in the pulse wave tracing in a woman with
a dilated cardiomyopathy. AA, aortic area; MA, mitral area; PCG,
FIGURE 30.18. Development of “power failure” complications of phonocardiogram.
MI, including cardiogenic shock, occurs in patients with the most
extensive myocardial necrosis from their infarcts.

1 A2 P2

A V H
JUG. C
PULSE

Y
X

VPB
Second LSB
(400 cps)

Fourth LSB
(400 cps)

A FIGURE 30.20. (A) Normal jugular (jug.) venous pulse

Jugular “Cannon” configutation. Note the prominence of the A wave and that
A the X trough is deeper than the Y trough. Heart sounds and
venous pulse the ECG are shown (top). (B) A “cannon” A wave in the
jugular venous pulse. Heart sounds are shown along with
the ECG (top). LSB, left sternal border; VPB, ventricular
premature beat.
 corona ry h e a rt dise a se sy n drom e s 6 81

A v
in regional LV compliance within the area of injury, with a
v
resultant systolic distention or bulging (dyskinesia) of the
injured heart segment. Over hours to a few days after MI, the
compliance of this region decreases (stiffness increases) and
the systolic bulging is replaced by reduced (hypokinetic) or
SEVERE absent (akinetic) regional wall motion. If the systolic bulging
a
a persists, a ventricular aneurysm may be present.
v v
Auscultation
MODERATE
a a S4’s are heard in most patients with acute and chronic CAD
(Fig. 30.22), and they are usually soft and best heard with
Y Y light application of the bell of the stethoscope over the middle
and lower left precordium. S4 is caused by a more forceful
Y atrial contraction against a ventricle whose compliance is
Y
reduced as a consequence of increased ventricular stiffness
a NORMAL caused by the physiologic effects of CAD.
c v c v
When the mitral valve apparatus is damaged, a murmur
of mitral insufficiency may be audible. These murmurs have
X Y
variable auscultatory characteristics; they may be ejection in
X Y
quality, peaking in intensity in mid- to late systole, or they
may be holosystolic (Fig. 30.23). Intermittent myocardial
ischemia with transient dysfunction of the posterior papil-
lary muscle of the mitral valve leads to a murmur of papillary
LR LR
muscle dysfunction typically associated with mild to moder-
1 2 3 1 2 3 ate mitral insufficiency. The murmur of papillary muscle
dysfunction usually begins after the first heart sound (S1),
B peaks in mid- to late systole, and extends up to S2. It is heard
at the cardiac apex and may radiate toward the left sternal
border or into the axilla. If caused by intermittent myocar-
dial ischemia, the murmur is transient. If caused by infarc-
tion of the papillary muscle, the murmur is usually
permanent. Rupture of a papillary muscle with acute MI
causes severe mitral insufficiency and often a soft apical
holosystolic murmur. However, sometimes no audible
murmur occurs with a ruptured papillary muscle, even
though severe mitral insufficiency develops. Acute mitral

FIGURE 30.21. (A) The jugular venous pulse normally (bottom) and Fifth lsb
with moderate (middle) and severe tricuspid insufficiency (top). Note (25 cps)
the marked prominence of the V wave with moderate and severe
tricuspid insufficiency. The V wave correlates with the second heart
S4 S1 SM S3
sound (bottom, 2). The holosystolic murmur of tricuspid insuffi-
ciency is also shown (bottom). Typically, it becomes louder along S2
the lower left sternal border with inspiration. L and R, timing of left
and right ventricular third heart sounds (3). Third heart sounds Apex
occur with moderately severe and severe valvular regurgitation, and (25 cps)
those emanating from the right heart become louder with inspira-
tion. (B) A preferred way to evaluate the jugular venous pulse wave-
form is to examine the right external jugular vein as shown and
simultaneously listen to the heart sounds, timing the A wave with
the first heart sound and the V wave with the second heart sound.
Carotid

FIGURE 30.22. Fourth heart sound (S4), third heart sound (S 3), and
a systolic ejection murmur (SM), representing mitral insufficiency.
LSB, left sternal border; S1, first heart sound; S2, second heart
sound.
682 chapter 30

insufficiency occurs most commonly in patients with infe-

M1 A2 P2 S3 M1 A2 P2 S3 rior or lateral STEMIs and in those with NSTEMIs.135–141
Similarly, those with inferior infarcts and structural damage
PCG-PA to the tricuspid valve may develop tricuspid insufficiency.
Rupture of the interventricular septum occurs most com-
monly in patients with acute anterior infarction, although
it may also occur in the patient with an inferior MI (Fig.
M1 A2 S3 M1 S3 30.24).142–151 The murmur caused by a ventricular septal
SM SM A2
MDM OS MDM defect (VSD) is located along the lower left sternal border, is
PCG-MA holosystolic, and is often associated with a left sternal border
systolic thrill. As pulmonary artery pressure and vascular
resistance increase, the systolic murmur of a VSD becomes
shorter, ultimately disappearing altogether with the develop-
ment of severe pulmonary hypertension (Fig. 30.24). Func-
tionally large acute VSDs (pulmonary to systolic blood flow
of 1.5 to 1 or greater) should be closed usually by surgical
CAROTID intervention when CHF develops in the patient with MI;
otherwise, rapidly progressive CHF and death may ensue. We
recommend prompt coronary arteriography and repair of an
acute VSD with the development of CHF.
ECG A murmur of relative mitral or tricuspid insufficiency
occurs in patients with LV or RV failure, respectively; it is
the result of a spatial abnormality in the orientation of the
FIGURE 30.23. Use of two simultaneous phonocardiograms (PCGs)
to identify heart sounds in the patient with mitral regurgitation. A papillary muscles of the mitral and tricuspid valves caused
loud holosystolic murmur (SM) is noted at both the pulmonary by marked dilatation of the left or right ventricle. The mitral
artery (PCG-PA) and the mitral area (PCG-MA). The aortic compo- and tricuspid insufficiency with these entities is usually
nent of the second heart sound (A 2) is masked by the latter part of mild or moderate and diminishes in severity with diuresis
the murmur, but it can be identified as the widely transmitted sound
immediately preceding the incisura of the carotid pulse tracing and unloading therapy.
(arrow). In this patient, mixed mitral regurgitation and stenosis Third heart sounds occur in patients with acute MIs who
coexist and a mitral valve opening snap (OS) can be seen occurring have ventricular filling pressures (LV end-diastolic pressures)
slightly later than the second pulmonic heart sound (P2) in the of 15 mm Hg or greater and in those with moderately severe
cardiac cycle. A prominent third sound (S3) is seen in both PCG
or severe mitral, aortic, or tricuspid valvular insufficiency
channels, and a mid-diastolic murmur (MDM) is present at the
mitral area. (Fig. 30.22). S3’s are heard in patients with CHF and in those
with rapid filling of the ventricles as a consequence of moder-
ate or severe mitral, tricuspid, or aortic valve incompetence.
S3’s may be rarely heard in some young individuals (i.e., those

A B
LSE

S1 S1
S2 S2
PA 22/ 11
C D E
LSE 2 LICS

S1 S1 S2 S1 E
S2
S2
FIGURE 30.24. The typical holosystolic murmur of a ventricular monary hypertension, the murmur becomes shorter and ejection in
septal defect (VSD) and the influence of increasing pulmonary artery timing. With severe pulmonary hypertension, the systolic murmur
(PA) pressure on the murmur. (A) Murmur of a VSD with normal PA of a VSD disappears. E, ejection click; 2 LICS, second left intercostal
pressure. (B–E) The influence of increasing PA pressure on the spaces; LSE, lower sternal edge.
murmur of a VSD shows that, with the development of severe pul-
 corona ry h e a rt dise a se sy n drom e s
Expiration Inspiration
1 22 1 22
Normal
A2 P2 A2 P2
L BBB
P2 A2 P2 A2
FIGURE 30.25. Normal and paradoxical splitting of the second
heart sound are shown at top and bottom, respectively. The influ-
ence of the left bundle branch block (LBBB) to produce paradoxical
splitting of the second heart sound is shown (bottom).
under 30 years of age) as a result of rapid filling of the
ventricle.
S2 normally splits into two components with inspiration,
the earlier aortic and the later pulmonary valve closure
sound, because inspiration increases venous return to the
right heart and delays pulmonary valve closure (Fig. 30.25).
However, the second sound may be paradoxically split (i.e.,
wider splitting of the second sound during expiration) in the
patient during angina pectoris, and in the patient with severe
LV failure, systemic arterial hypertension, LBBB, or pacing
from the right ventricle, and with the various forms of LV
outflow obstruction, including valvular, supravalvular, and
subvalvular aortic stenosis (see Fig. 30.24). The pulmonary
closure sound is increased in intensity in the patient with
moderately severe to severe pulmonary hypertension of any
etiology.
A pericardial friction rub is detected in some patients
with STEMIs and almost never in those with acute NSTEMIs.
Patients with audible pericardial friction rubs are usually
those with the largest MIs. If a large pericardial effusion
develops, the heart sounds may be distant and the jugular
venous pressure elevated. Cardiac tamponade results in the
development of hypotension, pulsus paradoxus (reduction in
systolic blood pressure during inspiration of more than
10 mm Hg), distant heart sounds, and an elevated jugular
venous pressure. This is a life-threatening occurrence and
requires the removal of the large pericardial effusion and
emergent pericardiocentesis.
Bibasilar or more extensive moist rales develop in patients
with LV failure. Pulmonary edema occurs with extensive
MI, in those with myocardial ischemia superimposed on
extensive previous MI, and in some who develop mechanical
complications (acute VSDs, acute mitral insufficiency, or
large ventricular aneurysms) as a complication of acute MI.
Myocardial Stunning and Hibernation
Transient myocardial ischemia followed by reperfusion may
lead to protracted recovery of segmental ventricular func-
tion, known as myocardial stunning. This is probably caused
by cellular calcium overload and free radical generation.152–159
Stunned myocardial segments may contribute to the devel-
683
opment of CHF when the area of ischemia or infarction is
large. Alternatively, persistent ischemia can lead to chronic
depression of segmental ventricular function, known as
myocardial hibernation, which may also contribute to
CHF and can be reversed, thereby correcting severe CHF,
in selected patients who undergo coronary artery
revascularization.
Electrocardiographic Diagnosis
As indicated earlier, unstable angina and NSTEMIs have
transient ST-T wave changes that are similar and include ST
segment depression and T-wave flattening or inversion in
ECG leads reflecting the myocardium perfused by the culprit
coronary artery. With LBBB, acute anterior MI is not recog-
nizable from the ECG, since the LBBB pattern simulates that
of an anterior MI in the left precordial leads. However, if the
LBBB pattern is otherwise altered by the presence of diminu-
tive R-wave voltage, S waves, or initial Q waves in leads I,
aVL, or V5 and V6, the patient may have had prior anterior
and lateral MI. Inferior STEMIs can be recognized in the
patient with LBBB because the evolution of Q waves in the
inferior ECG leads is not altered by LBBB. Abnormal T-wave
vectors reversed from the normal pattern in patients with
LBBB, that is, inverted T waves in V1 to V3 or upright T waves
in leads V4 to V6, may indicate anterior or lateral ischemia or
infarction. In patients with prior STEMI, recognition of new
injury in the same general regions of the left ventricle is dif-
ficult. Finally, with rapid electrocardiographic evolution of
the MI, it may not be possible to differentiate old from new
MI from the ECG alone. ST-segment elevation may also
occur under other circumstances: (1) with normal early repo-
larization; (2) with transient myocardial ischemia, as in
Prinzmetal’s angina, or with ischemia in an area of previous
MI; (3) in some individuals with chronic ventricular aneu-
rysms (Fig. 30.26); (4) transiently after electrical cardiover-
sion; (5) in the anterior precordial electrocardiographic leads
in patients with LBBB; (6) in the anterior precordial leads in
some patients with LV hypertrophy; and (7) in an occasional
patient with hyperkalemia.
Although the ECG is useful in the recognition of STEMI,
it does not enable one to recognize acute NSTEMI with cer-
tainty. In these patients, the ECG usually demonstrates ST
depression and T-wave inversion, and the only evolution is a
return to baseline (Fig. 30.27; see also Fig. 30.7). Unfortu-
nately, unstable angina, subendocardial ischemia, ventric-
ular hypertrophy, tachycardia, severe emotion, electrolyte
alterations (especially hypokalemia, hypomagnesemia, hypo-
calcemia), and the use of certain medications (including
cardiac glycosides) are often associated with similar electro-
cardiographic changes. Indeed, bizarre and deeply inverted
T-wave alterations occur in some patients with acute intra-
cerebral hemorrhage. The only useful rule in the electrocar-
diographic recognition of NSTEMI is that the deeper the
ST-segment depression and the longer it lasts, the more likely
is MI.
Serum Enzyme and Cardiac Intracellular
Substance Changes
The relationship of changes in cardiac enzyme concentra-
tions and other intracellular myocardial substances to the
684 chapter 30

1 2 3

aVR aVL aVF

V1 V2 V3

V4 V5 V6

FIGURE 30.26. Chest radiography (A) and corresponding ECG (B) reflect a ventricular aneurysm. Note the high lateral bulge in the left
ventricular silhouette in the chest x-ray and the persistent ST-segment elevation across the precordium (leads V1 through V6).

I II III aVR aVL aVF

V1 V2 V3 V4 V5 V6

03061

I V1

II V2

V3
III

FIGURE 30.27. (A) Electrocardiographic

aVR V4 patterns seen with an acute NSTEMI. The
T-wave inversion in leads II, III, and aVF and
the ST-segment depression and T-wave inver-
sion in the lateral precordial leads (leads V2
through V6) suggest the presence of NSTEMI.
aVL V5
Lower: Sinus rhythm, combination of
marked generalized, downloping ST depres-
sion and ST elevation more in lead aVR (B)
Provided by Hein J.J. Wellens and Anton
aVF V6 Gorgels. aVR that in lead V1, indicating isch-
emia or NSTEMI due to the left main stem
B 400 msec stenosis or 3 vessel disease.
 corona ry h e a rt dise a se sy n drom e s
development of acute MI is shown in Figure 30.28. A previ-
ously preferred enzymatic technique was the measurement
of CK and, in particular, the myocardium-specific CK-MB
isoenzyme, measured by spectrophotometry, fluorometry,
or radioimmunoassay.160–175 CK-MB usually increases in the
sera of patients 2 to 3 hours after the onset of acute MI,
reaches a peak at 10 to 12 hours, and returns to normal
within 24 hours after the event in patients with small infarcts
and in those who have reperfusion after endogenous throm-
bolysis. In patients with large infarcts, and those who fail to
experience reperfusion, CK and CK-MB often peak later (e.g.,
18 to 24 hours after infarction) and return to normal 30 to
40 hours after the event. Stuttering infarcts, defined as
repeated episodes of infarction with recurrent chest pain
over hours to days, result in repeated elevations of serum CK
and CK-MB.
Radioimmunoassay measurement of alterations in serum
myoglobin concentration allows a slightly earlier recognition
of acute MI, but there is no means to distinguish myoglobin
release from the heart and skeletal muscle when both cardiac
and skeletal muscle injury occur. Therefore, in the patient
with skeletal muscle damage from trauma, intramuscular
injection, recent surgery, cardioversion, heat exposure, con-
sumption of alcohol in excess, or primary skeletal muscle
disorders, determining the presence of MI is not possible by
measurement of serum myoglobin levels. However, in the
patient without skeletal muscle injury, measurement of serum
myoglobin by radioimmunoassay provides a sensitive and rel-
atively rapid means to detect MI within 1 to 2 hours of the
event. Myoglobin is released from injured myocardial cells
within 30 minutes to 2 hours of the event, peaks within 4 to
6 hours, and returns to normal values within 10 to 12 hours.
Radioimmunoassay measurement of alterations in the
serum concentration of the light chain of myosin may also
allow a relatively early and precise recognition of acute
MI.166,167 Measurements of serum transaminase values were
made in the past, but these are nonspecific and they are not
relied on now for MI detection. Serial serum measurements
2X
Elevation of value
Normal
0 2 4 6 8 10 12 24 48 72 96 120
Time (hrs)
FIGURE 30.28. Typical changes in several substances measured in
a patient with an evolving acute MI. Increases in serum myoglobin
concentration are the earliest change indicative of MI. Note that the
white blood cell count (WBC) rises early after infarction and that
the serum creatine kinase (CK) and MB isoenzyme of CK (CK-MB)
rise before the serum troponin I and T. The erythrocyte sedimenta-
tion rate (ESR) and lactic dehydrogenase (LDH) rise relatively late
after acute MI.
685
of lactic dehydrogenase (LDH) and LDH isoenzymes have
also been used to recognize acute MI. There are five LDH
isoenzymes, and increases in LDH isoenzymes 1 and 2 are
consistent with MI, such that when LDH-1 or -2 elevations
represent more than 50% of the total, they are often indica-
tive of an acute MI. Increases in LDH occur 18 to 30 hours
after MI and usually return to normal within 48 to 72 hours.
Therefore, LDH measurements allow the detection of some
patients with MI who delay their hospital admission in
whom it is not possible to rely on changes in CK and CK-MB
for infarct detection. However, these are almost never used
in contemporary practice.
Measurements of CK isoforms, as well as myoglobin,
have proved useful in detecting reperfusion after thrombo-
lytic therapy or release of an experimental coronary artery
occlusion.169–173 The conversion of CK isoform from CKMM-1
to CKMM-2 in the peripheral circulation appears to correlate
with successful reperfusion therapy. Staccato increases in
serum myoglobin in the first 4 to 6 hours after MI are indica-
tive of reperfusion; rapid peaking of increases in serum CK
and CK-MB (within 10 to 12 hours from symptom onset) are
also often indicative of reperfusion of the MI.
Presently, the preferred marker of myocardial necrosis for
detecting MI is a troponin. Three troponin subunits regulate
muscle contraction by modulating the calcium-dependent
interaction of actin and myosin: the tropomyosin-binding
subunit T, the calcium-binding subunit C, and the actomyo-
sin–adenosine triphosphatase (ATPase)-inhibiting subunit I.
Troponin I exists in three isoforms: slow-twitch, fast-twitch,
and cardiac. Cardiac troponin I (cTn-I) is the 26.5-kd isoform
of the muscle subunit and is genetically and structurally
distinct from that produced in extracardiac muscle.
Previous studies have shown that increases in cTn-I and
cardiac troponin T (cTn-T) correlate with acute myocardial
necrosis in the general population.168,174,175 Both substances
are increased in the systemic circulation within 6 to 8 hours
after acute MI or other forms of myocardial necrosis, and
they may remain elevated for at least 2 to 3 days. However,
in patients with renal failure, spurious cTn-T elevations and
increases in CK-MB have been found.79 Studies have shown
that cTn-I accurately predicts myocardial injury in patients
with renal failure. Martin and coworkers79 evaluated 56
WBC patients with acute or chronic renal failure or end-stage renal
Myoglobin disease, assessing the sensitivity and specificity of cTn-I for
CK and CK-MB detecting myocardial injury in these patients. During a 6-
ESR
LDH month period, patients admitted with suspected MI were
Troponin I and evaluated. These patients had end-stage renal disease, chronic
Troponin T or acute renal failure, and a mean age of 62 years. There were
an equal number of males and females. Further cardiac
testing, including echocardiography, stress testing, or arteri-
ography, was performed at the discretion of the primary phy-
sician. Increased cTn-I levels were associated with increased
in-hospital mortality. The sensitivity and specificity for CK-
MB were 44% and 56%, respectively, whereas they were 94%
and 100% for cTn-I. In this study, elevated cTn-I levels were
associated with increased short-term mortality and an ability
to risk-stratify patients with severe renal failure and myo-
cardial injury. Troponin T values were slightly elevated in
patients with renal disease, although not necessarily outside
of the normal range. Troponin I values appeared to be more
reliable in infarct detection in these patients.79
686 chapter 30

In patients with unstable angina and NSTEMI, elevations

in CRP and troponin I or T identify patients who usually
benefit from interventional therapy, including PTCA and
stent placement when the coronary anatomy allows or coro-
nary artery revascularization when the coronary stenoses are
very diffuse and severe.176

Myocardial Scintigraphy
Radionuclide myocardial scintigraphy techniques for identi- Ant
fication of acute MI can be useful.177–189 These techniques
enable one to visualize the region(s) of acute MI (infarct-avid
imaging technique) or to identify areas of nonreversibly
decreased myocardial perfusion (myocardial perfusion
imaging technique). The prototype infarct-avid imaging
agent, technetium 99m (99mTc) stannous pyrophosphate,
accumulates in irreversibly damaged myocardium 1 to 5
RV
days after MI; its sensitivity in the detection of acute MIs of
3 g or larger is greater than 90% (Fig. 30.29).179,180,189
With successful reperfusion, MI may be detected within
2 to 3 hours of the event.184,185 An alternative to pyrophos-
phate imaging is the use of an antimyosin antibody labeled LAO

a 1b 1c

LL
a 2b 2c

FIGURE 30.30. A thallium 201 myocardial scintigram from a

a 3b 3c
a 4b 4c
FIGURE 30.29. Various transmural MIs as evidenced by techne-
tium 99m stannous pyrophosphate myocardial scintigraphy in the
anterior, left anterior oblique, and left lateral imaging views. (1a–1c)
Large “doughnut” anterolateral MI. (2a–2c) Inferior MI. (3a–3c)
Inferolateral MI. (4a–4c) True posterior MI.
patient with an acute MI in the anterior (Ant), left anterior oblique
(LAO), and left lateral (LL) views. Only a portion of the interior and
posterior wall of the heart are normally perfused. The anteroseptal
and anterolateral aspects of the heart have marked decrease in
thallium 201 perfusion, as shown by the straight arrows. RV, right
ventricle (curved arrow).
with technetium or iodine, which binds to myosin with
myocyte membrane injury and MI.186–188 It has the same sen-
sitivity in MI detection as pyrophosphate, but it does not
accumulate in bone. However, neither of these approaches is
used frequently now.
Thallium 201 (201Tl) and Tc-sestamibi are myocardial per-
fusion imaging agents that accumulate in the myocardium
in direct proportion to blood flow (Fig. 30.30).182,183
When used within 24 hours after acute MI, their sensi-
tivities for infarct detection are approximately 90%. The size
of the initial 201Tl or 99mTc-sestamibi defect after acute MI
appears to have prognostic significance, as do persistently
abnormal pyrophosphate scintigrams,189 that is, ones that
remain abnormal for 3 months or longer after MI. Large MIs,
as detected by extensive perfusion defect or by pyrophosphate
or antimyosin antibody uptake, and persistently abnormal
pyrophosphate scintigrams, are associated with an increased
risk for future coronary events and heart failure. 99mTc-
sestamibi provides information similar to that of 201Tl, but
 corona ry h e a rt dise a se sy n drom e s
also allows an evaluation of global and regional systolic func-
tion, including systolic wall thickening.
In addition to these imaging techniques, the cardiovas-
cular blood pool can be identified with technetium-labeled
erythrocytes to characterize the impact of acute MI on
regional and global ventricular function by dynamic myocar-
dial scintigraphy.190–193 This latter technique allows measure-
ment of ventricular ejection fraction, ventricular volumes,
regional wall motion, left-to-right shunts (i.e., VSDs), and
valvular insufficiency, including mitral or tricuspid regurgi-
tation and the identification of ventricular aneurysms.
Two-dimensional (or three-dimensional) echocardio-
graphic measurements can also be used to detect intramyo-
cardial masses and to evaluate global and segmental ventric-
ular functional alterations in patients with acute MI.194–198
Transthoracic and transesophageal two-dimensional echo-
cardiography can also be used for detection of LV thrombi
complicating acute MIs.196–198 Patients with acute anterior
STEMIS more frequently develop LV mural thrombi acutely
(10% to 40% of such individuals prior to development of
reperfusion therapies), but probably less often with early
reperfusion. This occurs more commonly in patients with
acute STEMI than in those with NSTEMI. These patients
have an increased risk for systemic embolic events, requiring
that they receive anticoagulants unless there is some contra-
indication. Echocardiography with Doppler, transthoracic
and transesophageal, enables one to detect and estimate the
severity of mitral insufficiency and VSDs, to identify ven-
tricular aneurysms and pseudoaneurysms, and to assess the
extent of wall motion abnormalities in patients with infarc-
tion.199–206 Detection of these abnormalities is important,
especially in patients with a low-output state, hypotension,
or heart failure, since proper medical management or surgi-
cal repair may save the patient’s life.
Pseudoaneurysms (false aneurysms) developing after MI
(most commonly acute STEMIs) represent partial tears in the
left ventricle and an immediate risk for complete rupture.
They are distinguished from true aneurysms by demonstra-
tion—on two-dimensional echocardiogram, angiography,
radionuclide ventriculography, or magnetic resonance
imaging (MRI)—of their communication with the true left
ventricle by a narrow channel or neck. True LV aneurysms
communicate with the LV cavity by an imperceptible
pathway. False LV aneurysms rupture spontaneously and
should be surgically corrected as soon as they are identified.
Patients at greatest risk for heart rupture after MI are those
with systemic arterial hypertension who are experiencing
their first MIs and elderly patients. Blood pressure elevations
should be prevented in patients with MIs to minimize this
risk. When myocardial rupture occurs after MI, most patients
die suddenly of exsanguinations or cardiac tamponade. A few
develop tamponade with a sealing of the tear by a blood clot
in the pericardial space. Although blood does not usually clot
in the pericardial space, in the patient with extensive MI, it
may clot as a consequence of the loss of segmental wall
motion in the infarcted segment. Thus, continued bleeding
is prevented, providing the observant physician an opportu-
nity to recognize the development of an enlarging pericardial
effusion with early tamponade and to intervene surgically to
correct the tamponade and repair the myocardial rupture. It
appears best to place these patients on cardiopulmonary
687
bypass and evacuate the pericardial fluid/thrombosis while
they are on bypass rather than attempting to treat the peri-
cardial tamponade by pericardiocentesis before placing the
patient on bypass. The classic finding in the patient with
sudden myocardial rupture is the development of electrome-
chanical dissociation (EMD), in which the patient loses
blood pressure and becomes unresponsive but has continuing
electrical activity on the ECG for the subsequent seconds to
minutes. Electromechanical dissociation is not specific for
myocardial rupture because it may also occur with a large
anteroseptal infarct, pericardial tamponade of any etiology,
and severe systemic hypoxemia or acidosis.
Differential Diagnosis
In theory, the differential diagnosis of acute NSTEMI and
STEMI includes any cause of chest pain, cardiac arrhyth-
mias, new systolic murmur of mitral insufficiency or VSD,
heart failure, and sudden death. Important diagnostic
considerations include (1) unstable angina, (2) Prinzmetal’s
angina, (3) pericarditis, and (4) dissecting aortic aneurysm.
Other diagnostic considerations, although less commonly
presenting with pain classical for MI, include (1) peptic ulcer
disease, (2) pancreatitis, (3) cholecystitis, (4) pulmonary
embolic disease, (5) spontaneous pneumothorax, and (6)
pneumonitis. Careful attention to history, physical examina-
tion, relevant blood tests, ECGs, and noninvasive or invasive
imaging test results usually enables one to make the correct
diagnosis.
Estimation of Infarct Size
Accurate measurements of the extent of reversible and irre-
versible cell damage can be useful in predicting prognosis
and selecting optimal future therapy for patients. Ideally,
such measurements should be relatively noninvasive, appli-
cable early in the patient’s clinical course, capable of being
repeated with reasonable frequency, able to provide quantita-
tion of the extent of damage with various types of infarcts,
and generally available. No perfect measurement of infarct
size or of the extent of ischemic damage exists at present,
although several methods have been used: (1) enzymatic
indices of infarct size, most importantly, measurement of
CK-MB enzyme release from the heart207; (2) scintigraphic
measurements of infarct size, including infarct-avid scinti-
graphic techniques (with 99mTc stannous pyrophosphate or
antimyosin antibody)208–210 and myocardial perfusion tech-
niques (201Tl or 99mTc-sestamibi and other technetium-based
perfusion markers); (3) two-dimensional transthoracic or
transesophageal echocardiography; and (4) dynamic myocar-
dial scintigraphy to estimate abnormalities of global and
segmental ventricular function, using either first-pass or
equilibrium techniques. Evaluation of global LV function
with MRI and utilizing Gadolinium allows estimation of
infarct size. Each of these techniques has its limitations, but
each also provides important information concerning the
location and relative size of an infarct.
Three-dimensional estimates of the extent of myocardial
damage are needed for accurate scintigraphic measurements
(single photon emission computed tomography) and with
other imaging techniques, including three-dimensional
688 chapter 30

echocardiography and MRI. Distinction of reversibly (“viable”

myocardium) and irreversibly injured myocardium can be
made in patients by positron emission tomography (PET)
imaging evaluation that combines estimates of myocardial
perfusion (rubidium or other PET perfusion marker) and fluo- PA
Thermistor and
rodeoxyglucose studies to identify reversibly injured myocar-
SVC distal lumen
dium as regions with reduced perfusion but persistent
metabolic activity. Persistent metabolic activity is indicated
by uptake and utilization of fluorodeoxyglucose (indicative
of reversible injury to the myocardium) even when perfusion Balloon
is markedly reduced or absent. One may also demonstrate RA inflated
reversible wall motion abnormalities by echocardiography,
radionuclide ventriculography, or MRI when potent inotropic Proximal
stimuli, such as dobutamine, dopamine, or paired electrical lumen
stimulations, are used, or during low-level exercise 5 to 7
days after MI.211–220 Finally, the extent of myocardial scar
may be identified by MRI and estimated by a QRS scoring RA
system.221,221a

Evaluation of Ventricular Function mm Hg

Invasive and noninvasive techniques can be used to allow
more precise characterization of ventricular function in
patients with reduced systemic arterial blood pressure and
uncertain LV functional status. Flow-directed catheters, such
as the Swan-Ganz catheter, allow measurement of LV filling
pressure without entering a systemic artery or the LV (Fig.
30.31).222
This balloon-tipped, flow-directed catheter can be placed
in the pulmonary artery from a systemic vein (Fig. 30.31).
The Swan-Ganz catheter is positioned in the pulmonary
artery either with the aid of fluoroscopy or with continuous
pressure monitoring to identify the characteristic right atrial,
RV, and pulmonary artery pressures. Once the catheter is in
the pulmonary artery, the balloon is inflated, facilitating the
measurement of pulmonary capillary wedge pressure. In
the absence of mitral valve disease, the mean pulmonary
capillary wedge pressure is the same as the LV end-diastolic
pressure (Fig. 30.31).
Measurement of LV filling pressure with the Swan-Ganz
catheter enables one to differentiate hypotension caused by
hypovolemia from cardiogenic shock and LV failure. Mean
pulmonary capillary wedge pressures less than 12 mm Hg
with hypotension occur with hypovolemia and those 15 mm Hg
or higher are usually associated with cardiogenic shock and
LV failure. In addition, cardiac output may be measured with
the same catheter. The patient with an acute MI and shock
should also have an indwelling arterial cannula placed to
allow accurate measurement of and to detect moment-to-
moment changes in systemic arterial pressure. The flow-
directed pulmonary arterial catheter may also be utilized to
help idealize mean pulmonary capillary wedge pressure either
with volume infusion with normal saline when the patient is
hypovolemic or by diuresis when the patient is hypervolemic
to values of 15 to 18 mm Hg in the hypotensive patient.
Both LV and RV function after acute MI can be assessed
noninvasively with either dynamic myocardial scintigraphy,
echocardiography, or MRI. These methodologies facilitate
measurement of ventricular ejection fraction, ventricular
dimensions or volumes, and segmental wall motion. Two-
dimensional echocardiography and transesophageal echocar-
LA
30
25 A a PAW
20
c V v
15 C
10
5
I second
FIGURE 30.31. (A) Path taken by a Swan-Ganz catheter. The cath-
eter is inserted into a systemic vein, threaded into the right heart,
and positioned in the pulmonary artery (PA). In this location, pul-
monary artery and pulmonary capillary wedge pressures and cardiac
output may be measured. RA, right atrium; RV, right ventricle; SVC,
superior vena cava. (B) The pulmonary artery wedge (PAW) pressure,
and the A, C, and V waves in both the LA and PAW pressure wave
forms.
diography with Doppler assessment facilitate the detection
of LV thrombi, VSDs, and mitral insufficiency, as well as an
estimation of their severity. Transesophageal echocardiogra-
phy facilitates a more precise detection of small intracardiac
thrombi than does transthoracic echocardiography. Three-
dimensional echocardiography has been developed, and it
may facilitate even more accurate characterization of sys-
tolic function and detection of thrombi in the future.
Prognosis
Most patients with acute MIs who survive to reach the hos-
pital and subsequently receive appropriate therapy for their
MIs have a relatively uncomplicated course. However, some
patients develop life-threatening complications during the
first 1 to 2 weeks, and others die (Table 30.3). During the
early 1970s, more than 50% of patients died before reaching
the hospital, primarily due to ventricular arrhythmias during
the seconds or minutes after onset of chest pain. Since the
 corona ry h e a rt dise a se sy n drom e s
TABLE 30.3. Life-threatening complications of acute myocardial
infarction
Ventricular arrhythmias (ventricular tachycardia, ventricular
fibrillation or asystole)
Extremely rapid atrial arrhythmias in association with extensive
MI (atrial flutter or atrial fibrillation)
Heart block [second-degree (Mobitz II) or third-degree]
Marked bradycardia
Infarction ≥40% of left ventricle
Extensive RV infarction
Acute ventricular septal defects
Acute and severe mitral regurgitation
Severe pulmonary edema
Rupture of the heart
Systemic and/or pulmonary emboli
Extension of the MI
Markedly increased LV end-systolic volume after MI
Occluded proximal LAD after anterior MI
* LAD, left anterior descending coronary artery; LV, left ventricular; MI,
myocardial infarction; RV, right ventricular.
late 1980s, emergency ambulance systems have achieved a
25% to 30% reduction in the incidence of death before hos-
pitalization of patients with acute MIs and sudden cardiac
arrest syndromes.223–225
Overall mortality in patients with acute MIs who reach
the hospital ranges from 3% to 30%, depending on the popu-
lation studied and the promptness and success of the therapy
given in opening the infarct-related artery. In general, patients
with anterior MIs have a higher mortality than those with
inferior MIs, probably because of a greater loss of LV
muscle.
Patients can be categorized into groups with differing
prognoses on the basis of their initial hemodynamic mea-
surements. Patients without LV failure and with a mean
systolic arterial pressure of greater than 110 mm Hg, an
average cardiac index greater than 2.5 L/min/m2, and a
normal pulmonary capillary wedge pressure (or pulmonary
artery diastolic pressure) have low mortality rates. Death in
these patients is usually caused by a ventricular arrhythmia,
later infarct extension, or a mechanical complication (e.g.,
myocardial, septal, or papillary muscle rupture).
A ruptured papillary muscle of the mitral valve leads to
fulminant left heart failure with pulmonary edema and
often hypotension, and the patient is typically unresponsive
to diuretics and unloading interventions. This catastrophic
event should be suspected when a patient with an inferior,
lateral or NSTEMI abruptly develops fulminant left heart
failure with a new apical murmur, often soft, of mitral insuf-
ficiency. On occasion, however, the severity of the LV failure
is such that no murmur is generated. Prominent V waves are
usually found in the pulmonary capillary wedge tracing by
flow-directed catheter. An echocardiogram and Doppler eval-
uation demonstrate severe mitral regurgitation and some-
times a flail mitral leaflet. Ordinarily, the only chance for
survival is immediate surgical repair or replacement of the
mitral valve.
689
Papillary muscle dysfunction, mediated by ischemia
with a transient apical systolic murmur or by infarction with
a permanent apical systolic murmur, usually causes less
severe mitral regurgitation, and the patient can generally
be stabilized by unloading therapy with a diuretic and
nitroprusside or, if needed, temporary intraaortic balloon
support.
Chordae tendineae rupture is not usually caused by MI,
but instead may lead to acute mitral regurgitation as a con-
sequence of spontaneous rupture, in the Marfan syndrome
patient, in some women with mitral valve prolapse, in
patients with chest wall trauma, or secondary to trauma on
the mitral valve apparatus of significant valvular aortic
insufficiency, with endocarditis, or as a consequence of acute
rheumatic fever.
Acute VSDs occur primarily in the muscular septum and
develop within 1 day to 2 weeks after MI, resulting in a new
holosystolic murmur along the lower left sternal border,
often associated with a systolic thrill in the same location
and a significant oxygen step-up between the right atrium
and the right ventricle. The VSD places a pressure and volume
load on the left and right ventricles and may result in sudden,
or gradual, hemodynamic decompensation, with severe CHF,
hypotension, and relentless hemodynamic deterioration. We
believe that immediate surgical correction of a large VSD is
indicated with the development of the earliest signs of hemo-
dynamic deterioration (e.g., increased respiratory rate, tachy-
cardia, hypotension). In the future, it may be possible to do
this in the cardiac catheterization laboratory with a device,
such as a “clam shell” occluder. Such patients are often
placed on an intraaortic balloon and other unloading therapy
and are usually taken to the cardiac catheterization suite
for coronary arteriography and then to surgery to repair the
VSD and bypass significantly narrowed coronary arteries. In
patients with large left-to-right shunts, 1.5 to 2.0 or greater,
surgical closure of the VSD becomes mandatory to prevent
the subsequent development of severe pulmonary artery
hypertension. However, in the hemodynamically stable
patient, VSD closure can be delayed for 4 to 6 weeks
with resultant lowering of operative risk. Antibiotic
prophylaxis against infective endocarditis with dental or sur-
gical work is necessary in these patients, even after VSD
closure.
Patients with cardiogenic shock and systolic arterial
pressures of 80 mm Hg or less, decreased peripheral perfu-
sion without a reversible cause, reduced mean cardiac index
(<2 L/min/m2), and an increased pulmonary capillary wedge
or pulmonary artery diastolic pressure (>25 mm Hg) have an
increased mortality, unless the infarct-related artery can be
opened by percutaneous coronary intervention (PCI) or
emergent surgery within the first 1 to 2 hours after the
event.226 Percutaneous coronary intervention is capable of
more rapid reperfusion than thrombolysis in desperately
ill patients with MI and cardiogenic shock and, if the
cardiac catheterization facility is available and an experi-
enced team on site or close by, is the preferred means for
providing rapid and potentially lifesaving reperfusion in
these patients.227 Very early reperfusion, that is, within 2
hours, in patients with cardiogenic shock or severe heart
failure by PCI may save the lives of more than half of these
patients.227
690 chapter 30

Longer-term mortality after recovery from an initial MI

25
is related to the presence of ventricular arrhythmias, the Open
extent of myocardial damage, the age of the patient, and the Closed
LV end-systolic volume (Fig. 30.32). Persistent occlusion of 20
the infarct-related artery, most especially the proximal left

anterior descending coronary artery, is also associated with
a reduced long-term survival (Fig. 30.33).
In general, if the patient is less than 50 years of age at the
time of the initial MI, the annual mortality rate is approxi-
mately 5% or less. If the patient is 50 years of age or older,
the mortality rate is approximately doubled. If a patient sur-
vives for 1 year after MI, there is a 75% chance of 5-year
survival. If a patient survives for 5 years after MI, there is an
approximately 50% or greater chance of 15-year survival.
These numbers will improve in the coming years with exten-
sive efforts at prevention of future coronary events, utilizing
potent lipid-lowering, antioxidant, and antithrombotic thera-
pies and with earlier reperfusion in patients with STEMI.
In-hospital and immediate posthospital complications
are related directly to infarct size. When more than 40% of
the LV muscle mass is irreversibly damaged and reperfusion
is not accomplished by PCI or surgical revascularization
within the first 1 to 2 hours, one can expect power-failure
complications, including cardiogenic shock, CHF, and medi-
100
90 EF ≥50%
80
21ESV ≥55 mL (n = 1931)
70 12 ESV ≥55 mL (n = 186)
100
90 EF 40 − 49%
23 ESV >95 mL (n = 60)
Survival (%)
Mortality (%)
15
10
5
0
Save Tami Welty Kander Eur Anderson
et ai et ai coop meta-
analysis
FIGURE 30.33. Mortality in patients with an open versus a closed
infarct-related artery after MI. The presence of an open artery at
discharge confers a significant survival benefit in the first year after
acute MI.
cally refractory ventricular arrhythmias. Patients with small
MIs (irrespective of the location) are less likely to experience
such complications. However, a strategically located small
MI may cause heart block, acute development of a VSD, or
papillary muscle dysfunction or rupture resulting in acute
mitral insufficiency. In addition, patients with multiple
small MIs may ultimately develop cardiogenic shock, medi-
cally refractory CHF, or medically refractory arrhythmias as
a consequence of the cumulative muscle loss. Even a small
MI may be associated with ventricular arrhythmias; there-
fore, continuous electrocardiographic monitoring is neces-
sary for at least 2 to 3 days after MI, irrespective of infarct
size or clinical complications.
Accurate predictors of longer-term prognosis in patients
with acute MI are needed. Serial CK measurements can be
important prognostically, as patients with the largest MIs are
most likely to experience cardiogenic shock, refractory CHF,

80
or refractory ventricular arrhythmias; however, several hours
70 to a few days are required to complete such measurements.
60 Myocardial perfusion imaging, 201Tl, or 99mTc-sestamibi
myocardial scintigraphy may be used at hospital admission
50 ESV ≥95 mL (n = 60)
13 to estimate the extent of the myocardial perfusion defect.
100 Patients with the largest perfusion defects have a poorer
90 EF <40% prognosis during hospitalization and a higher mortality in
80
the short-term follow-up. Similarly, patients with the most
extensive ventricular functional abnormalities (as detected
70 by radionuclide ventriculography, echocardiography, mag-
60 16 ESV >130 mL (n = 53) netic resonance imaging, or angiography) and those with
50
large anterior MIs may develop “pump failure” and impor-
tant ventricular arrhythmias. Patients with anterior STEMIs
40 16 ESV ≥130 mL (n = 53) who extend their infarction in hospital have increased mor-
0 1 2 3 4 5 6 7 8 9 10 bidity and mortality.227–229
Years Patients with ventricular ejection fractions below 40%
and those with similar ventricular dysfunction and complex
ventricular ectopy (frequent ventricular premature beats,
FIGURE 30.32. Actuarial survival curves for patients with low coupled ventricular premature beats, or short bursts of ven-
end-systolic volume (ESV) versus high ESV at various ejection frac-
tions (EFs) after MI. In patients with left ventricular EF <50%, tricular tachycardia) at the time of hospital discharge, and
ESV plays a greater role in predicting survival than does left ven- those with severe global and segmental ventricular dysfunc-
tricular EF. tion or a reversible perfusion or function defect on low-level
 corona ry h e a rt dise a se sy n drom e s
exercise or stress testing at the time of hospital discharge,
have a relatively poor prognosis unless the infarct-related and
other critically narrowed arteries can be better perfused by
PCI or surgical therapy.
Remodeling of the Left Ventricle
(“Infarct Expansion”)
Infarct expansion or remodeling of the infarct and peri-infarct
regions refers to shape alterations in the infarct and peri-
infarct areas that result from stress and strain alterations in
the infarct and adjacent areas. Most likely, metalloproteinase
release and alterations in myocardial wall stress related to the
local influence of angiotensin and endothelin play a role in the
remodeling process. The remodeling phenomenon causes
changes in contractile patterns in the infarct and peri-infarct
regions and dilatation of the heart over time.230–233a Infarct
expansion or remodeling occurs primarily in patients with
anterior STEMIs, in those with large MIs, in those with sys-
temic arterial hypertension, in those with permanently
occluded infarct-related arteries, and in older individuals.
Infarct remodeling leads to increases in LV end-diastolic and
end-systolic volumes and dimensions and decline in LV func-
tion with a fall in LV ejection fraction in the several weeks to
years after the infarct. Previous studies have demonstrated
that angiotensin-converting enzyme inhibitors reduce the
magnitude of the remodeling phenomenon and preserve LV
function when administered hours to a few days after MI,
especially in patients with anterior STEMIs.233–241 The same is
likely to be true for the angiotensin receptor antagonists and
the combination of angiotensin-converting enzyme inhibi-
tors and angiotensin receptor antagonists. Revascularization
with subsequent patency of the infarct-related artery also
reduces the magnitude of post-MI remodeling. Inhibutors of
matrix metalloproteinases are also being evaluated.233a
Infarct Extension
Infarct extension is the result of new MI hours to days after
the original event, often associated with reocclusion of
the infarct-related artery with a STEMI after thrombolytic
therapy or PCI or as a consequence of increases in myocar-
dial oxygen demand or relative decreases in LV regional
oxygen availability, such as occur with tachycardia, severe
systemic arterial hypertension, severe anemia, hypotension,
or worsening CHF. Reductions in myocardial oxygen deliv-
ery associated with hypotension or decreased substrate avail-
ability as with hypoglycemia may extend MIs. Every effort
should be made to prevent increases in myocardial oxygen
demand and decreases in oxygen delivery in patients with
CAD, especially those with MIs. Infarct extension is poorly
tolerated hemodynamically in those with anterior and previ-
ous MIs and seems to occur most commonly in those with
NSTEMI and possibly in those with anterior STEMIs who
are not treated with PCI or thrombolytic therapy.
Van Belle and colleagues,242 using coronary angioscopic
techniques in patients with MIs, have shown that healing of
the infarct-related coronary artery lesion requires more than
1 month and that an unstable yellow plaque with adherent
thrombus is commonly present during that period. These
findings may help explain the risk for some patients with
unstable angina and acute MIs to reocclude the culprit artery
in this time period and the need to provide effective anti-
6 91
thrombotic therapy for at least several weeks after the event.
Reclosure of the infarct-related artery is associated with a
poor prognosis.
Summary
The acute coronary artery disease syndromes are usually
caused by atherosclerotic plaque fissuring or ulceration.
Patients with unstable angina and NSTEMI should be hospi-
talized as an emergency in a coronary care unit. There, they
should receive medications directed at preventing the stabi-
lization and persistence of a thrombus and the associated
vasoconstriction at the sites of fissured or ulcerated athero-
sclerotic plaque(s) (see Chapter 27A). Patients with STEMI are
treated by PCI or thrombolytic therapy acutely (see Chapters
40 and 44). There is a continuum from unstable angina to
NSTEMI and STEMI that usually depends on the duration
of severe coronary artery narrowing by dynamic thrombosis
and vasoconstriction. When the thrombosis and associated
vasoconstriction are transient and repetitive but developing
and resolving within 5 to 15 to 20 minutes, one has unstable
angina. When the thrombosis and associated vasoconstric-
tion are more durable but persist for 30 minutes up to 2 hours
before resolving, one has a NSTEMI. In some patients, a
partially but not completely occlusive coronary thrombus,
also causes unstable angina and NSTEMI. When the throm-
bosis and associated vasoconstriction are more permanent,
one has a STEMI.
Acute and longer term prognosis and best therapies, that
is, medical versus interventional (PCI or coronary artery
bypass graft) for patients with unstable angina and NSTEMI
may be selected by measuring several biomarkers, including
serum CRP, BNP, and troponin. Increases in CD40L, and
CD40, serum amyloid protein, interleukin-6, myeloperoxi-
dase, asymmetric dimethylarginine, VCAM, and ICAM also
appear to identify patients at risk for adverse events in the
future.
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 3 Silent Ischemia
1 Matthew B. O’Steen and Neal S. Kleiman

Historical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699 Detection and Documentation of Silent

Mechanisms of Altered Pain Perception During Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
Myocardial Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . 699 Prognosis in Patients with Silent Ischemia . . . . . . . . . . 705
Size of the Ischemic Area (“Ischemic Burden”) . . . . . . . 701 Treatment of Silent Myocardial Ischemia . . . . . . . . . . . 707
Hemodynamics and Left Ventricular Function . . . . . . . 702 Results of Suppressing Ischemia . . . . . . . . . . . . . . . . . . . 708
Silent Ischemia in Patients with Diabetes Mellitus . . . 702 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708

Key Points that, as is seen in many other disease processes, not only MI
and sudden death but also myocardial ischemia could occur
• Multiple mechanisms of silent ischemia have been
in the absence of symptoms.
proposed.
The results of an early study by Twiss and Sokolow,7 in
• The incidence and clinical significance of silent ischemia
which 21 of 66 patients with exertional angina pectoris
and the need for screening and therapy vary depending
underwent two-step exercise testing without developing
on the population being studied.
chest discomfort, led the authors to state, “The electrocar-
• Multiple methods for evaluating silent ischemia are
diographic changes after exercise are not dependent on the
available; each has utility in different clinical settings.
reproduction of pain while allowing that the percentage of
positive results is much greater if pain is induced.” Eventu-
ally, the use of more mechanistically based and hence more
Historical Perspective sensitive and specific nuclear and echocardiographic imaging
adjuncts to stress testing reinforced the prognostic signifi-
Since Heberden’s original description in 17721 of an exer-
cance of decreased blood flow to viable areas of myocardium
tional “disorder of the breast” and the subsequent recogni-
both in the presence and in the absence of symptoms. Simi-
tion that angina pectoris was associated with obstructive
larly, the development of drugs that could delay the develop-
narrowing of the coronary arteries, clinicians caring for
ment of ischemia and of successful revascularization
patients with coronary artery disease (CAD) have regarded
techniques that could prevent the development of previously
angina as the benchmark by which to measure the prognosis
demonstrable ischemia led to increased interest in studying
and gauge the treatment of patients with coronary arterial
and characterizing asymptomatic or “silent” ischemia. This
atherosclerosis. However, reports of coronary atherosclero-
effort was followed by attempts to determine whether treat-
sis, occasionally severe, in asymptomatic young soldiers
ment of silent or asymptomatic ischemia would improve the
killed in the First World War and the Korean War1,2 and in
outcome of patients in whom it was present. Therefore, it
pilots,3 coupled with the increasing recognition that the elec-
was no longer clear that adequate control of symptoms con-
trocardiographic changes of infarction were often present in
stituted optimal treatment for all patients with ischemic
individuals with no history of chest pain,4–6 led to the uneasy
heart disease.
acceptance that interruption of blood supply to the myocar-
dium was not necessarily heralded by angina pectoris. As the
ability to recognize myocardial ischemia increased, so did Mechanisms of Altered Pain Perception
the awareness that objective measures of detection were nec- During Myocardial Ischemia
essary in patients who were either asymptomatic or whose
symptoms did not fulfill typical descriptions. It is now well It is likely that a multitude of mechanisms are responsible
accepted that a large proportion of patients has evidence of for the variability of individuals’ ability (or willingness) to
remote myocardial infarction (MI) but give no clinical history sense pain as a result of myocardial ischemia. Experimental
suggesting such an event. The development and acceptance studies have demonstrated that activation of the baroreceptor
of Masters’ two-step test from the 1920s through the 1950s, reflex arc by pressor agents can induce hypoanalgesia in rats.
and later of the exercise treadmill test, led to the recognition Accordingly, stimulation of the efferent loop of this arc

699
70 0 chapter
(cardiopulmonary vagal pathways) may be responsible for the
absence of pain in humans.8 Because increases in the blood
pressure repeatedly stimulates this pathway, it has been pos-
tulated that hypertensive patients have a higher pain thresh-
old than nonhypertensives. Patients with angiographically
documented CAD and hypertension, for example, tend to
have a higher mean dental pain threshold than normotensive
patients, and experience fewer episodes of angina during
daily life.9 Patients with infiltrative autonomic neuropathies,
such as that associated with diabetes, may also have dimin-
ished afferent loop sensitivity. This group is discussed sepa-
rately in a later section.
Altered Central Nervous System
Processing Mechanisms
For a noxious stimulus to be perceived as pain, frontal
cortical activation must occur. Cortical activation can be
traced physiologically by detecting increased blood flow
using positron emission tomography (PET). Comparison of
changes in regional cerebral flow reveal equivalent degrees
of thalamic activation in both angina as well as in silent
ischemia, but a lesser extent of cortical activation in patients
with painless ischemia.10 This finding suggests differential
gating of afferent stimuli at the thalamic level with only
some impulses being allowed to pass through to the frontal
cortex.
Endorphins and Angina
β-endorphins are recognized as modulators of pain; elevated
plasma endorphins raise an individual’s threshold for expe-
riencing pain. Since these endogenous compounds antago-
nize the same central receptors that are blocked by opiates,
which have been used successfully for a century to treat
angina, it is tempting to consider that endorphin production
or sensitivity may play a role in moderating the perception
of angina. In patients with established coronary artery
disease, β-endorphin levels in patients with silent ischemia
have been reported to be almost twice as high as in asymp-
tomatic individuals.11 The same finding has been noted in
patients undergoing percutaneous transluminal coronary
angioplasty: Plasma levels of β-endorphins are lower in
symptomatic patients and decrease significantly during
balloon inflation. In patients with silent ischemia, plasma
levels of β-endorphins have been reported to be higher before
and to remain stable during balloon angioplasty when com-
pared with patients who develop angina during ischemic
symptoms, suggesting that endogenous opiate levels and
their variation during ischemia are associated with individ-
ual experience.12 Investigation of percutaneous trans-
luminal coronary angioplasty (PTCA)-induced ischemia, has
suggested that there may be a threshold beyond which
β-endorphins must increase in order to suppress anginal
symptoms in response to ischemic stimuli.13 However, when
the induction of angina is compared to perception of other
noxious stimuli, the same elevations in β-endorphin levels
(as high as fivefold) that decrease perception of electrical pain
stimuli14 or of exogenous radiant heat15 do not appear to
affect the sensation of exercise-induced angina. It is possible
that higher endorphin levels may affect the angina threshold.
31
It remains fair to state that the role of endorphins in mediat-
ing the perception of cardiac ischemia remains unresolved.
Silent Ischemia and Inflammation
Recent speculation has focused on the role of inflammatory
processes in the perception of cardiac ischemia. Many
inflammatory mediators have nociceptive properties; vascu-
lar and perivascular inflammatory processes may stimulate
or sensitize local afferent fibers. Patients with silent isch-
emia have been noted to have an antiinflammatory pattern
of cytokine production (increased levels of IL-4 and IL-10, and
decreased monocytes expression of CD11b/CD18), which
may increase the threshold for nerve activation and block the
pain transmission pathway.16 Mazzone and colleagues16 eval-
uated the expression of the peripheral benzodiazepine recep-
tor on circulating leukocytes in 24 patients with and 33
patients without angina during exercise-induced myocardial
ischemia. Flow cytometric determinations showed increased
expression of peripheral benzodiazepine receptors on all
classes of leukocytes in patients whose ischemia was silent
compared with patients who developed symptoms during
ischemia. It is unknown whether the presence of these recep-
tors on leukocytes plays a causal role in the lack of symp-
toms during myocardial ischemia or whether leukocytes
merely represent one cell class in which peripheral benzodi-
azepine receptor expression is upregulated.17
Central Nervous System Processing:
Evaluation of Pain Threshold
Silent ischemia is induced daily in many patients undergoing
coronary angioplasty of a vessel supplying viable myocar-
dium. However, it has been estimated that 16% to 47% of
patients do not experience pain during the procedure. Con-
sequently, this procedure may provide a model for evaluating
silent ischemia. Falcone et al.18 evaluated pain threshold
using dental stimulation in patients with and without angina
during daily life undergoing PTCA. During pulpal stimula-
tion, 66.2% of patients reported pain whereas 33.7% remained
asymptomatic, even at maximal stimulation, recognizing
that sedation and analgesia may also modify the sensation
and reporting of pain. The study cohort was then divided into
two groups according to the presence or absence of angina
during myocardial ischemia. Although the two groups
appeared demographically similar, dental pain could be pro-
voked in 81% of patients with and 36% of patients without
symptoms during PTCA. The authors concluded that indi-
vidual profiles of generalized pain perception were likely to
influence their perception of angina during episodes of myo-
cardial ischemia. Duration or intensity of ischemia and left
ventricular dysfunction were not absolute factors in deter-
mining the occurrence of angina. However, it is worth noting
that the same may not apply to angina during exercise or
during daily living, possibly due to different pathophysio-
logic mechanisms involved (Table 31.1).
Psychological Aspects of Silent Ischemia
In CAD as in most other disease states, psychological factors
may influence the perception of discomfort as pain. These
 silent ischemia
TABLE 31.1. Proposed mechanisms of silent ischemia
Differences in somatic pain thresholds
Increased endorphin levels
Alterations in immunoinflammatory response to pain
Autonomic neuropathy
Abnormal central nervous system processing/gating of pain
factors may affect the response to therapy as well. The psy-
chological comfort associated with increased medical sur-
veillance as well as the perception that a medical strategy is
being pursued may result in a significant “placebo effect.”
For example, Amsterdam et al.19 reported that in patients
with silent ischemia, placebo therapy led to a 44% reduction
of ischemic episodes and 50% reduction in total duration of
ST depression.
In an elegant study, Friedman et al.20 showed a strong
relation between silent ischemia and “type A” personality.
When 10 patients with this behavioral trait underwent psy-
chological counseling, which resulted in marked decreases
in the feeling of “time urgency” and hostility (markers of
type A personality), the mean frequency of ischemic episodes
declined from an initial 6.6 to 3.1 ischemic episodes per 24
hours. Whether this decrease resulted from a truly altered
perception threshold or reduction in endorphin secretion and
in rate-pressure product is not known. Similarly, data from
the Canadian Amlodipine/Atenolol in Silent Ischemia Study
(CASIS) suggest that quantitatively determined high levels
of daily psychological stress may reduce the threshold at
which angina is reported in patients with clinically stable
coronary artery disease.21
Size of the Ischemic Area (“Ischemic Burden”)
The relation between the amount of ischemic myocardium
and the presence and severity of symptoms is hotly debated.
In a study of 963 patients, Narins and coworkers22 examined
7 01
the differences between patients with silent ischemia and
those with symptomatic ischemia during exercise testing 1
to 6 months after recovery from a coronary event. Compared
with patients with symptomatic ischemia during testing,
those with silent ischemia had less extensive reversible
defects on stress thallium scintigraphy (Table 31.2), less func-
tional impairment during treadmill testing (longer exercise
duration and longer time to ST depression), and less frequent
ST depression during ambulatory electrocardiographic moni-
toring. In a similar study, Zellweger and colleagues23 reported
that when stress scintigraphy was performed on 356 patients
6 months after successful percutaneous coronary interven-
tion (PCI), 62% of patients in whom ischemia was docu-
mented were asymptomatic and the summed stress score
(i.e., the degree of stress-induced ischemia) was substantially
lower among asymptomatic compared with symptomatic
patients.
In another study of 300 consecutive patients with docu-
mented CAD and reversible hypoperfusion on exercise ses-
tamibi tomography, Marcassa and colleagues24 compared the
extent of hypoperfusion and the presence of symptoms
during exercise stress testing. Patients with painful ischemia
had lower values for workload, exercise time, and peak-rate
pressure product. These patients more frequently had signifi-
cant ST segment depression during exercise than did patients
with silent ischemia. Patients with symptoms during isch-
emia had more evidence of reversible hypoperfusion than did
patients with silent ischemia (16% ± 10% vs. 11% ± 7%)
despite comparable extent of stress hypoperfusion (22% ±
12% vs. 22% ± 13%).
In contrast, Elhendy and associates25 studied 224 con-
secutive patients with limited exercise capacity and com-
pletely or partially reversible perfusion abnormalities during
dobutamine stress sestamibi single photon emission com-
puted tomography (SPECT) and found no difference in the
extent or severity of perfusion defects between symptomatic
and asymptomatic patients.
Discordant results have been reported in at least 10
studies that used myocardial perfusion scintigraphy to

TABLE 31.2. Thallium-201 myocardial perfusion scintigraphic studies comparing the amount of ischemic myocardium in patients with
or without chest pain during exercise testing
First author Year No. of patients Method Selection criteria Reversible defects (% of patients)

Amount of ischemia equal in patients with or without chest pain

Hecht27 1989 112 SPECT CAD; reversible defects 100%
Gasperetti 28 1990 103 Planar Reversible defects 100%
Heller29 1990 234 Planar Reversible defects 100%
Mahmarian30 1990 356 SPECT Unselected 54%
Bandu131 1994 294 SPECT Unselected 94%
Amount of ischemia greater in patients with than without chest pain
Kurata31 1990 471 SPECT Unselected 37%
Galli32 1990 200 Planar Old MI; reversible defects 100%
Travin33 1991 268 Planar Reversible defects 100%
Hendler34 1992 152 SPECT Ex ECG+ 83%
Klein 26 1994 117 SPECT Ex ECG+ 80%
Ex ECG+, positive exercise electrocardiogram; MI, myocardial infarction; Pts, patients; SPECT, single-photon emission computed tomography.
702 chapter
compare the amount of ischemic myocardium in patients
with and without chest pain during exercise testing.26–34
Several potential explanations exist for these discrepant
findings. The earlier studies were conducted using widely
different patient populations, ranging from clinically asymp-
tomatic patients to only those with evidence of a marked
ischemic response to exercise. Multivariable analysis was
seldom performed in these studies, and varying definitions
of silent ischemia were used.
Hemodynamics and Left Ventricular Function
In general, acute left ventricular dysfunction is a conse-
quence of the extent of ischemia. Hence, findings relating
the presence of ischemic symptoms to left ventricular func-
tion might be expected to follow those related to the level of
ischemic burden. Similar discrepancies exist in the literature
concerning left ventricular performance during exercise
testing in patients with silent and symptomatic ischemia. In
a study that included 131 patients with angiographically
documented coronary artery disease, Bonow and associates35
found that patients with silent ischemia were less likely to
develop a decrease in left ventricular ejection fraction during
exercise radionuclide ventriculography than were patients
who developed angina during testing. A similar observation
was made by Matsubara et al.12: pulmonary artery wedge
pressure at peak exercise was significantly lower and the
cardiac index was significantly higher in patients with silent
ischemia compared with patients who experienced angina.
On the other hand, Cohn and associates36 and Vassiliadis and
colleagues37,38 found no differences in global ejection fraction
or regional wall motion abnormalities during exercise testing
in symptomatic and asymptomatic patients. The inclusion
of patients with prior myocardial infarction in the latter two
studies may explain the differences from the former study.
Silent Ischemia in Patients with
Diabetes Mellitus
Patients with diabetes represent a classic example of patients
in whom the afferent loop of the cardiac sensory mechanism
is altered. The afferent fibers that accompany the cardiac
sympathetic nerves are felt to be responsible for transmission
of cardiac pain. Using the synthetic radiolabeled norepineph-
rine analog metaiodobenzylguanidine (MIBG), Langer and
colleagues39 demonstrated a decrease in cardiac catechol-
amine uptake, indicative of cardiac sympathetic denerva-
tion, in patients with versus those without diabetes. This
abnormality was more severe in patients with clinically
documented autonomic dysfunction and in patients in whom
ischemia was asymptomatic. These findings suggest a direct
link between worsening of cardiac sympathetic denervation
in diabetics and silent ischemia.
It is well established that CAD is a major complication
of diabetes mellitus, representing the ultimate cause of death
in more than half of all the patients with this disease.40
Furthermore, myocardial infarction in people with diabetes
is usually more extensive and more severe than in patients
who have diabetes, and is associated with higher mortal-
31
ity.41–46 The Detection of Ischemia in Asymptomatic Diabe-
tes (DIAD) investigators evaluated patients with type II
diabetes mellitus and no symptoms suggesting CAD; 522
patients underwent adenosine sestamibi SPECT. Sixteen
percent of patients had evidence of abnormal myocardial
perfusion; 6% had perfusion defects ≥5% of the left ventricu-
lar mass. Predictors of these moderate to large defects
included male sex, diminished heart rate response to the
Valsalva maneuver, and symptoms of autonomic dysfunc-
tion.47 The cohort is currently being followed for clinical
outcomes. Some authors have suggested that the occurrence
of silent ischemic responses in patients with diabetes appears
to be related to the severity of microvascular disease, partic-
ularly as manifested by microalbuminuria. The combination
of microvascular disease and silent myocardial ischemia in
patients with diabetes appears to be associated with a con-
siderably greater likelihood of subsequent events.47–50
Although it is commonly accepted that asymptomatic
ischemia is more common among people with than among
people without diabetes, there are conflicting data regarding
the frequency of silent ischemia in individuals with diabetes
mellitus. The Framingham Study investigators initially
reported that in subjects with diabetes, the incidence of pain-
less myocardial infarction was higher than in those without
diabetes.51 Several studies suggested that diabetic patients
may have a high incidence of transient silent ST changes
during ambulatory Holter monitoring.52,53 In a well-
controlled patient population, Nesto et al.54 demonstrated
that only 28% of patients with diabetes who had thallium
scintigraphic indications of ischemia experienced angina
pectoris during a treadmill test compared with 68% of
patients without a diagnosis of diabetes. An analysis of
patients with diabetes enrolled in the Asymptomatic Cardiac
Ischemia Pilot (ACIP) database study revealed different
results when patients with and without diabetes were com-
pared. As expected, multivessel disease was more common
in the group with diabetes (87% vs. 74%). However, the per-
centage of patients without angina during the exercise test
was similar in both groups (36% and 39%, respectively). The
percentage of patients with only asymptomatic ST-segment
depression during the 48-hour ambulatory electrocardiogra-
phy (AECG) were also comparable (94% vs. 88%, respec-
tively). An even more surprising finding was that despite
more extensive and diffuse CAD, patients with diabetes
tended to have less measurable ischemia during the 48-hour
AECG monitoring period, perhaps related to lower achieved
workloads. Among patients with diabetes, total ischemic
time per 24 hours, ischemic time per episode, and maximum
depth of ST-segment depression were also lower compared
with nondiabetic individuals.55 A study of 1737 people with
type II diabetes and known CAD referred for nuclear stress
testing found the frequency of scintigraphic evidence of CAD
was no different in patients without angina (39%) from those
with angina (44%). However, among patients presenting with
the complaint of shortness of breath, the prevalence of CAD
was 51%.56 These disparate findings suggest that such factors
as selection bias (particularly with regard to comorbidities),
the degree of stress to which patients with diabetes are sub-
jected during diagnostic testing, and the manner in which
clinical histories are obtained may affect the frequency with
which ischemia is reported.
 silent ischemia
Detection and Documentation of
Silent Ischemia
Exercise Stress Testing
Exercise testing has been the hallmark of the detection of
myocardial ischemia since the development of the two-step
exercise test by Masters and Geller.57 Although ST-segment
deviation in individuals with previously undetected coro-
nary artery disease is the sine qua non of a positive test when
used for screening purposes in a large and generally asymp-
tomatic population, much interest in silent ischemia has
been focused on events in patients who are known to have
CAD. This interest in patients with documented CAD who
are already at higher risk than the general population is
perhaps in part a necessary part of the enterprise of establish-
ing that silent ischemia is a bona fide physiologic phenome-
non rather than an artifact of the testing methods. In a
retrospective analysis of 1698 patients with CAD who under-
went exercise treadmill testing, Mark and associates58
reported that ST-segment deviation occurred in 842 (50%).
These electrocardiographic (ECG) changes were painless in
242 (14%) and were accompanied by angina in 600 (35%). In
this study, as in a report from the Coronary Artery Surgery
Study (CASS) registry, prior angina and more frequent epi-
sodes of angina during daily activity were more common
among patients who developed symptoms during ischemia.
Patients with exercise-induced angina were more likely to
have three-vessel CAD, a shorter peak exercise time, and a
lower peak heart rate, although the median degree of ST-
segment deviation observed with electrocardiography was
not different.59 These findings confirmed that the presence
of angina during exercise testing was likely to reproduce
symptoms that occurred during everyday life, and by exten-
sion, suggested that patients in whom ischemia could be
provoked without producing angina (or its equivalent) were
likely to experience asymptomatic ischemia during daily
activity.
Ambulatory Electrocardiographic Monitoring
Proof that silent ischemia is a common occurrence among
patients at risk for coronary heart disease has relied largely
on the use of AECG (Holter) monitoring, because it has
extended the ability to detect ischemia from the clinic to the
daily activities of life and because it has demonstrated that
“ambulant” ischemia commonly occurs during daily activi-
ties even in the absence of angina. Golding and coworkers60
initially reported that transient elevation of the ST segment
occurred in seven of 174 patients undergoing Holter monitor-
ing for detection of arrhythmias. It is unlikely that all epi-
sodes of ST-segment depression (particularly in a population
in which the presence of disease is not established) represent
myocardial ischemia. However, even in patients in whom
exercise-induced ischemia can be demonstrated, it is rare to
detect prolonged ST-segment depression in normal subjects
if proper data acquisition techniques are used. Since tran-
sient changes in position can produce brief periods of devia-
tion in the ST segment, changes are usually required to last
for at least 30 seconds before they are interpreted as repre-
sentative of possible ischemic events. Studies of individuals
703
with a low likelihood of CAD and without cardiac symptoms
have revealed episodes of ST-segment depression exceeding
30 seconds in fewer than 5% of subjects.61
In patients with CAD, it is considerably more common
to detect ST-segment deviation on Holter monitoring. Other
corroborating evidence of ischemia during daily life can be
found during such episodes of asymptomatic ST-segment
depression. Experience with a lightweight nonimaging
radionuclide gamma camera that can be worn strapped to a
patient’s chest has demonstrated frequent episodic asymp-
tomatic reductions in left ventricular ejection fraction during
daily activity,62 especially during periods of mental stress.63
These episodes are often, but not always, accompanied by
ST-segment depression.64 It is therefore likely that many epi-
sodes of ST-segment depression that occur in patients with
obstructive CAD represent actual ischemic events in the
myocardium. Conversely, ST-segment depression without
reduction in the left ventricular ejection fraction may repre-
sent ischemia that does not involve an amount of myocar-
dium sufficient to cause left ventricular dysfunction or may
be nonischemic in origin.
Painless depression of the ST segment on AECG has been
reported in 40% to 85% of patients with CAD.57,65–74 In
patients with unstable rest angina or recent MI, reports from
some centers have indicated that as many as 50% have
evidence of ambulatory ischemia,70–74 although considerable
controversy exists concerning the frequency with which
ambulant ischemia can be detected. For example, in the
National Heart, Lung, and Blood Institute sponsored
Thrombolysis in Myocardial Ischemia study (TIMI-3) of 1473
patients with unstable angina or non–Q-wave MI, ischemia
exceeding 20 minutes in duration, observed during 24 hours
of Holter monitoring with results interpreted in an experi-
enced core laboratory, was present in fewer than 4% of
patients.75 In most cases when ischemia is detected, multiple
daily episodes are present with considerable variation in each
individual patient from day to day and week to week.66 In
most such studies, between two thirds and three quarters of
such episodes in any given patient are not accompanied by
angina.
Limitations of Ambulatory
Electrocardiographic Monitoring
Several important limitations of AECG should be kept in
mind. Studies have repeatedly shown that ischemic ST-T
changes, even though strictly defined by the Minnesota code,
are not specific for CAD and can be seen in healthy individu-
als or in patients with documented coronary artery disease
but without provocable ischemia. On the other hand, studies
performed in patients hospitalized with acute coronary syn-
dromes or MI have shown relatively high frequencies of
silent ST-segment shifts, and have indicated that patients in
whom such shifts occur are at significantly higher risk than
are those in whom they are absent.76 However it is important
to recognize that such studies have been performed in
patients with extremely high a priori risk (i.e., high pretest
probability) of ischemia and the results may differ in ambula-
tory patients in whom the risk is lower. As during PCI, the
influence of sedation on the sensation of angina should also
be considered. In addition, changes in left ventricular loading
70 4 chapter
conditions may also produce alterations in the surface elec-
trocardiogram and in left ventricular function, particularly
in patients with depressed ejection fractions, which may be
interpreted mistakenly as representing ischemia.11 Among
the many causes are T-wave inversions recorded in young
adults, electrolyte disturbances, valvular heart disease, car-
diomyopathy, drugs, intracranial lesions, and recent food
ingestion.77 Boon and associates78 demonstrated that the dis-
crepancy in reported ischemia greatly depends on the spe-
cific criteria used to define ischemia. In an analysis of Holter
monitors of 194 asymptomatic hypertensive patients, 11.3%
were reported to have silent ischemia as defined using the
commonly used criterion of >0.1 mV of ST segment devia-
tion. When baseline ECG abnormalities were accounted for
and more stringent criteria were used to define ischemia,
such as eliminating sudden ST segment deviation likely to
be caused by body movement requiring down-sloping of the
ST segment and duration of the shifts >1 minute, as well as
requiring >0.2 mV ST segment shifts in the presence of
resting ST deviation, the incidence of ischemia was reduced
to 5.2%.
In comparison with the standard ECG, the standard two-
lead AECG is relatively insensitive for detecting ischemia,
even when attempts are made to reproduce the leads used
during standard 12-lead electrocardiography. When patients
with CAD hospitalized for USA or surgery were monitored
simultaneously using both a two-lead Holter monitoring
system and a 12-lead microprocessor-driven real-time ECG
monitor, the 12-lead microprocessor system detected signifi-
cantly more ischemic events than did the two-lead monitor
and produced no false-positive results in the normal control
group.79 The utility of AECG as a quantitative technique is
also unclear. Neither the total duration of ischemic ST
depression nor the total number of ischemic episodes corre-
sponds well with the size of scintigraphic perfusion defects80
or with the anatomic extent of angiographic coronary artery
disease.81 However, in patients hospitalized with MI and
non-ST elevation acute coronary syndromes, use of con-
tinuous 12-lead electrocardiogram and continuous vector-
cardiography recording devices does allow quantitative
measurement of ischemia, which appears to carry prognostic
significance.82–84
Relation Between Ambulatory Electrocardiographic
Monitoring and Exercise Stress Testing
The presence of painless ST-segment shifts on ambulatory
ECG and symptomatic status during exercise testing should
be viewed as providing complementary rather than redun-
dant or even competing information. Differences between
ischemic responses noted on treadmill testing and on ambu-
latory monitoring ischemia may be related in part to dis-
similarities in the provoking stimuli. Episodes of ambulatory
ischemia often occur during sedentary activity and can be
provoked by stressors as diverse as mental stress,68,85 cold
exposure,69 or cigarette smoking.86 Psychological stressors,
especially situations that trigger emotional distress, cause
increases in heart rate and blood pressure and may also
trigger coronary vasoconstriction.87–89 In addition, in patients
who have painless ischemic responses on ambulatory ECG,
ischemia induced during exercise testing may be accompa-
31
nied by angina. Most patients exhibit a combination of both
symptomatic and symptomless ST-segment changes,
although the difference between ECG characteristics of
silent and symptomatic episodes in a given patient is not well
documented. Both the degree of ST-segment deviation and
the duration of the episodes appear to be similar. When
patients with CAD are subjected to differing exercise proto-
cols, ischemic ST-segment depression usually occurs at
similar rate-pressure products. However, the ischemic thresh-
old on ambulatory ECG monitoring is considerably more
variable88,90 and usually occurs at a lower rate-pressure
product than during treadmill exercise,66,67,90–94 even in cir-
cumstances when an increase in rate-pressure product pre-
cedes the onset of ischemia.95
Deanfield et al.66 reported that among patients with
ST-segment depression on exercise testing, the ST-segment
changes noted during ambulatory monitoring occurred, on
average, at heart rates of 20 beats per minute (bpm) less than
the ischemic threshold detected on exercise testing. These
episodes also occurred more frequently in the morning hours
after rising,91,95,96 following established circadian patterns for
physiologic increases in plasma catecholamines97 and plate-
let aggregability,98 as well as in blood pressure,99 heart rate,92
and for such clinical events as MI100–102 and sudden cardiac
death.103
Assessment of asymptomatic ischemia is often used to
evaluate the adequacy of medical therapy. However, despite
the (very) roughly concordant information they provide con-
cerning whether symptoms occur during ischemia, exercise
testing and the AECG may detect different effects of anti-
anginal treatments. For example, the CASIS investigators
evaluated the influence of amlodipine and atenolol on myo-
cardial ischemia during exercise stress testing and AECG
monitoring. Ischemia during treadmill testing was more
effectively suppressed by amlodipine, whereas ischemia
during AECG monitoring was more effectively suppressed
by atenolol. The combination of both drugs was more effec-
tive than either drug alone in either setting.104
Nuclear Scintigraphy
The same issues of sensitivity and specificity that led to the
introduction of nuclear imaging for detection of CAD also
apply to detection of ischemia. Tomographic imaging is
highly reproducible and has also allowed quantification of
the amount of ischemic myocardium. When these studies are
interpreted by competent readers, the variation in measuring
the size of an ischemia defect is less than 10% in 95% of
patients.105 As a consequence, exercise SPECT has become
accepted as a very accurate technique for the evaluation of
ischemia suppression.106–108 Adenosine-induced stress during
SPECT can also be used to track changes in myocardial
ischemia after medical therapy as well as after mechanical
revascularization.109
Relation Between Ambulatory
Electrocardiographic Monitoring and
Myocardial Perfusion Imaging
As mentioned above, ambulatory electrocardiographic
changes in a patient with CAD may not necessarily represent
 silent ischemia
active ischemia. In the Asymptomatic Cardiac Ischemia
Pilot (ACIP) study, 106 patients with recent coronary angi-
ography underwent both AECG monitoring and stress SPECT
within 3 days. Seventy-four percent of patients with signifi-
cant CAD had SPECT abnormalities, whereas 61% had isch-
emia detected by AECG monitoring. The most important
predictors of SPECT abnormalities were the severity of
coronary stenosis, followed by total exercise duration, and
patient age. The only predictor of AECG abnormalities was
the presence of ST depression on the initial treadmill test.
The concordance observed between the SPECT and AECG
results was only 50%, and no relation was observed between
the frequency or duration of AECG ischemia and the quanti-
fied myocardial perfusion defect size as assessed by SPECT.
Thus, these techniques may detect different pathophysio-
logic manifestations of ischemia and may be complementary
in more fully defining the functional significance of
CAD.80
Exercise and Dobutamine Stress Echocardiography
Exercise and pharmacologic stimulation with catecholamine
derivatives increase cardiac contractility in normal subjects.
Consequently, when normal segments of myocardium are
visualized using echocardiography, hyperkinetic wall motion
is observed. In patients with obstructive CAD and normal
wall motion at baseline, ischemia becomes manifest as an
abnormality of local wall contractility. Stress echocardiogra-
phy has been validated as a sensitive method of ischemia
detection; however, the method of evaluating wall motion
during stress test depends on a semiquantitative visual eval-
uation with a limited scoring scale of different grades of
dyssynergy.110,111 Despite this limitation, several studies have
shown that stress echocardiography and SPECT have similar
sensitivity in detecting ischemia, ranging from 58% and 61%
(with echocardiography and SPECT, respectively) for one-
vessel disease to 94% for three-vessel disease.112,113 The infu-
sion of dobutamine during stress echocardiography increases
the degree of left ventricular dysfunction in patients with
functionally significant coronary artery disease and thus
may be a more sensitive indicator of ischemia.114 On the other
hand, as stressors are compounded, the degree to which this
intense combination of tachycardia and increased activity
reproduces the stresses experienced by an individual during
everyday life becomes questionable. Anginal chest pain is
frequently induced in patients with stable coronary artery
disease during stress testing. However, following MI, pain
during stress testing may not be associated as clearly with
an increased risk of adverse event compared with patients
who did not experience angina despite a similar extent of
CAD.115
Prognosis in Patients with Silent Ischemia
That asymptomatic episodes of ischemia occur in patients
with CAD is now established. Subsequently most attention
has become directed toward determining the prognostic
implications of silent ischemia, its utility at expanding the
number of patients who can be identified as being at risk for
catastrophic events, and the ability to extend therapy to a
705
previously unidentified group of patients. The frequency
with which ischemia is detected and the outcomes of patients
with silent ischemia are likely to depend on the extent of
ischemic myocardium as well as other characteristics such
as age, ventricular function, and the clinical setting in which
the effort to detect ischemia is undertaken. In addition, the
diagnostic techniques used to detect ischemia are likely to
differ depending on the clinical setting. For these reasons,
conclusions concerning silent ischemia are likely to differ
among ambulatory patients in whom the presence of CAD
is uncertain, and patients who are hospitalized with acute
coronary syndromes. Consequently, the subsequent sections
of this chapter will consider patients with known CAD sepa-
rately from those in whom the presence of coronary athero-
sclerosis has not been determined.
Prognosis in the Patient with Known Coronary
Artery Disease
The Bypass Angioplasty Revascularization Investigation
(BARI) trial offered a unique opportunity to follow patients
with multivessel CAD systematically and serially following
revascularization. Protocol-mandated symptom-limited
exercise treadmill testing (ETT) was performed at 1, 3, and 5
years after revascularization with either angioplasty or coro-
nary artery bypass surgery. At the time of the 1-year exercise
test, 26% of patients had ST segment depression during exer-
cise; 82% of these patients did not report angina during
exercise testing; 69% (18% of the total) had angina neither
before nor during the test. Only 1% of patients who did not
experience angina between the time of revascularization and
exercise testing required a further revascularization; more
than half of these patients had a negative exercise test. Exer-
cise time at the 5-year test was associated with decreased
survival 2 years after the test, but exercise parameters deter-
mined on the 1- and 3-year tests were poor predictors. This
study pointed out a selection bias that plagues all attempts
to relate stress-induced ischemia to clinical outcome: the
strongest predictor of survival was not the result of exercise
testing, but whether patients were able to undergo exercise
testing at all. Mortality at 5 years was 25.9% in patients who
did not exercise compared with 8.1% in the group that did
take the test. These results do not support routine stress
testing after revascularization for multivessel disease;
however, they do not exclude the use of other diagnostic
modalities in patients who are unable to undergo ETT due
to comorbid illnesses.116
Details from the ROSETTA Registry provide further
insight in relation to the risk of recurrent disease after a
revascularization procedure. In this registry, 791 patients
who had undergone PCI were followed to determine the
difference in cardiac events between patients who received
“routine” (i.e., in the absence of angina) versus “selective”
(clinically determined) functional testing after revascular-
ization. After adjustment for baseline risk characteristics,
routine functional testing allowed prediction of a composite
of cardiac events at 6 months in patients who had undergone
balloon angioplasty but not among patients who had under-
gone coronary stenting.117 The implication of these two
studies is that in the initial period after revascularization,
routine surveillance for ischemia in the asymptomatic
70 6 chapter
patient is likely to be fruitful only if the perceived risk of
either graft failure or restenosis is high (e.g., after balloon
angioplasty without stenting or after placement of bare metal
stents over a long segment of coronary artery). However, the
longer-term implications are less clear, particularly in
patients with more severe disease or in patients who have
received saphenous vein grafts at the time of bypass surgery.
When 356 patients recruited in a Dutch study underwent
routine follow-up angiography and scintigraphic stress testing
6 months after PCI, 62% of patients with target vessel reste-
nosis were asymptomatic. Follow-up for 4 years revealed a
risk gradient with the lowest risk for patients without isch-
emia, greater risk of recurrent events in patients with silent
ischemia, and the greatest risk in patients with symptomatic
ischemia.23
Prognosis in Asymptomatic Patients Without
Known Coronary Artery Disease
Elhendy and associates118 evaluated the utility of exercise
echocardiography in 1618 middle-aged patients (average age
55 years with low risk for CAD based on a prespecified
algorithm). In this very low risk cohort, the rates of cardiac
mortality and nonfatal MI were 0.1 and 0.25 per 100 person-
years, respectively. In models used to predict cardiac events
using clinical variables, exercise stress variables, and echo-
cardiography variables in a sequential fashion, none of the
exercise ECG features predicted future cardiac events.
Changes in the wall motion score index predicted outcome;
however, over half of the patients with subsequent cardiac
events did not have abnormal stress echocardiographic
results. Taken in aggregate, these findings call into question
the routine use of exercise testing to screen low-risk asymp-
tomatic patients.
Marwick and associates119 evaluated the utility of exer-
cise stress echocardiography for predicting mortality in a
cohort of 1859 patients without angina or other evidence of
CAD. Only four (0.2%) patients developed angina during
exercise and 215 (12%) patients developed ST-segment depres-
sion during exercise, indicating that the vast majority of
ischemic episodes in this cohort were silent. Overall annual-
ized mortality was 0.9%, with annualized cardiac mortality
of 0.2%. Although ischemia detected by stress echocardiog-
raphy was a predictor of mortality at an average of 4.7 years,
multivariate analysis revealed that only resting ejection frac-
tion and Duke treadmill score (annualized mortality 2% for
an intermediate- or high-risk score and 0.4% for patients
with a low-risk score) were predictive of outcomes. These
findings suggested that in a group with a low a priori risk of
cardiac events, the detection of silent ischemia provides little
prognostic information.
A clearer perspective on the relation of basal risk to the
prognostic value of silent exercise-induced ischemia comes
from the Kuopio Ischemic Heart Disease (KIHD) risk factor
study. Laukkanen and associates120 performed bicycle ergome-
try on 1769 asymptomatic middle-aged men with a broad
spectrum of known risk factors for CAD. Eleven percent of
participants had silent ischemia during exercise and an addi-
tional 3.1% had silent ischemia after exercise. After adjust-
ing for conventional risk factors, men with silent ischemia
during exercise had an increased risk of acute coronary
31
events and of cardiac death, 1.7- and 3.5-fold, respectively.
Using men without ischemia as a reference group, there was
a clear relationship between the presence of risk factors and
the likelihood of cardiac death during follow-up. Viewed in
light of the preceding studies, it appears that the prognostic
information contained in the detection of silent ischemia
increases as patients’ baseline risk increases.
In one of the largest epidemiologic reports of silent
ischemia published to date (Reykjavik study), 9139 randomly
selected men were screened with a standard resting 12-lead
ECG and followed for 4 to 24 years. Patients were categorized
by the presence of ischemic symptoms and indications of
ischemic heart disease on the resting ECG. The prevalence
of ST-T changes (classified as ischemic by the Minnesota
code) in the absence of angina among men without overt
coronary artery disease was strongly influenced by age,
increasing from 2% at age 40 years to 30% at age 80 years.
Men with ST-T changes, but no symptoms were older and
had higher serum triglyceride levels, more frequently were
hypertensive, had left ventricular hypertrophy, and took
antihypertensive medications, digitalis, or diuretics. The
serum cholesterol level did not differ between the two groups.
After adjustment for other risk factors, the risk ratio among
men with silent ST segment shifts was 2.0 for death from
CAD and 1.6 for subsequent MI in men with these ST changes
when compared with asymptomatic men with no evidence
of exercise-induced alterations in the ST segment.121 Although
the prognostic value of stress testing in women has also been
assessed,122,123 there are currently no data to indicate whether
the frequency or prognosis of silent ischemia differs accord-
ing to sex.
Ambulatory Electrocardiographic Monitoring,
Exercise Stress Test, and Prognosis
The prognosis associated with asymptomatic myocardial
ischemia detected using electrocardiographic means also
appears to be related to the overall clinical risk group
from which patients are selected. Ambulatory electrocardio-
graphic findings in patients hospitalized in a coronary care
unit with unstable rest angina are associated with a high
likelihood of impending MI. On the other hand, studies in
patients with stable manifestations of CAD tend to indicate
that the risk associated with silent myocardial ischemia
is more questionable. Quyyumi and colleagues81 studied
patients with CAD categorized as low risk (i.e., excluding
patients with left main disease, three-vessel disease with left
ventricular dysfunction at rest, three-vessel disease with
inducible ischemia, two-vessel disease with impaired left
ventricular function, and inducible ischemia). Among these
“low-risk” patients, 39% had ST depression during AECG
monitoring; 82% of those episodes were asymptomatic,
which, however, did not predict higher risk for cardiac events
in the future.
In a retrospective analysis of 1402 patients with ECG
evidence of ischemia during treadmill testing, Cole and Elle-
stad124 reported that coronary events (cardiac death, MI, or
progression of angina) were twice as frequent in patients
with symptomatic ischemia than those with silent ischemia.
In reviewing the 5-year outcome of 842 consecutive patients
in the Duke Cardiovascular Database who had angiographi-
 silent ischemia
cally documented coronary disease and abnormal exercise
test results, Mark et al.58 found that patients with silent
ischemia during exercise testing had significantly better
overall survival and infarct-free survival rates than did
patients with angina. Similarly, among 1773 veteran patients
referred for treadmill testing, a difference in mortality at
2 years was observed based on the development of angina
during exercise.125
The importance of asymptomatic ischemia on exercise
testing after MI is often debated. Villella et al.126 studied 6296
patients undergoing an exercise test an average of 28 days
after intravenous thrombolytic therapy for a myocardial
infarction. Residual ischemia was detected in 26% of patients,
of whom 67% were asymptomatic. The 6-month mortality
was 1.7% for those with a positive test, 0.9% for those who
had a negative test, and 1.3% for patients whose test was not
diagnostic. After adjustment for myocardial ischemia accom-
panied by symptoms of angina, only symptomatic induced
ischemia and low-work capacity were associated with an
increased risk of death at 6 months, although asymptomatic
ischemia was not. Even after analysis of silent ischemia by
the occurrence of ST-segment depression at maximal or sub-
maximal levels of exercise or on the degree of ST-segment
depression, exercise-induced asymptomatic myocardial isch-
emia was not significantly associated with a higher risk of
death compared with exercise stress testing with negative
results. The ability to exercise for more than 6 minutes was
a predictor of good prognosis regardless of the associated
ECG changes.
The Asymptomatic Cardiac Ischemia Pilot (ACIP) trial
contributed significantly to our understanding the impor-
tance of silent ischemia.127 Conti et al.127 compared the
outcome of patients who had angina either within the 6
weeks prior to enrollment or during the period of the study.
These investigators reported that symptomatic patients in
ACIP had a higher incidence of death, MI, or hospitalization
for ischemic events (15.3% symptomatic vs. 7.8% asymptom-
atic per 12 months). Interestingly, this difference was present
mainly in patients who had angina within the 6 weeks pre-
ceding the study period. Unlike patients who were symptom-
atic during the period of recruitment, patients with angina
occurring only during AECG or stress testing were not found
to have a higher incidence of adverse cardiac events than
asymptomatic patients.128
Nuclear Imaging and Prognosis
In recent years, tomographic myocardial scintigraphy has
gained acceptance as the most widely used and reliable
measure of the quantity of myocardium that is ischemic.
Consequently, the relationship between ischemic defect size
and prognosis has recently garnered much attention. There
is consensus that, viewed on the background of other risk
factors for mortality, the size of the ischemic defect is related
to the likelihood of suffering a cardiac event. Reports from
several large nuclear laboratories indicate a largely dichoto-
mous relationship. Defects exceeding 15% to 20% of the
myocardium are associated with a significantly higher likeli-
hood of catastrophic events at 1 to 2 years than are smaller
defects. While the concept that the quantity of myocardium
at risk determines a patient’s outcome is not new, it is worth
707
noting that several investigators have established that the
size of an ischemic defect is a critical determinant of outcome,
independent of symptoms.129
Treatment of Silent Myocardial Ischemia
While the treatment of ischemia for the purpose of relieving
angina or dyspnea has been established for several decades,
the management of asymptomatic ischemia has been a
matter of greater controversy. Only recently as revasculariza-
tion techniques, particularly percutaneous coronary inter-
ventions with the use of drug-eluting stents, have been
refined, and the results become more robust, has consensus
been reached about the use of revascularization strategies to
treat ischemia in the asymptomatic patient.
The ACIP trial was designed as a pilot study to determine
precisely whether suppression of silent ischemia was possible
using one of three strategies: angina-guided medical therapy,
ischemia-guided medical therapy, or revascularization using
balloon angioplasty or bypass surgery. Patients selected for
this study had evidence of myocardial ischemia on both
ambulatory and exercise treadmill testing. Ischemia sup-
pression after a period of 12 weeks using medical therapy
was performed using one of two regimens: (1) atenolol and
nifedipine, or (2) diltiazem and isosorbide dinitrate. With a
regimen of atenolol and nifedipine, ischemic changes on the
AECG could be suppressed in 47% of patients. In the group
treated with diltiazem and isosorbide dinitrate, ischemia
was suppressed in 31% of patients. In the medical therapy
group, the average doses (combined ischemia- and angina-
guided therapy) of each medication at 12 weeks were as
follows: atenolol 84 mg, nifedipine 34 mg, diltiazem 91 mg,
and isosorbide dinitrate 36 mg. Thus, the degree of medical
therapy can be described as moderately intense. The degree
of ischemia suppression was similar in the ischemia- and in
the angina-guided groups. The revascularization strategy led
to suppression of ischemia in 70% of patients having bypass
surgery versus 46% of patients undergoing angioplasty. It is
likely that the prevalent use of drug-eluting stents would
increase the latter figure significantly.
The findings of other trials have been similar. In CASIS,
patients were selected according to the presence of ischemia
during treadmill testing and ambulatory monitoring and
subsequently were assigned to receive either atenolol or
amlodipine. Each group underwent a counterbalanced, cross-
over evaluation of single drug and placebo, followed by evalu-
ation of the combination. Suppression of ischemia during
exercise testing and ambulatory monitoring was similar in
patients with and without exercise-induced angina. Exercise
time to angina improved by 29% with amlodipine, 16% with
atenolol, and 39% with combination therapy. Similarly in
the ASIST trial, after 4 weeks of treatment with atenolol of
patients with Canadian Cardiovascular class I or II angina,
the number and duration of ischemic episodes on ambulatory
ECG decreased significantly compared with placebo.104 In a
similar study, Frishman and colleagues130 were able to sup-
press ambulatory ischemia as well as exercise-induced isch-
emia using a long-acting preparation of verapamil, atenolol,
or amlodipine. In a smaller study, Dakik et al.109 compared
intensive medical therapy to percutaneous revascularization
70 8 chapter
in minimally symptomatic patients with large ischemic
defects (total defect ≥20% and ischemic defect ≥10% of the
left ventricle) on thallium scintigraphy in patients after
recent myocardial infarction. The medical regimen in this
trial was much more intense compared with those in other
studies. The average daily dose of medications was 113 ±
23 mg of isosorbide dinitrate, 131 ± 57 mg of metoprolol,
272 ± 58 mg of diltiazem, and the extent of ischemia was
measured by highly reproducible adenosine thallium 201
SPECT. The above medical regimen resulted in a 12% ± 10%
reduction in the ischemic defect size and was equally effec-
tive as angioplasty.
Results of Suppressing Ischemia
The relationship between suppression of ischemia and clini-
cal outcome still remains uncertain, particularly in patients
with stable manifestations of CAD. However, in ACIP, at 1
year, mortality was 4.4% in the angina-guided group, 1.6% in
the ischemia-guided group, and 0% in the revascularization
group. There was a direct correlation between number of
ischemic episodes on ambulatory ECG and event rate.
However, it must be kept in mind that this trial was a pilot
study with confidence levels too broad to allow definitive
conclusions to be drawn. In ASIST, there was a nonsignificant
trend for fewer serious events (death, resuscitation from ven-
tricular fibrillation/tachycardia, nonfatal MI, or hospitaliza-
tion for unstable angina) in atenolol-treated patients compared
with those assigned to placebo. The most powerful univariate
and multivariate correlate of event-free survival was the
absence of ischemia on an ambulatory ECG 4 weeks after
beginning therapy. Most data available thus far indicate that
event-free survival is likely to be related to the reduction of
the amount of ischemia present regardless of the presence or
absence of symptoms and the treatment chosen. Large trials
comparing revascularization to aggressive medical therapy
(COURAGE, BARI 2D, INSPIRE) are currently nearing com-
pletion. It is likely that these trials will contain substantial
proportions of patients with asymptomatic ischemia and will
provide guidance for selecting therapies in the future.
Summary
The clinical manifestations of CAD range from sudden death
to transient asymptomatic ischemia noted on ambulatory
ECG monitoring. Although the exact mechanism causing
ischemia to be asymptomatic has not been elucidated, there
is evidence that multiple mechanisms contribute. The clini-
cal implication of silent ischemia varies depending on the
setting in which it occurs. In general, patients with increas-
ing numbers of CAD risk factors, comorbid illnesses, and
larger areas of ischemic myocardium detected using imaging
studies have a worsened prognosis. Although routine screen-
ing of patients at low risk of having CAD is very unlikely to
be of benefit, evaluating subsets of patients with known
CAD will identify patients at higher risk for adverse cardiac
outcomes. The most effective therapy for treating silent isch-
emia is not clearly defined; ongoing trials will provide guid-
ance for future management.
31
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109. Dakik HA, Kleiman NS, Farmer JA, et al. Intensive medical
therapy versus coronary angioplasty for suppression of myocar-
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110. Sawada SG, Segar DS, Ryan T, et al. Echocardiographic detec-
tion of coronary artery disease during dobutamine infusion.
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111. Salustri A, Fioretti PM, McNeill AJ, Pozzoli MM, Roelandt JR.
Pharmacological stress echocardiography in the diagnosis of
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parison between dobutamine and dipyridamole. Eur Heart J
1992;13:1356–1362.
112. Quinones MA, Verani MS, Haichin RM, Mahmarian JJ, Suarez
J, Zoghbi WA. Exercise echocardiography versus 201Tl single-
photon emission computed tomography in evaluation of
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1992;85:1026–1031.
113. Penfornis A, Zimmermann C, Boumal D, et al. Use of dobuta-
mine stress echocardiography in detecting silent myocardial
ischaemia in asymptomatic diabetic patients: a comparison
with thallium scintigraphy and exercise testing. Diabetic
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114. Elhendy A, Geleijnse ML, Roelandt JR, et al. Stress-induced left
ventricular dysfunction in silent and symptomatic myocardial
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115. Bigi R, Galati A, Curti G, et al. Different clinical and prognos-
tic significance of painful and silent myocardial ischemia
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echocardiography after uncomplicated myocardial infarction.
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116. Krone RJ, Hardison RM, Chaitman BR, et al. Risk stratification
after successful coronary revascularization: the lack of a role
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117. Mak KH, Eisenberg MJ, Tsang J, Okrainiec K, Huynh T, Brown
DL. Clinical impact of functional testing strategy among
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120. Laukkanen JA, Kurl S, Lakka TA, et al. Exercise-induced silent
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122. Berman DS, Kang X, Hayes SW, et al. Adenosine myocardial
perfusion single-photon emission computed tomography in
women compared with men. Impact of diabetes mellitus on
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AS. Prognostic significance of silent ischemia. J Nucl Cardiol
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 3 Coronary Disease
2 in Women
Allen P. Burke, Frank D. Kolodgie, and
Renu Virmani
Epidemiology of Coronary Disease in Women . . . . . . . . 713
Risk Factors for Coronary Artery Disease
in Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
Clinical Features of Coronary Heart Disease
in Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716
Key Points
• There are pathologic and physiologic differences in coro-
nary artery disease in women as compared to men.
• Hormone replacement therapy: failure of a promise?
• Risk factors: do they have the same impact in women as
in men with coronary disease?
• Small vessel coronary disease plays a role in women.
• Plaque erosion is important in premenopausal women.
Epidemiology of Coronary Disease in Women
Cardiovascular disease remains the number one cause of
mortality for women in the United States, and coronary
artery disease accounts for more than half of cardiovascular
deaths. Coronary artery disease results in the deaths of more
than 250,000 women each year and is therefore the single
largest killer of American women. For several decades, the
underrepresentation of women in clinical trials led to a
general misconception that coronary artery disease was
mostly a disease of men. Epidemiologic studies focusing on
women have demonstrated that they are indeed vulnerable
to coronary atherosclerosis, but that it typically develops 10
to 15 years later than in their male counterparts. Although
controversial, many studies suggest that sex differences exist
in the mortality rates of ischemic heart disease, with women
having a worse prognosis, possibly due to delayed diagnosis.
Consequently, early and accurate diagnosis of coronary
artery disease is crucial for reducing mortality rates in
women.1
The Nurses’ Health Study has tracked cardiovascular
disease in women with data available through 1994. From
1980 to 1992, there was a 31% decrease in the incidence of
coronary disease. During this period, there were positive
Physiology of Coronary Disease in Women . . . . . . . . . . 718
Postmenopausal Hormone Replacement Therapy
and Risk of Coronary Disease . . . . . . . . . . . . . . . . . . 719
Pathology of Coronary Disease in Women . . . . . . . . . . . 720
Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 724
trends in the traditional coronary risk factors, with a decrease
in cigarette smoking and improvement in diet and lipids. In
this study, an increase in postmenopausal hormone replace-
ment therapy was considered beneficial. However, the preva-
lence of overweight, defined as a body mass index (BMI) of
25 or more, increased by 38%. Therefore, obesity-related mor-
bidity, including metabolic syndrome and type 2 diabetes,
appears to be increasingly important as a coronary risk factor
in women.2
In approximately 50% of patients, the first manifestation
of coronary heart disease (CHD) is sudden death. Sudden
cardiac death occurs in more than 300,000 persons per year
in the United States and is the most frequent cause of death
in the industrialized world. The most frequent cause of
sudden death is coronary artery disease, which is thought to
be a male-predominant disease.3 Data from the Framingham
study show that sudden death in women lags behind men by
almost 20 years, somewhat longer than the lag period of
acute coronary syndromes. The annual sudden death rate in
women is approximately half that in men for all ages com-
bined. Only 94 of 2873 women died suddenly compared with
230 of 2336 men of comparable age.4 The incidence of sudden
death in men and women increases with age, approximately
doubling with each decade of age in women. In both sexes
26% of deaths occur in persons without overt CHD. In
women, 63% of death occurred in the absence of prior CHD
compared with 44% in men. Of the CHD deaths in men and
women, 76% were sudden deaths. In men with prior CHD,
34% of deaths were sudden as compared with 16% in women.4
Thus it appears that coronary sudden death is less frequent
in women than in men, but it is more likely to occur in
women without prior coronary disease.
While similar mechanisms operate to induce coronary
artery disease in women and men, gender-related differences
713
714 chapter
exist in the anatomy and physiology of the myocardium, and
sex hormones modify the course of disease in women. The
morphologic basis for the clinical differences between men
and women with acute coronary syndromes remain unclear,
but ongoing studies are providing valuable data that will
refine in the future gender-based treatment strategies for a
highly prevalent disease.
Risk Factors for Coronary Artery Disease
in Women
The usual risk factor for coronary artery disease, cigarette
smoking, diabetes mellitus, hypertension, dyslipidemia,
obesity, sedentary lifestyle, and poor nutrition, are similar
in women and men. In general, women with unstable angina
and non–Q-wave myocardial infarction are, in comparison
to men, older, less frequently white, and have a higher inci-
dence of diabetes and hypertension.5
Diabetes
Obesity and sedentary lifestyle in the United States have
been linked to increased risk of coronary artery disease in
men and women. The prevalence of obesity has increased in
the last decade and it is estimated that currently 30% to 40%
of adult women are obese.2 In the Nurses’ Health Study, the
multivariate relative risks of fatal CHD across categories of
diabetes duration (up to 25 years) ranged from 2.75 to 11.9,
compared with nondiabetic women.6
Diabetes mellitus is a more significant risk factor for the
presence and severity of CHD in women than in men. Women
appear to be at particularly high risk as the gender advantage
for CHD is counterbalanced by an increased incidence of
obesity and diabetes.7 Diabetes is linked to both hyperlipid-
emia and obesity in men and women but especially in
women.8,9 In a recent meta-analysis, the relative risk of coro-
nary death from diabetes was 2.58 [95% confidence interval
(CI) 2.05–3.26] for women and 1.85 (1.47–2.33) for men; the
difference was statistically significant (p = .045).10
There is evidence that the role of diabetes as a risk factor
for coronary artery disease in women is influenced by race.
The population-attributable risk of CHD incidence associ-
ated with a medical history of diabetes has been calculated
at 8.7% in African-American women, compared to 6.1% in
American women of European background. A history of dia-
betes was a significant predictor of CHD incidence and mor-
tality in African-American women and explained some of
the excess coronary incidence in younger African-American
compared to American women of European background.11 In
Australia, aboriginal women with diabetes experience a sig-
nificantly higher risk of CHD than women without diabetes,
and women with diabetes had a higher CHD risk than men
with diabetes.12
There is a complex interaction between diabetes and
other risk factors for coronary disease in women. Obesity
enhances the risk of CHD among women with type 2 diabe-
tes mellitus (DM), especially when it precedes the diagnosis
of overt diabetes.13 Increased insulin resistance in associa-
tion with elevated plasminogen activator inhibitor-1 (PAI-1)
and dyslipidemia appears to underpin the increased risk of
32
CHD in women with type 2 DM.14 Cigarette smoking is
strongly associated with an increased risk of CHD among
women with type 2 DM, and quitting smoking seems to
decrease this excess risk substantially.15
Dietary factors may mitigate the risk of coronary disease
in diabetic women. A higher consumption of fish and long-
chain omega-3 fatty acids was associated with a lower CHD
incidence and total mortality among diabetic women.16 Mod-
erate alcohol consumption was associated with reduced CHD
risk in women with diabetes.17
Dietary Factors
In the Nurses’ Health Study, frequent nut consumption was
associated with a reduced risk of both fatal CHD and nonfa-
tal myocardial infarction in women.18 Consumption of fish
is associated with a significantly reduced progression of coro-
nary artery atherosclerosis in women with coronary artery
disease.19 In a different study, no protective effect of dietary
phytoestrogens (isoflavonoids and lignans) was demonstrated
in women against cardiovascular disease risk, although a
small risk reduction with higher lignan intake was suggested
for smokers.20
Body Mass Index/Metabolic Syndrome
Obesity and metabolic syndrome are interrelated risk factors
for coronary disease in women. The influence of BMI on
cardiovascular disease in women may be greater than previ-
ously thought, with increased adverse outcomes even at
moderately increased body weight.21 In a recent prospective
study, however, the metabolic syndrome, but not BMI, pre-
dicted future cardiovascular risk in women.22
In women with suspected myocardial ischemia, the met-
abolic syndrome modifies the cardiovascular risk associated
with angiographic coronary disease. In one study, the meta-
bolic syndrome was found to be a predictor of 4-year car-
diovascular risk only when associated with significant
angiographic coronary artery disease.23 Although weight loss
should be advised in overweight and obese women, control
of all modifiable risk factors in both normal and overweight
persons to prevent transition to the metabolic syndrome
should be considered the ultimate goal.
There are measures of obesity other than simple BMI that
have been espoused in assessing coronary risk in women.
The waist/hip ratio and waist circumference have been inde-
pendently associated with risk of coronary disease in
women.24 Also known as the hypertriglyceride waist,
increased waist/hip ratio is associated with increased coro-
nary risk factors among women.25 In a forensic autopsy study
in women with preclinical atherosclerosis, the coronary
intima–media thicknesses were highest with increased
amounts of intraperitoneal fat, a reflection of the waist/hip
ratio.26
As with diabetes, there is an interplay between measures
of obesity and metabolic syndrome and other traditional risk
factors. Smoking adversely affects insulin secretion (β-cell
function) and whole blood viscosity in postmenopausal
women with established coronary artery disease, which
could be of importance as a mechanism for the increased risk
in female smokers.27
 corona ry dise a se i n wom en 715
TABLE 32.1. Mechanism of death and risk factors in 51 women who died suddenly from severe coronary artery disease
Mechanism of death (n) Age >50 years, % Total cholesterol, mg/dL Body mass index Glycohemoglobin, mean % Cigarette smokers, n (%)

Plaque erosion (18) 3 (17%) 191 ± 68 27 ± 4.3 6.7 ± 0.7 14 (78%)

Plaque rupture (8) 7 (87%)* 272 ± 61* 31 ± 4.4* 8.8 ± 4.4 4 (50%)
Stable plaque, no 2 (29%) 178 ± 57 30 ± 10.6 8.0 ± 4.5 2 (29%)
infarct (7)
Stable plaque, 9 (50%) 198 ± 61 28 ± 9.0 10.2 ± 5.0* 9 (50%)
healed infarct (18)
p value *.001 vs. plaque *.01 vs. stable plaque; *.02 vs. eroded *.001 vs. eroded plaque
erosion; .03 vs. .01 vs. stable plaque, plaque
stable plaque, no healed infarct; .02 vs.
infarct plaque erosion

Hypertension
Epidemiologic studies have documented a strong association
between high blood pressure (systolic and diastolic) and risk
of CHD in men and women. In women >45 years of age, 60%
of whites and 79% of blacks have hypertension. After adjust-
ing for other risk factors, 29% of CHD events in women (>30
years) were attributable to blood pressure levels that exceed
high normal (>130/85 mm Hg).28
elevated levels of lipoprotein (a) [Lp(a)] (>500 mg/L) was found
to be an important risk factor for CHD in both black and
white women.32 However, the importance of smoking as a
risk factor, overrides the effect of Lp(a), which is lower in
smokers compared with nonsmokers.27
In contrast to prior data among hyperlipidemic men, the
current data suggest that lipoprotein associated phospholi-
phase A2 [Lp-PLA(2)] is not a strong predictor of future car-
diovascular risk among unselected women.33

Dyslipidemia
In contrast to men, women show only a weak association of
total cholesterol and low-density lipoprotein (LDL) levels
with CHD.29 However, high-density lipoprotein (HDL) cho-
lesterol is closely and inversely associated with CHD risk in
women. Triglycerides are an independent predictor of coro-
nary artery disease in older women but not in men.15,29
However, more current data support recommendations for
aggressive lipid lowering in women with existing CHD, or
who are at risk for developing CHD.30
Other serum lipid components have been demonstrated
as potential risk factors for atherosclerotic heart disease in
women. In a cross-sectional study, women with CHD had
higher plasma concentrations of apolipoprotein B100 (apoB),
as well as total cholesterol, LDL cholesterol, triglycerides,
and lower levels of HDL cholesterol. In this study, apoB was
superior to other lipids in discriminating between women
with and women without coronary disease.31 Because of this
association, measurement of apoB has been recommended as
a screening risk factor especially in women. In another study,
Smoking
More than 50% of myocardial infarctions among middle-
aged women are attributable to cigarette smoking.34 It has
been reported that the excess risk for CHD in women from
smoking was two- to fourfold and was similar to that in
men.35 The evidence associating cigarette smoking, elevated
serum cholesterol, and high blood pressure and coronary
disease in women is strong.36
Plaque Morphology and Classic Risk Factors
Clinical studies relating risk factors and coronary disease in
women cannot take into account plaque morphology and the
morphologic heterogeneity of coronary atherosclerosis. In an
autopsy study of sudden coronary death, coronary plaque
morphology was related to risk factors in 51 sudden coronary
deaths in women (mean age 50 ± 12 years) and compared to
15 women (mean age 50 ± 19 years) who died a traumatic
death (Tables 32.1 and 32.2).37 The risk factor analysis was
performed in all cases at autopsy. The postmortem serum
was evaluated for total cholesterol (TC), HDL cholesterol,

TABLE 32.2. Multivariate association between risk factors and morphology of culprit plaque in 51
women, compared to 47 noncoronary deaths (trauma and cardiac noncoronary)
Multivariate

Risk factor Plaque morphology p (univariate) Z p Odds ratio

Total cholesterol, mg/dL Rupture <.0001 3.0 .002 31

Cigarette smoking Erosion .003 2.5 .01 16
Glycosylated hemoglobin >8 Stable plaque .001 2.8 .006 7.1
Hypertension Stable plaque .006 2.3 .02 4.0
716 chapter
and thiocyanate levels. Smokers were identified as those
with a thiocyanate level of >90 mg/dL. Glucose intolerance
(diabetic screen) was determined by red blood cell glycosyl-
ated hemoglobin, and hypertension was assessed by renal
vascular morphometric analysis. Compared with control
subjects, women with plaque ruptures had elevated TC (270
± 55 vs. 194 ± 44 mg/dL, p = .002), and those with erosions
were more likely to be smokers (78% vs. 33%, p = .01).
Women with stable plaque and healed infarct had elevated
glycosylated hemoglobin (10.2% ± 5.0% vs. 6.4% ± 0.4% in
control subjects, p = .001) and were more likely to be hyper-
tensive (50% vs. 15% in control subjects, p = .03). By multi-
variate analysis, cigarette smoking was associated with
plaque erosion [p = .03, odds ratio (OR) 21], glycosylated
hemoglobin with stable plaque and healed infarct (p = .03,
OR 41), total cholesterol with plaque rupture (p = .02, OR 7),
and hypertension with stable plaque with healed infarct (p =
.02, OR 15). Effective risk factor modification is therefore
essential in women, as in men, in reducing the risk of sud-
den coronary death, due to a variety of morphologic
substrates.37
Genetic Risk Factors
Hereditary factors as well as multiple risk factors are essen-
tial when coronary artery disease is expressed in women.38
The genetics of coronary artery disease has been studied in
the context of single nucleotide polymorphisms in both men
and women, in cross-sectional studies. In one study from
Japan, diabetes and smoking were the two classic risk factors
most strongly associated with heart disease in women; in
addition, two polymorphisms (the replacement of four gua-
nines with five guanines at position –668 in the PAI-1 gene
and the replacement of five adenines with six adenines at
position –1171 in the stromelysin-1 gene) were associated
with a significant risk of myocardial infarction.39 In another
Japanese study, the –11751/5A→6A SNP (6-SNP-single nucle-
otide polymorphism) of the stromelysin-1 gene [matrix metal-
loproteinase-3(MMP-3)] was significantly associated with
CHD in low-risk women, and the 3932T→C SNP of APOE
gene was associated with CHD in high-risk women.40
Observational cross-sectional studies have shown that
short legs in women, in relation to body height, are associ-
ated with coronary artery disease.41 The reason for this obser-
vation, which presumably has a genetic basis, is unknown.
Inflammatory Markers
Serum levels of high-sensitivity C-reactive protein (hsCRP)
have been found to be a better predictor of coronary artery
disease than LDL in young women.42,43 These observations
have been expanded to older women as well.44 More recent
studies, however, have emphasized the importance of plasma
lipids in assessing coronary risk in women, beyond that of
inflammatory markers.45,46
Serum CRP levels have been used in conjunction with
other risk factor markers in women. Serum hsCRP adds
clinically important prognostic information to the metabolic
syndrome.47 Lp-PLA(2) and CRP may be complementary in
identifying middle-age men and women at high risk.48
Other inflammatory markers have been used as risk
factors for CHD in women. Tumor necrosis factor-α receptor
32
levels, by univariate analysis, was associated with risk in
women nurses.45 An independent relationship between serum
A amyloid and angiographic coronary artery disease was
established in women, greater than that for CRP.49 There is
evidence that plasma fibrinogen is associated with an excess
risk of heart disease in women.50 Confounding the relation-
ship between inflammatory markers and risk of heart disease
in women is the finding that there are independent relation-
ships between levels of interleukin-6 (IL-6) and age, BMI,
smoking, systolic blood pressure, alcohol use, presence of
diabetes, and frequency of exercise.51
A study evaluating women for suspected ischemia in the
absence of acute myocardial infarction or congestive heart
failure has found that lower hemoglobin levels are associated
with higher risk for adverse cardiovascular outcomes.52
Clinical Features of Coronary Heart Disease
in Women
Symptoms and Diagnosis
Women, especially those who are premenopausal, may expe-
rience symptoms of myocardial ischemia differently from
men, leading to underdiagnosis or misdiagnosis. Atypical
chest symptoms occur more frequently in premenopausal
women than in postmenopausal women with or without
hormone replacement therapy.53
Women, more than men, have their initial manifesta-
tion of CHD as stable or unstable angina, as opposed to
sudden death or acute myocardial infarction. In addition,
they are likely to be referred for diagnostic tests at a more
advanced stage of disease.54 In a large study from Sweden,
comprising men and women transported by ambulance to
an acute care center with symptoms that raised the suspi-
cion of coronary artery disease, women were older than
men, and had a lower incidence of previous acute myocar-
dial infarction, angina pectoris, and current smoking.
Among those patients with an acute coronary syndrome,
women more frequently complained of dyspnea than men,
and were less frequently described as clammy. Even though
women were less frequently diagnosed with an acute coro-
nary syndrome (22% vs. 37%) or acute myocardial infarc-
tion (10% vs. 18%), and less frequently showed signs of
myocardial ischemia on the electrocardiogram (ECG) upon
admission to the emergency department, the mortality rate
at 1 year was the same in women (17.2%) and men (18.7%).55
These results raise the suspicion that women may be under-
diagnosed with coronary disease, or that other factors such
as microvascular disease may be the basis for coronary
symptoms in women.
The diagnostic information from an ECG taken while the
patient is at rest and after exercise is considered less reliable
in women than in men. However, this lack of reliability is
mostly due to a high percentage of false-positive tests
explained by a lower prevalence of CHD. In postmenopausal
women with signs of unstable angina and ischemia on an
ECG taken while at rest, the prevalence of coronary athero-
sclerosis is high—85%. Although there is controversy regard-
ing the sensitivity of ECG changes in postmenopausal
women, ST-T changes at the early exercise test has been
 corona ry dise a se i n wom en
shown to have a high positive predictive value, especially in
combination with a low maximum workload.56
The sensitivity of stress myocardial perfusion studies is
similar in men and women with angiographically docu-
mented coronary artery disease.57 In addition, adenosine
stress testing with single photon emission computed tomog-
raphy has comparable incremental value for prediction of
cardiac death in women and men and is equally informative
for subsequent invasive management decisions in both
genders.58
Syndrome X
Cardiac syndrome X, a condition defined by the presence of
angina-like chest pain, a positive response to stress testing,
and normal coronary arteriograms, has been shown to occur
in approximately 20% to 30% of angina patients undergoing
coronary arteriography. The prevalence of syndrome X is
significantly higher in women than in men. Syndrome X is
likely a heterogeneous process, and the morphologic basis for
the syndrome is largely unknown. In the majority of patients
with chest pain and normal coronary arteriograms, symp-
toms may be noncardiac in origin, or result from small vessel
disease. The proportion of women with angina, normal coro-
nary angiograms, and undiagnosed epicardial disease (false-
negative angiograms) is not clear (Fig. 32.1). The morphologic
A B
C D
FIGURE 32.1. Cross sections of epicardial coronary arteries from a
56-year-old woman who died 1 day after coronary angiography with
severe necrotizing bronchopneumonia. Coronary angiography dem-
onstrated no significant stenosis (focal narrowing of less than 25%
717
differences between coronary atherosclerotic plaques in
pre- and postmenopausal women, and between men and
women in general, have been only incompletely studied
(see below).59
Prognosis and Treatment
The prognosis in women with coronary artery disease is
generally considered poorer than that of men. The overall
morbidity and mortality following the initial ischemic heart
event is worse in women, and the case fatality rate is greater
in women than in men.54 At 1-year following initial catheter-
ization, men report significantly better health-related quality
of life than women undergoing treatment for coronary artery
disease.60
It is unclear whether the relatively bad prognosis in
women is the result of late diagnosis, less aggressive treat-
ment, or inherent differences in pathophysiology. In a large
multicenter trial in the mid-1990s, women hospitalized with
acute myocardial infarction were older than men (66 vs. 58
years, p < .0001), more likely diabetic (19% vs. 10%, p = .03),
more frequently hypertensive (54% vs. 39%, p = .005), more
likely to have a history of prior congestive heart failure (5%
vs, 0%, p = .002), and presented later after symptom onset
(229 vs. 174 minutes, p = .0004). The in-hospital mortality
in women was 3.3-fold higher than in men (9.3% vs. 2.8%,
in the left anterior descending). There are multifocal areas of sig-
nificant stenoses at autopsy. (A) Proximal left anterior descending.
(B) Left diagonal. (C) Proximal right coronary. (D) Proximal left cir-
cumflex artery.
718 chapter
p = .005), but after adjustment for comorbid baseline charac-
teristics, only advanced age independently correlated with
mortality. Such data suggest that the gender difference in
prognosis is related to lack of timely care and control of risk
factors.
There is less consensus on gender differences in prognosis
after coronary interventions. Concerns about possible sex-
related complications should not dissuade physicians from
performing percutaneous interventions when clinically indi-
cated in women. After angioplasty performed for unstable
angina and rest pain, survival rates in two separate studies
were shown to be excellent in both women and men, without
gender bias in subsequent myocardial infarction rates. During
follow-up, however, women were more likely to have severe
angina and were less likely to have had coronary artery
bypass grafting.61,62 In a recent study of primary percutaneous
intervention, women had a higher 30-day mortality, but this
was based on increased age, a higher incidences of comorbidi-
ties, and longer times of reperfusion.63 Other data suggest,
however, that women have more adverse in-hospital out-
comes after percutaneous transluminal coronary angioplasty
and stenting compared with men. Data from the Nationwide
Inpatient Sample demonstrated that in 1997, women had a
roughly twofold higher mortality than men in every compari-
son group, including conventional angioplasty alone and
stents, and significantly higher coronary artery bypass graft
rates than men whether or not there was acute myocardial
infarction at the time of presentation.64 In the fragmin during
instability in coronary artery disease (FRISC) study, an early
invasive strategy in women with unstable coronary syn-
dromes did not reduce the risk of future events, unlike that
in men.65 The benefit of an early invasive strategy incorporat-
ing intracoronary stents in women with unstable coronary
artery disease has been more recently espoused, however.66
Among patients with acute myocardial infarction ran-
domized to thrombolytic therapy, mortality and intracranial
bleeding was significantly higher in women than in men. In
contrast, women and men had similar in-hospital mortality
after randomization to primary angioplasty.67 More recently,
women and men presenting with an acute ST-segment eleva-
tion myocardial infarction were randomized to receive either
direct angioplasty or accelerated tissue plasminogen activa-
tor. Although the relative benefit of direct angioplasty to
thrombolytic treatment appeared to be similar in women
and men, women derived a larger absolute benefit from direct
percutaneous intervention with stenting.68
In a more recent study of women receiving coronary
stents, they are over twice as likely as men to have proce-
dural failure or complications and suffer hospital mortality.
However, the increase in female morbidity may largely be
due to more adverse baseline characteristics, and long-term
event-free survival and restenosis rate are similar in men and
women.69 An Israeli study showed that coronary stenting has
similar success rates among women and men, with similar
restenosis rates as well as early and late major adverse cardiac
events.70 In another study, in which women were older and
with a higher incidence of comorbidities and more unstable
presentation, women treated with coronary stenting showed
acute and midterm clinical results similar to those observed
in men, but were significantly more likely to develop angio-
graphic restenosis.71
32
There is no doubt that women fare worse than men after
coronary artery bypass graft surgery. The reasons for women’s
bad prognosis stem from anatomic differences (smaller native
coronary arteries), a lower number of anastomoses, and a
lower internal thoracic (mammary) artery availability.
Women have a higher 12-month mortality (14% in women
vs. 6% in men), and higher morbidity in terms of readmis-
sions, angina symptoms, antianginal drug use, and effort
tolerance.72 The higher hospital mortality and morbidity in
women undergoing coronary surgery are partially related to
the severity of coronary atherosclerosis and comorbid condi-
tions.73 Diabetes is an especially bad prognostic factor in
women undergoing coronary artery bypass grafting, and is
more prevalent in women.74 Although there is no doubt that
early mortality is significantly higher for women after coro-
nary artery bypass graft surgery, long-term relative mortality
risk for women is similar to that of men.75 Both men and
women improve in physical, social, and emotional function-
ing after surgery, and recovery over time is similar in men
and women. However, women’s health-related quality-of-life
scale scores remained less favorable than men’s through 1
year after surgery.76
Information on the relative benefit of coronary artery
bypass grafting versus stent-assisted percutaneous coronary
intervention for improvement of cardiac-related health status
in women and how it compares with men is limited. In the
Stent or Surgery Trial, 206 women and 782 men with multi-
vessel disease were randomized to surgery and percutaneous
coronary intervention (PCI). At 1 year after intervention,
both procedures appeared equally effective in women,
although surgery was clearly superior in men.77 The type of
bypass surgery may play a role in women’s prognosis. Evi-
dence suggests that off-pump coronary artery bypass graft
(CABG) surgery may be better for women than on-pump
CABG surgery because it appears to reduce mortality and
respiratory complications, shorten the time of hospitaliza-
tion, and increase discharges directly home.78
In patients requiring emergent surgery after percutane-
ous angioplasty, a Kaplan-Meier model with follow-up aver-
aging 5.3 years, showed a markedly increased in-hospital
mortality in women compared to men (p = .003), but a com-
parable long-term survival.79 In this study, women had an
increased initial risk for failure of angioplasty, although
gender was not found to be an independent predictor of post-
operative death.79
Physiology of Coronary Disease in Women
Sex Hormones and Vascular Disease
Much of the research in the pathophysiology of coronary
disease in women stems from observations noting differ-
ences in pre- and postmenopausal disease. Although these
differences likely have a hormonal basis, it has been demon-
strated that a large part of the increased risk for coronary
artery disease in postmenopausal women versus perimeno-
pausal women stems from a great increase in traditional risk
factors as age progresses.80 However, qualitative differences
in the clinical and pathologic expression of coronary disease
in premenopausal women cannot be ignored.
 corona ry dise a se i n wom en
Estrogens have in vitro vasodilatory effects, and have
been shown to improve dilator responses of atherosclerotic
coronary arteries in monkeys.81 Estrogen’s effects on vas-
cular reactivity have been used to explain the symptoms
of syndrome X in postmenopausal women, and justify the
use of hormone replacement therapy, especially in such
women. Estrogen vasoactive properties involve endothelium-
dependent effects and, in postmenopausal women, forearm
vasodilatation induced by acetylcholine is potentiated by the
acute local administration of intravenous estradiol. Estro-
gen’s potentiation of endothelium-dependent vascular relax-
ation and its inhibition of vascular smooth muscle contraction
may contribute to some of the clinical findings of CHD in
women.82 The relationship, however, between vasomotor
abnormalities, coronary symptoms, and estrogen remains
speculative.59
In vitro studies have shown other effects of steroid hor-
mones of vascular function. A possible mechanism by which
estradiol exerts one of its cardioprotective effects is by limit-
ing the inflammatory response to injury by modulating the
expression of cellular adhesion molecules from the endothe-
lium.83 Furthermore, β-estradiol inhibits proliferation of
coronary smooth muscle cells.84
Hormonal variations have been observed in women with
clinically documented coronary artery disease. Among pre-
menopausal women undergoing coronary angiography for
suspected myocardial ischemia, disruption of ovulatory
cycling characterized by hypoestrogenemia of hypothalamic
origin appears to be associated with angiographic disease.85
Hyperandrogenemia and low levels of sex hormone
binding globulin are frequently found in women with meta-
bolic syndrome in postmenopausal women. Low plasma
levels of sex hormone binding globulin are associated with
CHD in women independently of insulin, obesity markers,
and dyslipidemia.86 In addition, in postmenopausal women
decreased serum testosterone levels are associated with coro-
nary artery disease independently of the other metabolic risk
factors.87
Coronary Microvascular Disease in Women
A decrease in vasodilator capacity of small vessels has been
documented especially in postmenopausal women and forms
the theoretical basis for syndrome X. Even in asymptomatic
women, assessment of coronary endothelium-independent
and -dependent function with intracoronary administration
of adenosine and acetylcholine has found that the postmeno-
pausal state is associated with a greater abnormality in
coronary endothelial function at the level of the micro-
circulation.88 The abnormal vasodilatory coronary blood
flow responses and an increased sensitivity of the coronary
microcirculation to vasoconstrictor stimuli in syndrome X
patients has been termed microvascular angina.59 The pro-
portion of women with syndrome X who suffer from myo-
cardial ischemia is unclear, however. Nevertheless, ischemic
electrocardiographic findings, the presence of myocardial
perfusion defects during stress testing, coronary sinus oxygen
saturation abnormalities and pH changes, as well as myocar-
dial lactate production and alterations of cardiac high-energy
phosphate, are seen during stress testing in a proportion of
patients with syndrome X.59 One in five women with chest
719
pain but without obstructive coronary artery disease (consti-
tuting syndrome X patients) have stress-induced reduction in
myocardial phosphocreatine-adenosine triphosphate ratio by
phosphorus 31 nuclear magnetic resonance spectroscopy
(MRS), consistent with myocardial ischemia.89
Women with angina and normal epicardial coronary
arteries (as assessed angiographically) have higher rates of
anginal hospitalization, repeat catheterization, and greater
treatment costs, suggesting that some patients with syn-
drome X may progress to overt coronary artery disease.89
These patients were found to have stress-induced reduc-
tion in myocardial phosphocreatine-adenosine triphosphate
ratio by phosphorus 31 nuclear MRS (abnormal MRS), con-
sistent with myocardial ischemia.89 In a follow-up study of
women with syndrome X, endothelial function testing with
intracoronary acetylcholine identified a group of patients
with diffuse vasoconstriction (in the absence of epicardial
spasm) who ultimately developed epicardial coronary
disease.90 Furthermore, the Women and Ischemia Syndrome
Evaluation (WISE), sponsored by the National Heart, Lung,
and Blood Institute, studied 163 women referred for clini-
cally indicated coronary angiography who underwent coro-
nary reactivity assessment with a median follow-up of 48
months. In this study, impaired coronary vasomotor response
to acetylcholine was independently linked to adverse car-
diovascular outcomes regardless of coronary artery disease
severity.91
Reduced coronary vasodilator function and impaired
response of resistance vessels to increased sympathetic stim-
ulation, as seen in postmenopausal women with syndrome
X, has also been demonstrated in premenopausal women
with diabetes.92 Diabetes has well-documented effects on
microvessels in the kidney, including hyalinization and
intimal thickening, but pathologic studies of coronary micro-
vasculature in diabetics are few.
Postmenopausal Hormone Replacement
Therapy and Risk of Coronary Disease
Healthy Women
It was long assumed that hormone replacement therapy
would reduce the risk of coronary artery disease in post-
menopausal women, because of estrogen’s apparent protec-
tive effect on atherosclerosis. However, the Women’s Health
Initiative, the first randomized prospective trial of the effect
of hormone replacement therapy on heart disease in healthy
women, demonstrated that conjugated equine estrogen plus
progestin does not confer cardiac protection and may increase
the risk of CHD, especially during the first year after the
initiation of hormone use.93 In healthy women with prior
hysterectomy, the use of conjugated equine estrogen increases
the risk of stroke, decreases the risk of hip fracture, and does
not affect the incidence of CHD incidence in postmeno-
pausal women.94 In a case-control study of British women,
hormone replacement therapy was associated with a small
increase in risk of acute myocardial infarction in the first
year of use (adjusted OR being 1.14), with subsequent reduc-
tions in the risk (OR 0.85 at 13 to 60 months, and OR 0.42
after 5 years).95
720 chapter
Women with Prior Heart Disease
Hormone replacement therapy has not been shown to be of
significant benefit in women with established coronary
artery disease. In the Heart and Estrogen/Progestin Replace-
ment Study (HERS), during an average follow-up of 4.1 years,
treatment with oral conjugated equine estrogen plus
medroxyprogesterone acetate did not reduce the overall rate
of coronary events in postmenopausal women with estab-
lished coronary disease.96 In the same cohort, estrogen plus
progestin use had no effect on all-cause mortality (hazard
ratio 1.0).97 In older postmenopausal women with established
coronary artery atherosclerosis, 17β-estradiol (the endoge-
nous hormone, as opposed to conjugated equine estrogen)
with or without medroxyprogesterone acetate had no signifi-
cant effect on the progression of atherosclerosis as assessed
by quantitative coronary angiography in a double-blinded
placebo study.98 In a 2-year follow-up study, estradiol valerate
did not reduce the overall risk of further cardiac events in
postmenopausal women who had survived a myocardial
infarction.99 In women with abnormal glucose tolerances,
postmenopausal hormone therapy was associated with a
worsening of coronary atherosclerosis and exacerbation of
the profile of inflammatory markers in women.100
In a nonrandomized observational study, postmenopausal
women undergoing coronary artery bypass had a signifi-
cantly improved in-hospital survival if they had been receiv-
ing hormone replacement therapy.101
Effect of Hormone Replacement on Coronary Risk
Current data do not support hormone replacement therapy
for the purpose of coronary risk reduction, in contrast to
earlier meta-analyses that suggested the opposite.102 The
reasons for the lack of estrogen’s protective effect are unclear.
The apparent protective effect of combination menopausal
hormone therapy with estrogen and progesterone is due to
differences in other patient characteristics and bias of healthy
women taking postmenopausal hormones.103 It has been pro-
posed that differences in hormone regimen (estrogen alone,
synthetic vs. endogenous) do not affect the outcome of the
Women’s Health Initiative data.104 However, others have
speculated that estrogen alone may have a beneficial
effect.103
The multiplicity of effects of exogenous hormones likely
play a role in their effects on coronary disease in women.
Hormone replacement treatment has both prothrombotic
and antiatherogenic effects, and its failure in reducing the
risk of cardiovascular events in postmenopausal women
might be because of the stage of their atherosclerosis at the
time of initiation of treatment.105 Furthermore, the early
increased risk of CHD and stroke with estrogen and proges-
tin therapy may be attributable to a rise in very low density
lipoprotein (VLDL) triglycerides in addition to thrombosis.106
Although oral estrogen replacement therapy in postmeno-
pausal women improves endothelial function, it also
increases plasma CRP and IL-6 concentration. It has been
suggested that lower doses of conjugated equine estrogen
may eliminate the increase in vascular inflammatory
markers while preserving the favorable effects of estrogen on
endothelial function.107
32
Pathology of Coronary Disease in Women
The characteristics of coronary artery plaques in women
have been studied by angiography, intravascular ultrasound,
and histopathologic means. In patients with unstable angina
and non–Q-wave infarction, angiography has revealed less
severe coronary artery disease in women than in men, with
fewer critical stenoses.5 Intravascular ultrasound of coronary
lesions has shown smaller coronary arteries in women than
in men,108,109 which was independent of body size in the
left anterior descending artery.109 Women and men had
similar reference and lesion plaque burden, eccentricity,
and calcium.108 In this study, reference plaque referred to
angiographically normal 5 mm segments maximal and distal
to lesions, and plaque burden calculated as plaque + media
divided by external elastic lamina area.
Few autopsy studies have analyzed plaque morphology in
women dying with severe coronary disease. Few histopatho-
logic studies have compared coronary plaques in women and
men. The plaque composition of the native coronary arteries
and saphenous venous conduits in women contain more cel-
lular fibrous tissue than dense fibrous tissue, interpreted as
representing plaques at a younger stage than in men.110 In an
autopsy study of eight women <40 years of age dying a coro-
nary death, the large amount of lipid-containing foam cells
and the relative lack of acellular scar tissue in coronary
plaques suggest a greater potential for reversibility of these
plaques.111 A different autopsy study comparing men and
women dying with acute myocardial infarction demonstrated
that there are more deaths in women during the acute phase
of myocardial infarction, in the first infarction, and from
rupture of the left ventricle, with less severe narrowing of
the left main coronary artery.112
Definition of Plaque Rupture and Erosion
More recent autopsy studies have addressed the mechanisms
of coronary thrombosis, plaque rupture and erosion, and
their prevalence in women and men. Coronary artery thrombi
have been separated into two types based on the morphology
of the underlying plaque. Coronary plaque rupture is defined
as a luminal thrombus overlying a disrupted fibrous cap; the
lipid core is in direct contact with the thrombus. In contrast,
plaque erosion is identified when serial sectioning of a
thrombosed arterial segment fails to reveal fibrous cap
rupture.113 Typically, the endothelium is absent at the plaque–
thrombus interface, with the exposed intima consisting pre-
dominantly of smooth muscle cells and proteoglycans, with
minimal inflammation (Fig. 32.2). It is important to note
that this form of thrombotic occlusion does not require a
necrotic core as lipid pools are commonly seen in the deep
intima.114
Clinical and Morphologic Differences of Plaque
Rupture Versus Superficial Erosion
The mean age in cases of coronary thrombosis due to
plaque rupture is significantly less than that of plaque
rupture, and the mean percent cross-sectional area stenosis
(excluding the thrombus itself) is likewise less. Plaque calci-
fication is significantly less in erosions, possibly reflecting
the younger age at presentation. The thrombus resulting
 corona ry dise a se i n wom en
A Movat B α-actin
D F-II E CD68
FIGURE 32.2. Acute plaque erosion. (A) Cross section of epicardial
coronary artery with nonocclusive thrombus caused by acute plaque
erosion. Movat pentachrome stain. (B) Immunohistochemical local-
ization of smooth muscle cells (anti–α-actin) at site of thrombus. (C)
from erosion is less likely occlusive than the thrombus
caused by rupture.113
Identification of cell type by immunohistochemical
staining demonstrates several differences between ruptures
and erosions. In plaque ruptures, macrophages are typically
seen infiltrating the thin fibrous cap at the margins of the
rupture site. Foci of KP-1–positive macrophages, universally
present in ruptures, are seen in only half of erosions. Con-
versely, clusters of α-actin–positive smooth muscle cells are
seen at the luminal surface adjacent to the thrombus in
almost all erosions, compared to a minority of ruptures,
likely those with ongoing healing. Cell activation, indicated
by anti–human leukocyte antigen DR (HLA-DR) staining, is
seen in both macrophages and T cells in almost all ruptures,
but in fewer than half of erosions.113
Erosions Present a Plaque Substrate Rich in
Proteoglycan and Hyaluronan
Proteoglycans (versican, biglycan, and decorin) and hyaluro-
nan are extracellular matrix molecules that have been shown
to accumulate in topographically distinct patterns within
the developing atherosclerotic plaque.115 The mechanically
active environment of the artery can sense mechanical
stimuli that result in the regulation of extracellular matrix
synthesis by the smooth muscle cells (SMCs). Lee et al.116
have shown that versican-hyaluronan aggregation is
enhanced, but the hydrodynamic size of proteoglycans is not
altered by mechanical SMC deformation. In addition, a four-
fold increase in steady-state messenger RNA (mRNA) for the
hyaluronan-binding protein TSG6 expression was observed
following deformation. Although early observations demon-
strated that plaque erosions were rich in proteoglycans, the
extensive nature of the extracellular matrix in culprit plaques
with or without coronary thrombi was unknown. A recent
7 21
C CD61
F CD45Ro
Immunohistochemical localization of luminal platelets (antiplate-
let glycoprotein, CD61). (D) Immunohistochemical localization of
fibrin (anti–fibrin II). (E,F). Paucity of macrophages (anti-CD68, E),
and T lymphocytes (anti-CD45RO, F) at site of erosive thrombus.
study from our laboratory explored the possibility of whether
the accumulation of specific types of proteoglycans discrimi-
nates among lesions types associated with sudden coronary
events. Plaque erosions demonstrated a selective increase in
hyaluronan and versican content at the plaque–thrombus
interface compared with the fibrous caps of ruptures or stable
plaques.117 These differences occurred despite similarities in
SMC phenotype between erosion and stable plaques. In fact,
plaque rupture sites contain very little proteoglycan content
relative to stable or eroded lesions.
The appearance of increased hyaluronan at the plaque–
thrombus interface is unique, and therefore we postulated that
hyaluronan might provide a high-risk substrate for the devel-
opment of thrombosis in erosion. Indirect support for this
notion comes from culture models demonstrating a decreased
potential for endothelial cell adherence, growth, and survival
on hyaluronan substrates.118 Further, the major cell surface
receptor for hyaluronan (CD44) was found highly localized to
a subset of SMCs at the plaque–thrombus interface as well as
in some platelets and inflammatory cells within the throm-
bus.117 Hyaluronan binds to the specific receptors, such as
CD44 and the receptor for hyaluronan-mediated motility
(RHAMM), as well as other proteins, such as TSG-6, collagen,
and proteoglycans. CD44 has been shown to mediate the adhe-
sion of platelets to hyaluronan.119 The de-endothelialized
surface of erosion exposes hyaluronan to the flowing blood,
thereby promoting platelet attachment via a CD44-dependent
mechanism.120 Moreover, the expression of CD44 in erosion
may also promote vascular cell activation and migration of
SMCs to the wounded edge represented by the loss of endothe-
lium. Consistent with a wounding hypothesis, acute erosions
are often superimposed on what appears to be repeated epi-
sodes of thrombosis and healing such that layers of platelets
and fibrin are commonly found deep within the plaque.114
The increase in hyaluronan/versican may be secondary to
722
mechanical deformation of SMCs in vivo because vessel vaso-
spasm has previously been reported to be more common in
women presenting with acute coronary syndromes.121
Unlike plaque rupture in which a precursor plaque can
be identified (i.e., vulnerable plaque) no such “pre-erosion
lesion” has been described for plaque erosion. Indeed, the
formation of thrombi in plaque erosion most likely involves
multiple factors including fibrinolytic dysfunction, or abnor-
malities to surface endothelium, SMCs, or both. Fibrinolytic
dysfunction, in particular, elevated plasma and tissue levels
of tissue factor and PAI-1 may represent a risk factor for coro-
nary thrombosis. Previous studies have shown alterations in
the plasminogen activator system in human coronary
plaque.122 Further studies of eroded coronary plaques have
shown tissue factor expression in both SMCs and macro-
phages in plaque erosions.123 Intimal expression of PAI-1 was
75% in eroded vessels as compared with 20% in control
nonthrombosed arteries.123
Differences Between Coronary Lesions in Pre- and
Postmenopausal Women
In a series of 51 cases of sudden coronary death and 47 control
deaths in women who died from noncoronary causes, and a
larger group of men, the number of acute plaque ruptures,
healed plaque ruptures, vulnerable plaques, and acute plaque
erosions were compared among groups (men, premenopausal
women, and postmenopausal women).124 Women older than
50 years of age were much more likely to have a ruptured
plaque than were younger, premenopausal women, and had
comparable numbers to the men (Fig. 32.3). Healed plaque
ruptures were infrequent in women, especially premeno-
.6
Women
.5
Mean # acute ruptures
Men
.4
.3
.2
.1
0
Male >50
Male ≤50
Fem >50
Fem ≤50
FIGURE 32.3. Frequency of acute plaque ruptures, men and women
dying suddenly with severe coronary disease, by age grouping. An
autopsy study of 51 women and 135 men dying with severe coronary
artery disease. Numbers of healed plaque ruptures quantitated per
heart. p = .006, females ≤50 years old vs. females >50 years old; p =
.02, females >50 years old vs. males ≤50 years old.
chapter 32
1.4
Men
1.2
Mean # healed plaque ruptures
1
Women
.8
.6
.4
.2
0
Male >50
Male ≤50
Fem >50
Fem ≤50
FIGURE 32.4. Frequency of healed plaque ruptures, men and
women dying suddenly with severe coronary disease, by age group-
ing. An autopsy study of 51 women and 135 men dying with severe
coronary artery disease. Numbers of healed plaque ruptures quan-
titated per heart. p < .0001, females <50 years old vs. males; p = .01,
females ≤50 years old vs. females >50 years old.
pausal women (Fig. 32.4). Plaque erosions were far more
common as a cause of coronary thrombosis in premeno-
pausal women (Table 32.1). These results suggest that plaque
instability in the form of plaque rupture is uncommon in
women with physiologic estrogen levels, and that plaque
progression by this mechanism, which has been detailed in
autopsy studies,125 begins at a later age than in men. In the
51 women who died of coronary disease, the mean number
of thin cap atheromas, the presumed precursor lesion of acute
plaque rupture, and numbers of plaque with a lipid core
increased significantly as women advanced into the post-
menopausal years, supporting this concept (Figs. 32.5 and
32.6).124 The mean thickness of the fibrous cap decreased in
postmenopausal women (Fig. 32.7). Because plaque progres-
sion may result both from repeated rupture and repeated
erosion, a better understanding of the effect of estrogen on
atherosclerosis may yield insights into the nature of coro-
nary artery disease.37,124,126
Coronary Artery Remodeling in Women
Data obtained from intravascular ultrasound have suggested
that arterial diameter in women may be smaller than
that in men with coronary disease, even adjusted for body
size.109 The role of coronary artery remodeling in response to
plaque enlargement is well known, but the gender effect on
remodeling has not been studied in detail. In one autopsy
study, the degree of positive remodeling in women was less
than that in men, especially in proximal arterial segments127
(Fig. 32.8). Further morphologic studies investigating the dif-
 corona ry dise a se i n wom en 723
1.4

Mean numbers of vulnerable plaques

1.2

.8

.6

.4
FIGURE 32.5. Mean number of thin cap fibroatheromas in 51 women
.2
who died suddenly from severe coronary disease. The left bar shows the
mean numbers in younger women, and the right bar, the mean number
in older women. The difference was significant (p < .0001, Student’s 0
t-test). <50 years >50 years

30 400

Mean thickness of fibrous cap, μm

350
25
300
Mean % lipid core

20 250
200
15
150
10
100

5 50
0
0 <50 years >50 years
<50 years >50 years FIGURE 32.7. Mean fibrous cap thickness (μm) in 51 women who
FIGURE 32.6. Mean proportion (%) of plaques with a lipid core in died suddenly from severe coronary disease. The left bar shows the
51 women who died suddenly from severe coronary disease. The left mean thickness in younger women, and the right bar, mean thick-
bar shows the mean proportion of such lesions in younger women, ness in older women. The difference was significant (p = .02, Stu-
and the right bar, the proportion in older women. The difference was dent’s t-test).
significant (p = .02, Student’s t-test).

.14

.12
lel - expected iel, mm2/plaque area

Proximal
.1 Distal

.08

.06

.04
FIGURE 32.8. Remodeling, as assessed by internal elastic lamina (IEL) expansion
adjusted for plaque size, was greater in proximal (left main, left anterior descend-
ing before diagonal, first 3 cm of right coronary, left circumflex prior to obtuse .02
marginal) as compared to more distal segments in both men and women. Remod-
eling was greater in men than women (p = .01, means table with Fisher’s post-hoc .0
test), and greater in proximal than distal segments (p < .0001, means table with
Fisher’s post-hoc test). Males Females
724 chapter
ferences between plaque composition in pre- and postmeno-
pausal women are needed before clinical differences in
coronary disease in men and women are better understood.
Summary
Coronary disease in women differs from coronary disease
in men in several key areas. Hormonal influences decrease
the mean age at onset. Although traditional risk factors for
coronary disease are similar in men and women, gender
appears to modify the relative effects of these risk factors.
Small vessel disease is likely to play a more important role
in coronary disease in women and men, and explains in part
differences in clinical presentation. The effects of sex hor-
mones on atherosclerotic plaque is complex, effecting both
thrombosis as well as inflammation; therefore, simple
hormone replacement therapy has not fulfilled its promise
as a preventative treatment in older women. There are patho-
logic differences in coronary atheromatous lesions between
men and women, and between pre- and postmenopausal
women. The significance of these differences and their basis
in hormonal and risk factor physiology remain to be
elucidated.
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 3 Exercise Testing
3 Bernard R. Chaitman, Masarrath J. Moinuddin,
and Junko Sano
Introduction and Safety of Exercise Testing . . . . . . . . . .
Indications and Contraindications . . . . . . . . . . . . . . . . . .
Interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Exercise Testing in the Diagnosis of Coronary
Artery Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction and Safety of Exercise Testing
Stress testing is a technique used primarily for the diagnos-
tic, prognostic, and functional assessment of patients with
known or suspected coronary artery disease (CAD).1 Exer-
cise, or the ability to do work, when used as the stressor can
reproduce symptoms and provide an objective estimate of
functional capacity that is a general measure of cardiopul-
monary and musculoskeletal reserve. Vagal tone is progres-
sively withdrawn as dynamic exercise progresses and
sympathetic discharge is increased. Cardiac output increases
coincident with the increase in heart rate, stroke volume, and
venous return. An estimate of an individual’s maximum
heart rate can be calculated from the formula 220 minus age
(years), assuming a standard deviation of 10 to 12 beats/min.
Systolic blood pressure increases with progressive levels of
work, and peak rate pressure product achieved (heart rate ×
systolic blood pressure) provides an estimate of myocardial
oxygen demand at specific workloads.
Exercise testing is often used in conjunction with an
imaging procedure, such as myocardial perfusion imaging
or echocardiography, to enhance its diagnostic accuracy,
particularly in patients with an intermediate pretest risk of
disease. In general exercise testing is a safe procedure;
however, in one report, four myocardial infarctions, deaths
or both, occurred per 10,000 tests performed.1,2 The risk is
greater in patients after myocardial infarction and in patients
undergoing evaluation for malignant ventricular arrhyth-
mias, and the risk is least in asymptomatic patients being
evaluated for an adverse risk profile. Because of the risks,
albeit small, exercise testing should be performed only by
well-trained technicians and physicians. In addition, the
staff must be advanced cardiac life support (ACLS) certified
and have immediate access to appropriate equipment and
medications to perform cardiopulmonary resuscitation if
required.
729 Prognostic Use of Exercise Testing . . . . . . . . . . . . . . . . . 736
729 Exercise Testing After Acute Coronary Syndrome or
731 to Risk Stratify in the Emergency Department . . . . 738
Other Uses of Exercise Testing. . . . . . . . . . . . . . . . . . . . . 739
735 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741
Indications and Contraindications
Good clinical judgment is the most important factor in
determining the indications and contraindications for exer-
cise testing. The patient should not eat or smoke for at least
2 hours before the test and should dress appropriately for
exercise. A brief history and physical examination should be
performed by appropriate trained medical personnel to rule
out contraindications to testing. Patients with a history of
intermediate- or high-risk unstable angina or increasing
chest pain at rest should not undergo exercise testing until
the condition stabilizes. Patients with poorly controlled or
unexplained low blood pressure or heart failure and those
with severe valvular or congenital heart disease, particularly
severe aortic stenosis, should be identified and usually not
undergo testing. Table 33.1 summarizes absolute and relative
contraindications to exercise testing. Standard indications
for exercise testing are found in Appendix 33.1.1 The indica-
tions should always be known before the test is performed
to maximize the informational content derived from the
test. The procedure, attendant risks, including the extremely
low risk of death and myocardial infarction, and benefits of
the test should be explained to the patient, and a written
informed consent form obtained.
The Mason-Likar modification of the standard 12-lead
electrocardiogram (ECG) is the most frequent lead system
used for exercise testing. This modification involves moving
the limb electrodes to the torso to minimize motion artifact.
It should be noted that the Mason-Likar lead placement
results in increased voltage in the inferior leads and a right-
ward axis shift. In some patients with a prior inferior Q-wave
infarction, the Mason-Likar configuration can cause inferior
Q waves to disappear and a Q wave in lead aVL to appear.
Therefore, a standard resting 12-lead ECG with the elec-
trodes placed at the extremities is usually obtained before
performance of the exercise test. After the limb leads have
729
730 chapter
TABLE 33.1. Contraindications to exercise testing
Absolute
Acute myocardial infarction (within 2 d)
High-risk unstable angina
Uncontrolled cardiac arrhythmias causing symptoms or
hemodynamic compromise
Symptomatic severe aortic stenosis
Uncontrolled symptomatic heart failure
Acute pulmonary embolus or pulmonary infarction
Acute myocarditis or pericarditis
Acute aortic dissection
Relative*
Left main coronary stenosis
Moderate stenotic valvular heart disease
Electrolyte abnormalities
Severe arterial hypertension†
Tachyarrhythmias or bradyarrhythmias
Hypertrophic cardiomyopathy and other forms of outflow tract
obstruction
Mental or physical impairment leading to inability to exercise
adequately
High-degree atrioventricular block
* Relative contraindications can be superseded if the benefits of exercise
outweigh the risks.
† In the absence of definitive evidence, the committee suggests systolic blood
pressure of >200 mm Hg and/or diastolic blood pressure of >10 mm Hg.
been moved to the torso, tracings should be recorded with
the patient in the supine and upright positions. The tracing
in the upright position is usually selected as the baseline
tracing from which exercise tracings are compared. Table
33.2 summarizes the main indications for termination of
an exercise test.1
Bicycle Ergometer Protocols
Bicycle ergometers have mechanical or electrical brakes to
vary workloads that are calibrated in kiloponds (kpm) or
watts (W). The initial power output is usually 25 or 50 W
depending on the ability of the particular patient, followed
by increases of 25 to 50 W every 3 minutes until the end
point of the test is reached. Bicycle ergometers are usually
less expensive, occupy less space, and make less noise than
a treadmill. In addition, upper body motion is usually less
than that with a treadmill, making it easier to measure
blood pressure, auscultate the chest, and record the ECG.
However, a significant proportion of patients experience dif-
ficulty in performing optimally on a bicycle compared with
a treadmill. In addition, maximal oxygen uptake tends to be
5% to 10% lower than with treadmill exercise, and maximal
cardiac output and stroke volume are correspondingly
reduced.
Treadmill Protocols
There are numerous treadmill exercise protocols; it is impor-
tant to select a protocol that is suited to the patient’s physical
ability. An optimal protocol should last at least 6 to 12
minutes. The most popular is the Bruce protocol because of
the extensive published data on the diagnostic and prognos-
tic use of this protocol. In patients with limited exercise
capacity, the Bruce protocol can be modified by adding an
initial zero stage (1.7 mph at 0% incline) and one-half stage
33
(1.7 mph at 5% incline). The main disadvantages of this pro-
tocol are the large increments in work that occur between
stages and the additional energy requirements in patients
who are required to run rather than walk in the fourth or
subsequent stages of the protocol. Other treadmill protocols
such as ramp protocols, 3 the modified Balke, Naughton, or
standard or modified Asymptomatic Cardiac Ischemia Pilot
(ACIP) protocols were developed to provide a more linear
increase in heart rate and oxygen consumption at progres-
sively increasing workloads. In patients with severe limita-
tion of exercise capacity, the 6-minute walk test can be used
to provide a more objective assessment of functional capacity
than a subjective description of symptoms. Although the 6-
minute walk test is popular to test patients with more severe
heart failure, it is not as objective as cardiopulmonary testing
in establishing peak aerobic capacity.
Postexercise Period
It is important to be aware that some abnormal responses
only occur in the postexercise recovery phase. To achieve
maximal sensitivity to detect ST-segment shifts, patients
should be in the supine position during the postexercise
period; however, this is not always desirable. In patients who
experience severe angina, dyspnea, or ventricular arrhyth-
mias during the exercise test, the lower preload associated
with the sitting or erect position may be preferable. In other
TABLE 33.2. Indications for terminating exercise testing
Absolute indications
Drop in systolic blood pressure of >10 mm Hg from baseline
blood pressure despite an increase in workload, when
accompanied by other evidence of ischemia
Moderate to severe angina
Increasing nervous system symptoms (e.g., ataxia, dizziness, or
near-syncope)
Signs of poor perfusion (cyanosis or pallor)
Technical difficulties in monitoring ECG or systolic blood
pressure
Subject’s desire to stop
Sustained ventricular tachycardia
ST elevation (≥1.0 mm) in leads without diagnostic Q-waves
(other than V1 or aVR)
Relative indications
Drop in systolic blood pressure of (≥10 mm Hg from baseline
blood pressure despite an increase in workload, in the
absence of other evidence of ischemia
ST or QRS changes such as excessive ST depression (>2 mm of
horizontal or down-sloping ST-segment depression) or marked
axis shift
Arrhythmias other than sustained ventricular tachycardia,
including multifocal PVCs, triplets of PVCs, supraventricular
tachycardia, heart block, or bradyarrhythmias
Fatigue, shortness of breath, wheezing, leg cramps, or
claudication
Development of bundle branch block or IVCD that cannot be
distinguished from ventricular tachycardia
Increasing chest pain
Hypertensive response*
* In the absence of definitive evidence, the committee suggests systolic blood
pressure of >250 mm Hg and/or a diastolic blood pressure of >115 mm Hg.
ECG, electrocardiogram; PVCs, premature ventricular contractions; ICD,
implantable cardioverter-defibrillator discharge; IVCD, intraventricular con-
duction delay.
 e x ercise t est i ng
patients, particularly those patients who attain a high work-
load, it is preferable to have a cool-down period to avoid
postexercise hypotension, which occasionally occurs. Moni-
toring should continue for approximately 5 minutes after
exercise or until hemodynamic changes stabilize and the
heart rate and ECG have returned close to baseline. If exer-
cise-induced ST-segment changes have improved but not
completely returned to normal, the patient may be discon-
nected from the electrocardiograph, sit in a location proxi-
mate to the laboratory, and 20 to 30 minutes later have a
repeat ECG done to confirm that the ECG has returned to
baseline.
Interpretation
Symptoms
The quality, character, intensity, and duration of chest pain
induced by exercise may be helpful in establishing a diagno-
sis even in the absence of ST-segment depression. It is impor-
tant to obtain an accurate account of symptoms, in particular,
chest pain that occurs during or after exercise testing.
Physical Signs
Cardiac examination immediately after exercise may reveal
a precordial bulge or third heart sound resulting from left
ventricular dysfunction. Papillary muscle dysfunction due to
transitory ischemia may result in a mitral regurgitation
murmur.
Heart Rate and Blood Pressure Response
Blood pressure is dependent on cardiac output and peripheral
resistance. Systolic blood pressure rises to 160 to 220 mm Hg
at peak exercise, whereas diastolic blood pressure does not
usually change by more than ± 10 mm Hg from the resting
value in normal subjects. An inadequate rise (<120 mm Hg)
or a progressive fall in systolic blood pressure (>10 mm Hg)
during exercise may be associated with severe CAD and
ischemic dysfunction (Table 33.3). However, some normal
subjects may have a transient drop in systolic blood pressure
shortly after maximal exercise due to a mismatch between
TABLE 33.3. Exercise parameters associated with an adverse
prognosis and multivessel coronary artery disease
Duration of symptom-limiting exercise <5 METs
Failure to increase systolic blood pressure ≥120 mm Hg, or a
sustained decrease ≥10 mm Hg, or below rest levels, during
progressive exercise
ST segment depression ≥2 mm, down-sloping ST segment, starting
at <5 METs, involving ≥5 leads, persisting ≥5 minutes into
recovery
Exercise-induced ST segment elevation (aV excluded)
Angina pectoris at low exercise workloads
Reproducible sustained (>30 sec) or symptomatic ventricular
tachycardia
Acute systemic illness (pulmonary embolism, aortic dissection)
7 31
Maximum predicted heart rate
Peak heart
Abnormal heart-rate
rate
Chronotropic
recovery is present
when the heart rate
Chronotropic incompetence if
in the first minute
reserve <85% age
postexercise does
predicted in the
not decrease by
absence of beta-
≥12 bpm from peak
blocker therapy
heart rate (see text)
Resst heart rate
Exercise 1-min post
FIGURE 33.1. Example of chronotropic incompetence and abnor-
mal heart-rate recovery (see text).
the rapid changes in cardiac output and autonomic tone that
occur in the immediate postexercise phase.
An inappropriate increase in the heart rate with exercise
may be observed in patients with impaired left ventricular
dysfunction. Alternatively, this response may be observed in
patients who are physically deconditioned, hypovolemic,
anemic, or in atrial fibrillation. A blunted heart rate response
may be a sign of chronotropic incompetence, a variable asso-
ciated with an increased risk of cardiac events in higher
clinical risk patients (Fig. 33.1). Chronotropic incompetence
is usually defined by inability to achieve 85% of age-
predicted maximum in the absence of beta-blocker therapy.
Alternatively, chronotropic incompetence can be defined by
the percent of heart rate reserve achieved (peak heart rate—
rest heart rate)/220—age—rest heart rate). Values <80% are
considered abnormal.4 Occasionally, the heart-rate response
in the early postexercise phase, when vagal tone is usually
high, takes longer to decelerate. This form of abnormal heart-
rate recovery is defined by a heart rate that fails to decrease
by at least 12 beats per minute (bpm) in the first minute
postexertion using a 2-minute cool-down or by 18 bpm if the
exercise test is stopped abruptly. Abnormal heart-rate recov-
ery is associated with increased long-term mortality even
after adjustment for exercise-induced ST-segment depression,
angina, coronary disease extent, left ventricular dysfunction,
and Duke treadmill score (Fig. 33.2).5
Electrocardiographic Changes
During exercise, there are changes in virtually all compo-
nents of the ECG in normal subjects, including progressive
shortening of the PR and QT intervals. The amplitude of the
P wave increases and the amplitude of the T wave decreases
during exercise. There is also a progressive rightward shift
in the QRS axis. R-wave amplitude changes have also been
noted to occur during exercise. J-point depression may occur,
particularly in older subjects, but the ST segment is rapidly
up-sloping (Fig. 33.3). Myocardial ischemia most often mani-
fests itself as ST-segment shifts. To determine the magnitude
of ST-segment shift, the ST level should be measured relative
to the PR segment. The PQ junction is often chosen as the
point of reference (Fig. 33.4). The J point is then identified
and the ST segment level is measured 60 to 80 ms after the
J point, depending on heart rate (ST 60 is usually measured
at heart rates >130 to 140/min). When the baseline ST segment
732 chapter 33

1 Both normal Exercise

Rest
0.9
Severe CAD
0.8
Survival

Abnormal HR recovery
0.7
0.6 Both abnormal II II

0.5
0 1 2 3 4 5 6 7 8
Years after stress test
No. at risk
Both normal 18171802 1784 1666 1415 1170 868 706 475
Severe CAD 280 273 264 251 210 161 127 90 79
Abnl HR Rec 697 678 665 614 508 395 299 243 143 PQ junction
Both abnormal 141 129 125 117 84 51 49 40 29
FIGURE 33.2. Kaplan-Meier plot showing heart rate (HR) recovery
with severity of coronary artery disease (CAD) and the risk of death.
The abnormal HR was independent of gender, age, left ventricular
systolic function (LVSF), functional capacity, exercise-induced
angina, beta-blocker usage, and severity of CAD in determining J ST80
prognosis.
FIGURE 33.4. A 74-year-old man referred for evaluation of stable
angina. The rest ECG exhibits 0.9 mm ST-segment elevation (early
repolarization) (arrow). The exercise tracing shows J-point depres-
is depressed, an additional 0.1 mV (1 mm) of flat or down- sion of 3.2-mm ST depression and 2.5-mm ST-segment depression
(STD) at 80 ms after the J point (ST80). The PQ junction represents
sloping ST-segment depression is required to call the test
baseline. The test was stopped for angina at a heart rate of 135/min.
abnormal. The standard criteria for abnormal ST-segment This type of slow up-sloping STD (bottom panel) represents an
depression is horizontal or down-sloping ST-segment depres- ischemic response in symptomatic patients or individuals with
sion of 0.10 mV (1 mm) ≥60 to 80 ms after the J point in three an intermediate to high-risk pre-test risk.
consecutive beats (Fig. 33.5). A slow, upward sloping (>0.7 to

1 mV/s) ST segment depressed 0.15 or more at 80 ms after the

J point in three consecutive beats is also considered by some
Patient A Patient B to be a manifestation of exercise-induced myocardial isch-
emia (Fig. 33.4).
In most laboratories, the exercise ECG is printed out in
V4
a 3 × 4 format or 2.5 sec/3-lead group. To maximize the
V4 opportunity of meeting the above criteria, some laboratories
have adopted a strategy of recording a full 10 seconds of ECG
data with leads II, aVF, and V5 when the tracing starts to show
abnormal beats close to the ischemic threshold. A 10- as
opposed to a 2.5-second tracing increases the likelihood of
capturing consecutive abnormal beats with a stable baseline
(Fig. 33.6). It will require future study to determine if two
consecutive abnormal beats for the majority of beats in a
10-second study has the same diagnostic accuracy as three
V5 V5 consecutive beats in a 3 × 4 format. Coronary artery disease
severity is usually greatest in the presence of down-sloping
ST-segment depression, followed by horizontal ST-segment
depression and finally slow up-sloping ST-segment depres-
sion (Figs. 33.4 and 33.7). The magnitude of the ischemic
response is related to coronary disease severity and extent.
Patients with early onset of myocardial ischemia manifest
as typical angina or an ST-segment shift at low exercise
workloads with an “ischemic” pattern that persists late into
V6 the recovery phase, and they have an increased risk of multi-
V6
vessel disease and future cardiac events.
FIGURE 33.3. Examples of two different patients with normal exer- ST-segment elevation may also indicate myocardial isch-
cise electrocardiograms at peak exercise heart rates of 175 to emia. Exercise-induced ST-segment elevation ≥1 mm occur-
180 bpm. Patient A has no J-point or ST-segment shift. Patient B has ring in a noninfarct territory usually indicates transmural
J-point depression of 1.6, 1.4, and 0.7 mm in leads V4, V5, and V6; the
ST segment is rapidly up-sloping in patient B, depressed <0.5 mm at
ischemia and is associated with severe proximal coronary
60 ms after the J-point. Both tracings are normal responses to exer- disease or coronary vasospasm. In this situation, the local-
cise. J-point depression is more common in older individuals. ization of the ST-segment elevation is relatively specific for
 e x ercise t est i ng 733

Lead V5

Rest

2:30 exercise

Peak exercise

FIGURE 33.5. A 58-year-old man with typical angina. The rest ECG is
normal. At 2 : 30 seconds of exercise at a heart rate of 125/min, the patient
manifests abnormal beats (star). At peak exercise, the ST segment is
down-sloping, depressed 1.5 mm 80 ms after the J-point. The ischemic
response persists at least 6 minutes in the postexercise phase. This type
of ischemic pattern in a symptomatic patient with ST segment depression 6-min post
appearing early during exercise, worsening as exercise progresses, associ-
ated with down-sloping ST segments that persist late into the recovery
phase is a high-risk study that normally warrants a cardiac catheteriza-
tion if there are no clinical contraindications.

the distribution of the coronary artery involved in contrast
to ST-segment depression, which does not help localize the
affected coronary arteries. ST-segment elevation ≥1 mm
during exercise in Q-wave leads from a prior myocardial
infarction (MI) is often associated with more extensive wall
motion abnormalities than patients without this finding; in
most patients, this type of pattern does not represent an
ischemic response (Fig. 33.8).
T-wave inversion, usually noted in the postexercise phase,
is not diagnostic of myocardial ischemia in the absence of

FIGURE 33.6. Example of a continuous ST80 0.4 1.7 1.8 0.8 1.0 0.8
lead V5 recording during exercise. Of the
six beats recorded with a relatively stable
baseline, three are abnormal (star) with
at least two consecutive beats that meet
criteria for abnormality (J-point and
ST80 ≥1 mm depressed). The remaining
beats show lesser degrees of ST segment
depression (0.4 and 0.8 mm ST80 depres-
sion) that do not meet criteria for abnor-
mality. This type of ECG pattern with at PR junction
least two consecutive abnormal beats
and at least 50% of all beats recorded
abnormal should be considered an abnor-
mal test in a patient that is at intermedi-
ate to high pretest clinical risk.
 Rest 3:00 Peak 4:00 Post
V1

V2

FIGURE 33.7. A 64-year-old man with

V3
chronic angina for 2 years is referred for
testing because of decreased exercise
tolerance over the past several months.
The rest ECG is normal. The exercise
V4 ECG is abnormal in leads V3 to V6 after
3 : 00 with slight worsening of the ST-
segment changes at peak. The ischemic
abnormality persists 4 : 00 postexercise
V5 with down-sloping ST-segment depres-
sion. This classic ischemic response to
exercise represents a high-risk study
manifest by early onset of ischemic
ECG changes involving five or more
V6
leads, persisting late into the recovery
phase associated with ST segment
depression ≥2 mm.

Rest Exercise

V1 V1

V2 V2

V3 V3

J J

FIGURE 33.8. A 46-year-old woman status post–anteroseptal myocar-

dial infarction and percutaneous coronary intervention (PCI) 4 days prior
to testing. The rest ECG exhibits QS complexes in V1 to V3 with J-point
elevation of 1.4 mm that becomes 2.5 mm at 80 ms after the J-point. The
postexercise tracing (magnified) shows J-point elevation of 2.5 mm that
becomes 3.5 mm at 80 ms after the J-point. Exercise-induced ST segment
elevation in an infarct territory with QS complexes indicates a more
extensive wall motion abnormality and decreased ejection fraction com-
pared to postinfarct patients without this finding. This type of abnormal-
ity does not generally indicate an ischemic response.
 e x ercise t est i ng
ST-segment depression criteria. The same is true for pseudo-
normalization of T waves (i.e., inverted T waves that become
upright with exercise).
Exercise Testing in the Diagnosis of Coronary
Artery Disease
Figure 33.9 illustrates how the sensitivity, specificity, and
predictive accuracy of a noninvasive test can be determined.
Sensitivity is decreased by false-negative results and specific-
ity is decreased by false-positive results. In general, the sen-
sitivity and specificity of a test are not influenced by the
pretest likelihood of disease. However, the predictive accu-
racy of a test is highly dependent on the pretest estimate of
disease according to bayesian theory.1
In a meta-analysis of published trials of patients undergo-
ing exercise testing and coronary arteriography, the mean
sensitivity and specificity for the diagnosis of obstructive
CAD ≥70% were 68% and 77%, respectively, and for three-
vessel or left main coronary disease ≥70% were 86% and
53%.6 The sensitivity to detect obstructive CAD with exer-
cise testing is increased when the coronary artery narrowing
is more severe (e.g., stenosis ≥70% vs. 50%) and when CAD
is more extensive (three-vessel vs. one-vessel disease). The
sensitivity for obstructive single-vessel right or left circum-
flex is approximately 50% even when the heart rate achieved
is ≥85% of age-predicted maximum. Thus, a patient should
never be told he or she does not have obstructive coronary
disease on the basis of a normal exercise electrocardiogram
and normal exercise capacity. The sensitivity of the test is
decreased when the level of exercise performed is submaxi-
mal, a limited lead set is used, or the ECG is abnormal with
findings that reduce the potential to detect ST-segment
depression (i.e., extensive anterior Q-wave MI). Most pub-
lished studies comparing noninvasive testing to coronary
angiography suffer from posttest referral bias that increases
Test Coronary disease
result
+ –
+ TP FP All + tests
– FN TN All – tests
CAD No CAD All tests
FIGURE 33.9. Sensitivity = TP/CAD; specificity = TN/no CAD;
predictive accuracy of a positive test = −TP/all + tests; predictive
accuracy of a negative test = TN/all − tests; efficiency = (TP + TN)/all
tests. FN, false negative; FP, false positive; TN, true negative; TP,
true positive.
735
Rest Exercise
II
FIGURE 33.10. A 63-year-old woman with left ventricular hyper-
trophy (LVH) and QRS duration of 98 ms (rest) developed a rate-
related left bundle branch block (LBBB) at a heart rate of 88/min that
persisted throughout the exercise test. The ST depression observed
(arrow) during the LBBB is nondiagnostic in the presence of the
conduction disturbance.
sensitivity and decreases specificity since patients with a
negative test tend not to be referred for catheterization,
whereas patients with an abnormal test are referred for
catheterization. When studies that avoid workup bias are
examined, the sensitivity and specificity of horizontal or
down-sloping ST-segment depression ≥0.1 mV for obstructive
CAD ≥70% is 50% and 90%, respectively.7,8
There are several situations in which the specificity of
the exercise test to exclude CAD is reduced. Patients with
left bundle branch block (Fig. 33.10), rest ST-segment depres-
sion ≥1 mm, Wolff-Parkinson-White syndrome (Fig. 33.11), or
left ventricular hypertrophy, or patients on digitalis therapy
may have changes with exercise that are nondiagnostic for
CAD; in this clinical setting it is best to perform the test in
conjunction with an imaging procedure (i.e., nuclear or echo-
cardiographic). During exercise, patients with right bundle
branch block may manifest exercise-induced ST-segment
depression in leads V1 to V4, a nonspecific finding for CAD
(Fig. 33.12). Other causes of a false-positive test include severe
Rest Exercise
I
V3
FIGURE 33.11. This 42-year-old man was referred for atypical chest
pain. The rest ECG shows a preexcitation pattern with a short PR
interval and delta wave (arrow). The exercise tracing shows persis-
tence of the delta wave and exercise-induced down-sloping ST
segment depression of 0.9 mm in lead I (arrow) and horizontal ST
segment depression of 1.9 mm in lead V3 (arrow). Exercise-induced
ST segment depression is a nondiagnostic finding for coronary
artery disease in patients with preexcitation syndrome.
736 chapter
Rest Exercise
V1
V1
V2 V2
V3 V3
FIGURE 33.12. A 62-year-old man referred for atypical chest pain
3 years after a coronary bypass procedure. The rest ECG exhibits
right bundle branch block (RBBB). In lead V2 at rest, the J point and
ST80 are depressed 0.8 mm and 1.3 mm. The postexercise tracing in
lead V2 shows 2.3- and 3.1-mm depression, respectively. Leads V1
and V3 are also more depressed than at rest. Exercise-induced ST
segment depression in leads V1 to V4 is a nonspecific finding in
patients with RBBB.
anemia, hypoxia, and hypokalemia. Mitral valve prolapse is
associated with an increased incidence of false positives,
particularly when the prolapse is moderate-severe. Women
have a higher incidence of exercise-induced ST-segment
changes than men, and in low-risk women the presence of
exercise-induced ST-segment depression is often a false-
positive finding for CAD. When the diagnosis of CAD is in
doubt, imaging studies should be considered. A negative ECG
test in a woman with excellent exercise capacity carries
similar diagnostic information as in men.
The posttest likelihood of CAD in a patient should be
estimated from the data obtained from the exercise test and
the pretest likelihood of CAD. Since the sensitivity and
specificity of exercise electrocardiography are less than
100%, false-positive tests are more likely in patients with a
low pretest likelihood of CAD such as young asymptomatic
women without atherosclerotic risk factors than in older
men with typical angina. The posttest likelihood of CAD is
increased in subjects with more abnormal exercise test
results (≥0.2 mV ST-segment depression at low exercise work-
loads vs. a borderline abnormal ECG at high exercise work-
loads). Similarly, false-negative results are more common
when the pretest likelihood of CAD is high. These bayesian
principles should be used to estimate posttest likelihood of
CAD and should also be applied when risk-stratifying patients
for future cardiac event rates using the exercise test.
33
Prognostic Use of Exercise Testing
Electrocardiography
A major indication for exercise testing is to estimate the
prognosis and determine the need for subsequent workup
that may include cardiac catheterization and coronary revas-
cularization. If the posttest likelihood of a cardiac event,
estimated using clinical and exercise test variables, cannot
be reduced by a coronary revascularization procedure (e.g.,
estimated 5-year risk of a cardiac event after exercise testing
<0.8%/year), then there is little need to proceed further. Exer-
cise test variables associated with an increased likelihood of
multivessel disease and future cardiac events include early
onset of ischemia (Figs. 33.5 and 33.7), angina, or complex
ventricular arrhythmias at low exercise workloads, inability
to complete low levels of work [i.e., functional capacity <5
metabolic equivalents (METs)], extensive and profound exer-
cise-induced ST-segment abnormalities, hemodynamic insta-
bility such as a drop in systolic blood pressure during exercise,
abnormal heart rate response (Fig. 33.1), and persistence of
ischemic changes late into the recovery phase (Fig. 33.7;
Table 33.3).
Functional capacity is one of the most important prog-
nostic exercise test variables since it provides a global esti-
mate of cardiac and pulmonary reserve. Patients who have
onset of ST-segment depression at high exercise workloads
(e.g., >10 METs) have a favorable prognosis regardless of
whether or not abnormal ST segment depression is present.2
Myers et al.9 reported a 12% increase in survival for every 1-
MET increment in exercise capacity in a 6213-patient cohort
followed for a mean of 6 years (Fig. 33.13).9 The risk gradient
for future cardiac events is greatest in individuals who
cannot perform exercise, followed by those who are unable
to complete the exercise protocol. The lower the exercise
capacity, estimated in METS, the greater the risk. Patients
with exercise-induced ischemia or hemodynamic compro-
mise (e.g., hypotension) at low workloads (i.e., <5 METS)
should be referred for cardiac catheterization and revascular-
ization if there are no clinical contraindications. The likeli-
hood of angiographic high-risk anatomy is high, and if
present, would be an indication for coronary revasculariza-
tion regardless of symptomatic status.
Exercise testing should never be categorized as positive
or negative based solely on the ST-segment response. The
entire variable set that includes final exercise capacity,
hemodynamic and heart rate responses, symptoms, and
workload at which symptoms or the ischemic response
become manifest are critical in order to provide the best
prognostic estimates possible. Mark and colleagues10 devised
a treadmill score and applied it to 2842 symptomatic inpa-
tients who were being evaluated by treadmill exercise testing
and cardiac catheterization. The treadmill score was calcu-
lated on the basis of the duration of exercise, the amount of
maximal electrocardiographic depression, and the presence
or absence of angina occurring during exercise. The authors
found that the treadmill score was a better discriminator
than clinical assessment alone and appeared to better distin-
guish patients who subsequently died from those who lived.
Approximately one third of patients had scores indicating
low risk (≥+7) with a 93% 5-year survival rate (i.e., annual
 e x ercise t est i ng 7 37

A Normal Subjects C Subjects with Cardiovascular Disease

100 100
>8 MET
75

Percentage Surviving

Percentage Surviving
75
5–8 MET >8 MET
50
<5 MET 50 5–8 MET
<5 MET
25
25
0
0 3.5 7.0 10.5 14.0 0
0 3.5 7.0 10.5 14.0
B Normal Subjects
100 D Subjects with Cardiovascular Disease
100
>100%
75

Percentage Surviving
75–100% 75

Percentage Surviving
50–74%
>100%
FIGURE 33.13. Survival curves for normal subjects 50 75–100%
stratified according to peak exercise capacity (A) and <50% 50 <50% 50–74%
according to the percentage of age-predicted exercise
capacity achieved (B) and survival curves for subjects 25
25
with cardiovascular disease stratified according to peak
exercise capacity (C) and according to the percentage of 0
age predicted exercise capacity achieved (D). These figures 0
0 3.5 7.0 10.5 14.0 0 3.5 7.0 10.5 14.0
show that the survival rate was lower for patients with Years of Follow-up
decreased exercise capacity. Years of Follow-up

mortality rate of 1.4%). High-risk scores (≤–11) occurred in
13% of patients; the mortality rate in this group was three
times greater, with a 67% 5-year survival rate (i.e., annual
mortality rate of approximately 7%).
The Duke treadmill score (DTS) has been extensively
validated and was tested in 613 outpatients by the Duke
group.11 It does not perform as well in elderly individuals
(≥75 years) as compared to patients <75 years.12 The DTS
was compiled in a younger patient population and the
elderly are known to have decreased exercise capacity com-
pared to younger individuals. The DTS-predicted cardiac
event rates for low-, intermediate-, and high-risk women are
less than those observed in men.13 Similarly, women tend
to have a lower exercise capacity than men, and middle-aged
women in general tend to have less extensive coronary
disease than men. Thus, it is apparent that the use of clini-
cal and exercise multivariate risk scores to estimate prog-
nosis is highly dependent on the population from which the
data are derived. Other scoring techniques developed in
populations different from those in which the original DTS
was derived, such as the score developed by Morise and col-
leagues,14,15 perform better than the DTS (Fig. 33.14). Pretest

Pretest score
1.00
Low
Survival

Intermediate-High
0.95

Log-Rand 46.12 p <.00001

0.90
0.0 1.0 2.0 3.0
Years

Exercise score Duke score

1.00 1.00
Low Low
Survival
Survival

0.95 Intermediate-High
0.95
Intermediate-High

Log-Rand 81.50 p <.00001 Log-Rank 20.62 p <.00001

0.90 0.90
FIGURE 33.14. Three Kaplan-Meier survival plots for
0.0 1.0 2.0 3.0 0.0 1.0 2.0 3.0
low- and intermediate-high risk groups using pretest,
exercise, and Duke treadmill scores. Years Years
738 chapter
and exercise test scores performed better than the Duke
treadmill score in stratifying women with a low prevalence
for coronary artery disease.14,15 However, in the final analy-
sis, exercise scores just like the ST-segment response are
imperfect, and clinicians should use all the clinical and
exercise test variables to estimate prognostic risk and base
their future management strategies on the totality of evi-
dence. It is clear that exercise scores do provide significantly
more information that just a single variable such as an ST-
segment shift.16
In patients with compensated heart failure, cardiopulmo-
nary exercise testing is effective in estimating mortality
risk. In eligible patients that reach anaerobic threshold and
have a peak volume of oxygen consumption (VO2) >14 mL
O2/min/kg, the survival rate may not be improved with
cardiac transplantation, whereas survival rates in patients
with a peak VO2 <14 mL/min/kg, or <50% of predicted VO2
are sufficiently low that cardiac transplantation should be
considered.17,18 Heart failure patients who improve over time
and have improved cardiopulmonary performance are often
removed from the transplant list. In one series of 508 patients
with heart failure, the predictive value of exercise gas
exchange parameters was attenuated with carvedilol
therapy.19 Exercise testing is not very useful after cardiac
transplantation to evaluate patients for rejection or coronary
vasculopathy.20 Dobutamine echocardiography is a more sen-
sitive test for this purpose.21
Asymptomatic Subjects
Exercise testing is not recommended as a diagnostic test to
screen the general population for CAD. However, in certain
circumstances, exercise testing may provide useful prognos-
tic information in asymptomatic subjects with a relatively
high pretest risk of coronary disease.22 In 25,927 apparently
healthy men evaluated at the Cooper clinic, 10-year survival
was 94% in subjects with atherosclerotic risk factors and an
abnormal exercise test compared to 99% in subjects without
risk factors and a normal test.23 Balady et al.24 evaluated 3043
offspring from the Framingham Heart Study (average age 43
years), and reported that in the highest Framingham risk
group of men (10-year predicted cardiovascular event risk
≥20%), failure to reach target heart rate and exercise-induced
ST depression both doubled the risk of an event; each MET
increment in exercise capacity reduced risk by 13% during
an 18-year follow-up. The use of the Framingham risk score
to establish a pretest likelihood of future cardiac events and
subsequent selection of intermediate- or higher risk individ-
uals for noninvasive testing using the exercise electrocardio-
gram or in some cases coronary artery calcification to provide
incremental prognostic information is well established.25 In
5721 asymptomatic women followed an average of 8.4 years
(mean age 52 years), mortality increased 9% for each unit
increase in Framingham risk score and decreased 17% for
each 1-MET increase in exercise capacity (Fig. 33.15).26 In a
different series of 2994 asymptomatic women with lower
Framingham risk scores, exercise capacity, abnormal heart-
rate recovery, and chronotropic incompetence were indepen-
dent predictors of cardiovascular mortality; exercise-induced
ST-segment depression did not predict mortality.27 Thus, in
asymptomatic men and women with moderate to high pretest
33
Hazards Ratio of Death
2.1
4 (2.1-4.8)
1.9
3 (1.3-2.9)
1.0
2.0
2 1.6
(1.3-3.2)
(1.1-2.4)
1.0
1
0
<5 MET 5–8 MET >8 MET
Adjusted for Age
Exercise Capacity Categories
Adjusted for
Framingham Risk Score
FIGURE 33.15. Hazards ratios of all-cause death when adjusted for
age (white bars) and Framingham risk score (FRS) (gray bars) for each
of the exercise capacity categories (in MET) <5, 5 to 8, and >8. The
highest exercise capacity category (>8 MET) was the reference cate-
gory. Hazards ratios are listed within the bars; 95% confidence
intervals (CIs) are shown.
clinical risk scores for future cardiac events such as death,
MI, or stroke (e.g., 1% to 3%/year), exercise testing may be a
useful procedure to further stratify prognostic risk.
Exercise Testing After Acute Coronary
Syndrome or to Risk Stratify in the
Emergency Department
Exercise testing after MI is widely practiced to risk-stratify
patients, assess therapy, evaluate functional capacity, and
determine home and work activity recommendations. In
many patients, reperfusion therapy is established early with
angioplasty to the infarct-related vessel, and uncomplicated
patients may be discharged 3 to 4 days after the index
event.28–31 In this setting, exercise testing is usually per-
formed 2 to 3 weeks or 3 to 6 weeks after discharge to estab-
lish recommendations for leisure or work physical activities.
In patients who are ineligible for the former strategy or
receive thrombolytic therapy only, submaximal exercise
testing before hospital discharge is useful to assess func-
tional capacity, determine residual ischemia, and assess exer-
cise-induced arrhythmias that might warrant a predischarge
cardiac catheterization and revascularization.1
In low- to intermediate-risk patients with unstable
angina, exercise testing can help determine if a patient needs
hospital admission and triage to the cardiac care unit (CCU)
or a step-down monitored bed, or can be discharged from the
emergency room after appropriate workup (e.g., asymptom-
atic, negative biomarkers, normal exercise test).32
In the emergency department, exercise testing with or
without imaging procedures is used to risk stratify individu-
als with a low-intermediate pretest likelihood of coronary
disease, such as a younger individual with atypical chest
pain without significant risk factors and a normal rest ECG
who presents to the emergency department because of an
episode of chest pain that occurred the prior day. A normal
exercise test in this setting is associated with a very low risk
of cardiac events over the next few years.33
 e x ercise t est i ng 739

Other Uses of Exercise Testing Elderly Patients

Cardiac Arrhythmias
The prognostic significance of ventricular arrhythmias
during or after exercise testing is well established.34–36 In
general, the mortality is greatest in patients who have
complex ventricular ectopy at low exercise workloads, par-
ticularly postexercise, or who have ventricular tachycardia.
In a study of 2885 Framingham Offspring Heart participants,
exercise-induced premature ventricular beats were associ-
ated with a significant increased total mortality risk during
a mean follow-up of 15 years, although the risk for hard
cardiac events (i.e., cardiac death or MI) was not significant.
The all-cause mortality risk persisted after adjustment for
left ventricular function, ischemic ST-segment response, and
presence of recovery premature ventricular beats.37 Frolkis
et al.38 studied 29,244 patients (mean age 56 years) over a
mean 5.3 years and reported that frequent ventricular ectopy
during the recovery phase of exercise was a better predictor
of total mortality than ventricular ectopy occurring during
exercise. O’Neill et al.39 reported complex ventricular ectopy
appearing in the postexercise phase predicted increased mor-
tality (hazard ratio of 1.76) in 2123 patients with an ejection
fraction <35% (Fig. 33.16).39
Exercise-induced atrial arrhythmias do not predict
cardiac mortality or the need for coronary revascularization,
although there is an increased future risk of spontaneous
supraventricular tachyarrhythmias.40 Exercise testing is
indicated to adjust settings in rate-adaptive pacemakers and
can be helpful in evaluating the ability to increase ventricu-
lar rate in subjects with congenital heart block.
1 emia. The value of early exercise testing after coronary revas-
Nonsevere VEA in recovery
0.8
Survival
Exercise protocols should be tailored for the elderly popula-
tion. Abrupt changes in walking speed or grade are not as well
tolerated as in younger individuals and may not allow as
accurate an estimate of aerobic capacity as a more gradual
protocol. Older patients are more likely to have cardiac events
and an increased risk for all-cause mortality. Jeger et al.41
studied 292 patients >75 years of age with chronic angina
receiving two or more antianginal drugs who underwent
exercise testing and were followed for 1 year. The 1-year mor-
tality rate was 1.4% versus 5.3% and the death/MI rate was
2.8% versus 15.8% in patients with a normal versus abnormal
exercise test. Lai et al.42 studied 1872 men ≥65 years of age
and reported that the peak METs achieved was an important
predictor of all-cause mortality, and exercise-induced ST-
segment depression predicted cardiovascular mortality. In an
angiographic substudy from the same population, a treadmill
risk score was developed that provided more diagnostic infor-
mation than ST-segment depression alone.42 In a 7354 study,
patients >65 years reported by Messinger-Rapport et al.,43
impaired functional capacity and abnormal heart-rate recov-
ery were independent predictors of all-cause mortality.
Revascularization
An exercise ECG is often performed before revascularization
in stable patients with coronary disease to provide an objec-
tive evidence of functional capacity and to document
myocardial ischemia. The exercise ECG may be normal in
patients with single-vessel coronary disease, particularly
when the right or left circumflex coronary artery is the
culprit vessel. Exercise electrocardiography is of little value
in localizing the territory of myocardial ischemia unless ST-
segment elevation occurs. Therefore, stress testing is usually
performed in combination with a nuclear imaging procedure
to determine the location and severity of myocardial isch-
cularization was evaluated in 1678 patients enrolled in the
bypass angioplasty revascularization investigation (BARI)
trial, a National Institutes of Health (NIH)-funded study that

tested coronary artery bypass graft (CABG) versus percutane-

No VEA in recovery ous transluminal coronary angioplasty (PTCA).44 The sub-
0.6 jects had serial symptom limited treadmill tests performed
Severe VEA in recovery at 1, 3, and 5 years after revascularization. Routine exercise
Log-rank χ2 = 15, df = 2, p = .0005 electrocardiography performed early after the procedure was
0.4 not predictive of subsequent cardiac events. Nevertheless,
0 1 2 3 4 5 the exercise ECG after coronary revascularization can be
Years after stress test useful in evaluating selected patients with symptoms due to
Number at risk incomplete revascularization, graft closure, or restenosis, as
No. VEA 1833 1425 1108 813 569 366 well as to assess functional capacity in selected patients
Nonsevere referred for cardiac rehabilitation.45 In this setting, knowl-
150 120 89 64 54 37
edge of the pre-revascularization exercise ECG findings can
Severe 140 99 79 50 39 21
facilitate interpretation of the post-revascularization exer-
FIGURE 33.16. Of 2123 patients with left ventricular systolic ejec-
tion fraction ≤35% who underwent treadmill exercise, 140 (7%) had cise findings by allowing comparison of ischemic thresholds
severe ventricular ectopy during recovery. Severe ventricular and change in functional capacity (Fig. 33.17). There is a
ectopy was defined as the presence of ventricular triplets, sustained small but finite risk of stent thrombosis when exercise
or nonsustained ventricular tachycardia, ventricular flutter, testing is done post–percutaneous coronary intervention
polymorphic ventricular tachycardia, or ventricular fibrillation.
Severe ventricular ectopy during recovery was associated with an
(PCI). Clinical stent thrombosis or access site complications
increased risk of death (3-year death rates 37% vs. 22%, Hazard ratio were not increased in a 1000-patient series randomized to an
1.76). exercise test versus no test 1 day after PCI.46
74 0 chapter 33

Exercise capacity Duke score between 35% and 80%. Values <40% are pathologically
reduced and indicate circulatory insufficiency. The breathing
100% 100%
Stage 3 reserve capacity of the ventilatory system is calculated as 1
–5 to 2
Percent survival

minus the ratio of peak exercise minute ventilation (VE) to

90% 90%
<Stage 3
80% 80%
Stage 3
70%
<Stage 3
70%
A B
60% 60%
0 1 2 3 4 5 6 0 1 2
Years from exercise test Years from exercise test
FIGURE 33.17. Survival curves 6 years after exercise test based on
ability to exercise to Bruce stage 3 (A) and the Duke scores (B).
Though both were used as prognostic indicators, exercise capacity
to Bruce stage 3 was an independent predictor of improved survival
for patients after revascularization.
Valvular Heart Disease
As a general rule, exercise testing should not be performed
in patients with severe aortic stenosis. However, in certain
circumstances, it may be of value combined with echocar-
diographic imaging to assess rest-exercise gradients and
provide an objective assessment of functional capacity in
patients with relatively high peak Doppler aortic valve gra-
dients. Exercise testing is contraindicated in patients with
severe aortic stenosis when the indication for surgical repair
is obvious. Testing should be carried out only by a physician
familiar with the patient, and the test should be terminated
if there is an inappropriate increase or decrease in blood pres-
sure, heart rate, or the development of cardiac arrhythmias
or symptoms such as angina or excessive dyspnea. Exercise
testing is also helpful to determine functional capacity in
patients with other forms of valvular heart disease such as
mitral stenosis or insufficiency (see Appendix).
maximal voluntary ventilation with normal values >30%.
≥3
≤–6 Lower values indicate ventilatory impairment, especially
when accompanied by oxygen desaturation. The respiratory
≥3
exchange ratio (Vco2/Vo2) is generally >1.2. Values <1.1,
–5 to 2 particularly <1.0 in the absence of other metabolic abnor-
≤–6 malities, suggest poor effort, anxiety, or mild disease. Car-
diopulmonary exercise testing of cardiac and pulmonary
3 4 5 6 response to exercise can be useful in clarifying the etiology
of a patient’s symptoms (Fig. 33.18).
Exercise Test Reporting
The exercise test report should include the indications that
prompted the test, a list of cardioactive medications that may
influence functional capacity or ECG response, and the exer-
cise protocol used. The report should list the reasons for
stopping exercise, the peak exercise capacity in minutes and
METs, the rest and peak heart rate and blood pressure, the
percent maximum heart rate achieved, and a description of
any abnormalities seen on the exercise ECG tracing. When
myocardial ischemia or angina occurs, the time of onset and
offset should be reported. Cardiac arrhythmias (simple or
complex) that occur during or after exercise should be noted.
It is often useful to standardize the report output to referring
physicians by designing a statement databank that remains
uniform over time. Statements such as “submaximal test, no
significant abnormalities noted at the workload performed”
to indicate that cardiac reserve may not have been fully
tested, or “high risk study, with exercise-induced angina and
ST-segment changes at low exercise workloads” to prompt
additional workup, or “excellent exercise capacity with
minor exercise-induced ST-segment changes that do not
meet diagnostic criteria for myocardial ischemia” to indicate
a lower risk study can facilitate patient management.

Cardiopulmonary Exercise Testing

Gas exchange data can provide important information to Peak VO2
evaluate functional capacity and distinguish cardiovascular
from pulmonary limitations during exercise.47 Testing Normal Low
involves measurements of respiratory oxygen uptake (Vo2), ≥85% predicted <85% predicted
carbon dioxide production (Vco2), and ventilatory parameters
during a symptom-limited exercise test. The relationship Mild Anaerobic threshold
Anxiety Obesity
between work output, oxygen consumption, heart rate, and disease
cardiac output during exercise is linear. Peak exercise capac- Normal Low
≥40% predicted <40% predicted
ity is decreased when the ratio of measured to predicted PkVO2 PkVO2
Vo2max is <85% to 90% for age and gender. Measured Vo2 in
mL/min/kg divided by 3.5 mL O2·kg−1·min−1 determines the Breathing Breathing
number of METs associated with activity. Work and leisure reserve reserve
activities can be calculated in multiples of METs; the in- Normal Low Normal Low
formation obtained can then be used to prescribe physical ≥30% <30% ≥30% <30%
activities or estimate disability.
The gas exchange anaerobic threshold is the point at Poor Deconditioning Coronary Ventilatory Circulatory Mixed
which Ve increases disproportionately relative to Vo2 and effort disease impairment impairment lesions
work; it usually occurs at 40% to 60% of Vo2max in normal, FIGURE 33.18. Gas exchange parameters can be used to help
untrained individuals with a wide range of normal values resolve cardiac vs. pulmonary causes of dyspnea (see text).
 e x ercise t est i ng
Summary
Exercise testing is a procedure associated with a very low
risk of complications that provides important diagnostic,
prognostic, and functional information for the evaluation of
patients with suspect or proven cardiac disease. When exer-
cise testing is used to establish a diagnosis of coronary
disease, the clinician should be aware that the diagnostic
accuracy of the test is imperfect and dependent on the pretest
risk of disease. Patients with excellent exercise capacity and
a normal electrocardiogram can be reassured that their prog-
nosis is favorable, but they should never be told they do not
have coronary disease on the basis of a normal test. Exercise
test variables associated with an adverse long-term prognosis
include typical angina or ischemic ECG changes, complex
ventricular arrhythmias at low exercise workloads (e.g., <5
METs), inability to increase heart rate or systolic blood pres-
sure with progressive workloads, a fall in blood pressure
during exercise, and abnormal heart-rate recovery. Exercise-
induced ischemic responses at a low workload are usually
considered an indication for cardiac catheterization and
coronary revascularization in the absence of a clinical con-
traindication. Functional capacity is one of the most impor-
tant variables used to estimate prognosis and provides an
objective measure of cardiopulmonary and musculoskeletal
reserve. Peak aerobic capacity is used for disability evalua-
tion, activity recommendations after a cardiac event, and
calibration of rate-related cardiac pacemakers. Cardiopulmo-
nary testing with gas exchange measurements should be
considered in patients with dyspnea where the etiology of
the symptoms (i.e., cardiac or pulmonary) is in doubt. Exer-
cise testing should be combined with an imaging procedure
if the rest ECG contains abnormalities that preclude assess-
ment of the exercise tracing, or if there are clinical indica-
tions that require the location(s) of the ischemic territory be
defined.
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after coronary bypass graft surgery in coronary artery disease
patients: results from the prognosis and evaluation of risk in
the coronary operated patient (PERISCOP) study. Eur Heart J
2003;24:916–926.
46. Roffi M, Wenaweser P, Windecker S, et al. Early exercise after
coronary stenting is safe. J Am Coll Cardiol 2003;42:1569–
1573.
47. Weisman IM, Marciniuk D, Martinez FJ, et al. ATS/ACCP
statement on cardiopulmonary exercise testing. Am J Respir
Crit Care Med 2003;167:211–277.
Appendix 33.1
I. The American College of Cardiology/American Heart
Association (ACC/AHA) classifications I, II, and III are
used to summarize indications as follows:
Class I: Conditions for which there is evidence and/or
general agreement that a given procedure or
treatment is useful and effective.
Class II: Conditions for which there is conflicting
evidence and/or a divergence of opinion about
the usefulness/efficacy of a procedure or
treatment.
Class IIa: Weight of evidence/opinion is in favor of
usefulness/efficacy.
Class IIb: Usefulness/efficacy is less well established by
evidence/opinion.
Class III: Conditions for which there is evidence and/or
general agreement that the procedure/treat-
ment is not useful/effective and in some cases
may be harmful.
II. Exercise testing to diagnose obstructive coronary artery
disease
Class I: Adult patients (including those with complete
right bundle-branch block or less than 1 mm or
resting ST depression) with an intermediate
pretest probability of CAD on the basis of
gender, age, and symptoms (specific exceptions
are noted under classes II and III below).
Class IIa: Patients with vasospastic angina.
Class IIb: 1. Patients with a high pretest probability of
CAD by age, symptoms, and gender.
2. Patients with a low pretest probability of
CAD by age, symptoms, and gender.
3. Patients with <1 mm of baseline ST depres-
sion and taking digoxin.
4. Patients with electrocardiographic criteria
for left ventricular hypertrophy (LVH) and
<1 mm of baseline ST depression.
Class III: 1. Patients with the following baseline ECG
abnormalities:
• Preexcitation (Wolff-Parkinson-White)
syndrome
• Electronically paced ventricular rhythm
 e x ercise t est i ng 74 3
• >1 mm of resting ST depression not done (symptoms limited; about 14 to
• Complete left bundle branch block 21 days).*
2. Patients with a documented myocardial 3. Late after discharge for prognostic assess-
infarction or prior coronary angiography ment, activity prescription, evaluation of
demonstrating significant disease have an medical therapy, and cardiac rehabilita-
established diagnosis of CAD; however, tion if the early exercise test was submaxi-
ischemia and risk can be determined by mal (symptom limited; about 3 to 6
testing (see sections III and IV). weeks).*
Class IIa: After discharge for activity counseling and/or
III. Risk assessment and prognosis in patients with symp-
exercise training as part of cardiac rehabilita-
toms or a prior history of CAD
tion in patients who have undergone coronary
Class I: 1. Patients undergoing initial evaluation
revascularization.
with suspected or known CAD, including
Class IIb: 1. Patients with the following ECG
those with complete right bundle-branch
abnormalities:
block or <1 mm of resting ST depression.
• Complete left bundle-branch block
Specific exceptions are noted below in
• Pre-excitation syndrome
class IIb.
• LVH
2. Patients with suspected or known CAD,
• Digoxin therapy
previously evaluated, now presenting with
• >1 mm of resting ST-segment depression
significant change in clinical status.
• Electronically paced ventricular rhythm
3. Low-risk unstable angina patients 8 to 12
2. Periodic monitoring in patients who con-
hours after presentation who have been
tinue to participate in exercise training or
free of active ischemic or heart failure
cardiac rehabilitation.
symptoms (level of evidence: B).
Class III: 1. Severe comorbidity likely to limit life
4. Intermediate-risk unstable angina patients
expectancy and/or candidacy for
203 days after presentation who have been
revascularization.
free of active ischemic or heart failure
2. At any time to evaluate patients with
symptoms (level of evidence: B).
acute myocardial infarction who have
Class IIa: Intermediate-risk unstable angina patients
uncompensated congestive heart failure,
who have initial cardiac markers that are
cardiac arrhythmia, or noncardiac condi-
normal, a repeat ECG without significant
tions that severely limit their ability to
change, and cardiac markers 6 to 12 hours
exercise (level of evidence: C).
after the onset of symptoms that are normal
3. Before discharge to evaluate patients
and no other evidence of ischemia during
who have already been selected for, or
observation (level of evidence: B).
have undergone, cardiac catheterization.
Class IIb: 1. Patients with the following resting ECG
Although a stress test may be useful before
abnormalities:
or after catheterization to evaluate or
• Preexcitation (Wolff-Parkinson-White)
identify ischemia in the distribution of a
syndrome
coronary lesion of borderline severity,
• Electronically paced ventricular rhythm
stress imaging tests are recommended
• 1 mm or more of resting ST depression
(level of evidence: C).
• Complete left bundle-branch block or
any interventricular conduction defect V. Exercise testing with ventilatory gas analysis
with a QRS duration >120 ms Class I: 1. Evaluation of exercise capacity and
2. Patients with a stable clinical course who response to therapy in patients with heart
undergo periodic monitoring to guide failure who are being considered for heart
treatment. transplantation.
Class III: 1. Patients with severe comorbidity likely to 2. Assistance in the differentiation of cardiac
limit life expectancy and/or candidacy for versus pulmonary limitations as a cause of
revascularization. exercise-induced dyspnea or impaired exer-
2. High-risk unstable angina patients (level cise capacity when the cause is uncertain.
of evidence: C). Class IIa: Evaluation of exercise capacity when indi-
cated for medical reasons in patients in whom
IV. After myocardial infarction
the estimates of exercise capacity from exer-
Class I: 1. Before discharge for prognostic assess-
cise test time or work rate are unreliable.
ment, activity prescription, evaluation of
Class IIb: 1. Evaluation of the patient’s response to spe-
medical therapy (submaximal at about 4
cific therapeutic interventions in which
to 6 days).*
improvement of exercise tolerance is an
2. Early after discharge for prognostic assess-
important goal or end point.
ment, activity prescription, evaluation of
medical therapy, and cardiac rehabilita-
tion if the predischarge exercise test was * Exceptions are noted under classes IIb and III.
74 4
2. Determination of the intensity for exer-
cise training as part of comprehensive
cardiac rehabilitation.
Class III: Routine use to evaluate exercise capacity.
VI. Special groups: women, asymptomatic individuals, and
postrevascularization patients
Exercise testing in asymptomatic persons without known
CAD:
Class I: None
Class IIa: Evaluation of asymptomatic persons with
diabetes mellitus who plan to start vigorous
exercise (level of evidence: C).
Class IIb: 1. Evaluation of persons with multiple
risk factors as a guide to risk-reduction
therapy.**
2. Evaluation of asymptomatic men older
than 45 years and women older than 55
years:
• Who plan to start vigorous exercise
(especially if sedentary) or
• Who are involved in occupations in
which impairment might affect public
safety or who are at high risk for CAD
due to other diseases (e.g., peripheral
vascular disease and chronic renal
failure).
Class III: Routine screening of asymptomatic men or
women.
Valvular Heart Disease
Class I: In chronic aortic regurgitation, assessment
of functional capacity and symptomatic
responses in patients with a history of equivo-
cal symptoms.
Class IIa: 1. In chronic aortic regurgitation, evaluation
of symptoms and functional capacity
before participation in athletic activities.
2. In chronic aortic regurgitation, prognostic
assessment before aortic valve replace-
ment in asymptomatic or minimally
symptomatic patients with left ventricu-
lar dysfunction.
Class IIb: Evaluation of exercise capacity in patients
with valvular heart disease. Comprehensive
discussion is found in the ACC/AHA valvular
heart disease guidelines.
Class III: Diagnosis of CAD in patients with moderate
to severe valvular disease or with the follow-
ing baseline ECG abnormalities:
** Multiple risk factors are defined as hypercholesterolemia
(>240 mg/dL), hypertension (systolic blood pressure >140 mm Hg or
diastolic blood pressure >90 mm Hg), smoking, diabetes, and family
history of heart attack or sudden cardiac death in a first-degree rela-
tive younger than 60 years. An alternative approach might be to
select patients with a Framingham risk score consistent with at
least a moderate risk of serious cardiac events within 5 years.
chapter 33
• Preexcitation
• Electronically paced ventricular rhythm
• >1-mm ST depression
• Complete left bundle branch block
Exercise Testing Before and After Revascularization
Class I: 1. Demonstration of ischemia before
revascularization.
2. Evaluation of patients with recurrent
symptoms that suggest ischemia after
revascularization.
Class IIa: After discharge for activity counseling and/or
exercise training as part of cardiac rehabilita-
tion in patients who have undergone coronary
revascularization.
Class IIb: 1. Detection of restenosis in selected, high-
risk asymptomatic patients within the
first 12 months after percutaneous coro-
nary intervention (PCI).
2. Periodic monitoring of selected, high-risk
asymptomatic patients for restenosis, graft
occlusion, incomplete coronary revascu-
larization, or disease progression.
Class III: 1. Localization of ischemia for determining
the site of intervention.
2. Routine, periodic monitoring of asymp-
tomatic patients after percutaneous
coronary intervention (PCI) or coronary
artery bypass grafting without specific
indications.
Investigation of Heart Rhythm Disorders
Class I: 1. Identification of appropriate settings in
patients with rate-adaptive pacemakers.
2. Evaluation of congenital complete heart
block in patients considering increased
physical activity or participation in com-
petitive sports (level of evidence: C).
Class IIa: 1. Evaluation of patients with known or
suspected exercise-induced arrhythmias.
2. Evaluation of medical, surgical, or
ablative therapy in patients with exercise-
induced arrhythmias (including atrial
fibrillation).
Class IIb: 1. Investigation of isolated ventricular
ectopic beats in middle-aged patients
without other evidence of CAD.
2. Investigation of prolonged first-degree
atrioventricular block or type I second-
degree Wenckebach, left bundle branch
block, right bundle branch block, or iso-
lated ectopic beats in young patients con-
sidering participation in competitive
sports (level of evidence: C).
Class III: Routine investigation of isolated ectopic beats
in young patients.
 3 Coronary Angiography
4 Robert F. Wilson and Carl W. White
Technical Aspects of Coronary Angiography . . . . . . . . . 745
Complications of Coronary Angiography . . . . . . . . . . . . 758
Coronary Anatomy and Radiographic Evaluation . . . . . 762
Key Points
• Nonionic, low osmolar, and iso-osmolar contrast media
have substantially less deleterious effect on ventricular
function and should be used in patients with acute isch-
emic syndromes, heart failure, severe aortic stenosis, and
left main coronary artery disease.
• High-grade stenoses are often associated with a total
failure of vascular remodeling. Calculating percent ste-
noses is flawed, and on average, overestimates diameter
stenosis by 30% when compared to an angiographic
equivalent.
• In patients with multivessel coronary atherosclerosis and
isolated discrete stenoses varying in severity between
10% and 95% stenosis, measurements of the anatomic
stenosis severity were not correlated significantly with
the reactive hyperemic response.
• In patients, a fractional flow reserve (FFR) of >0.75 is
highly correlated with noninvasive tests of myocardial
ischemia.
• Deferral of an interventional procedure based on a
normal coronary flow reserve or an FFR greater than or
equal to 0.75 is associated with a lower clinical event rate
than if the procedure had been done as originally
planned.
The advent of selective coronary angiography almost five
decades ago revolutionized the clinical practice of cardiology
and since then has added immeasurably to our understand-
ing of coronary artery disease and its sequelae. Since its
inception in the 1950s, it has become one of the most
common invasive medical procedures. In 2004, coronary
angiography was performed in over 2 million patients
in more than 1500 catheterization laboratories in the
United States and in an estimated 4.5 million patients
worldwide.1,2
Coronary Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . 776
Nonatherosclerotic Coronary Artery Disease. . . . . . . . . 788
Technical Aspects of Coronary Angiography
Facility Requirements
Radiographic Imaging
Radiographic imaging of coronary arteries is demanding
because they are small and move quickly with contraction
of the heart. A radiographic imaging system can be divided
into an x-ray generator consisting of a high-voltage trans-
former and x-ray tube, and an imaging chain that is com-
posed of an image detector and a display (video). The general
schematic is shown in Figure 34.1.3–5
X-R AY GENERATION
The x-ray photons are generated by a vacuum tube that has
a stationary cathode and a rotating anode. A focal spot on
the anode is bombarded by electrons from the cathode,
exciting the anode to produce high-energy photons with X
radiation wavelengths (less than 1 Å). The energy of the elec-
trons, and hence the energy (or wavelength) of the generated
photons, is determined by the voltage potential between the
cathode and anode. A high tension, three-phase transformer
is used to generate the voltage potential, which normally
ranges between 50 and 100 kV. The number of available elec-
trons accelerated into the anode, and hence number of
photons produced, is controlled by the amount of current
(measured in mA) passed through a filament in the cathode.
In practice, about 350 to 1000 mA of current through the
cathode is needed to generate an x-ray beam adequate for
cineangiography.
Less than 1% of the electron energy delivered to the
anode results in x-ray photons that become part of the x-ray
beam leaving the tube. A large fraction of the delivered
energy is converted into photons, which are reabsorbed
74 5
74 6 chapter
Video camera
C-arm gantry
Collimator
Aluminum
screen
Collimator
FIGURE 34.1. Schematic of radiographic imaging system for cine-
angiography. The x-ray beam is generated by an x-ray tube (lower
right box). The beam passes through a collimator (lower left box),
where lead apertures form and limit the beam. On intersection with
the patient, most of the beam is reflected or absorbed. The remain-
ing photons pass through to the image intensifier (upper right box),
where they impact on a cesium iodide crystal (A). Photons from the
within the anode and heat. Rotation of the anode effectively
increases the surface area over which the heat generation can
be dispersed. The capacity of the x-ray tube to dissipate heat
is of considerable practical importance to angiographic labo-
ratories because tubes with a low heat capacity limit the rate
at which angiographic pictures can be taken during the
procedure.
The sharpness of the image cast onto the imaging device
is affected by the size of the focal spot on the anode (the area
of the anode bombarded with electrons). The smaller the
focal spot, the crisper the shadow the x-ray beam can cast.
Conversely, however, fewer photons can be generated from
small focal spots. For thinner adults and shallow radiographic
angles, a focal spot of 0.6 to 0.7 mm provides good resolution
with an adequate number of photons to create a good image,
but focal spots of 1.0 to 1.2 mm may be needed for larger
patients and extreme angulation.
All x-ray tube anodes are beveled (Fig. 34.1). Less acute
bevels on the rotating anode reduce the focal spot and beam
angle and refine the x-ray beam because more lower energy
photons are absorbed within the anode. As the anode angle
is reduced, however, the amount of heat generated increases.
In practice, modern x-ray tubes for coronary angiography
have an anode angle of 8 to 10 degrees.
Within the emitted x-ray beam, the photons vary from
lower energy “soft” radiation to higher energy “hard” radia-
tion. By increasing the voltage potential (kilovolt, kV)
between the cathode and anode, a “harder,” higher energy
spectra is produced. This leads to increased radiographic pen-
etration and contrast. Good imaging also requires enough
34
H G
Cine camera F
E
D
Image intensifier
C
B
A
Cathode
X-ray tube
Anode
crystal cause electron emission from the photocathode (B). The
electrons are accelerated (C) and focused on a phosphor screen (D).
The image on the screen is split optically (F) and imaged with a
video pickup device (G) or 35mm cine film (H). A photo detector (E)
measures the photon output from the central zone of the phosphor
image and provides feedback to adjust the x-ray dose and iris
settings.
photons, or quantum, to create the image. An insufficient
number of photons reaching the imaging device leads to a
grainy image appearance (termed quantum mottling).
IMAGE DETECTION
After photon emission from the x-ray tube, the beam passes
through a filter to eliminate low-energy photons and through
a collimator, a series of lead apertures that form and limit
the beam directed at the patient. On interfacing with the
patient, some photons are absorbed, some are reflected (scatter
radiation), and some pass through entirely, reaching the
image detector. A grid over the image intensifier helps screen
out scatter radiation by passing only photons that are
relatively perpendicular to the image detector face and by
screening out low-energy x-rays.
On impact with the cesium iodide crystal on the face of
the image intensifier, the x-ray photons are absorbed and
cause the emission of lower energy photons. In older systems,
these photons are absorbed by a photocathode coating the
inner surface of the crystal and cause electron emission from
the photocathode. The electrons are accelerated and focused
onto a phosphor screen, where they liberate photons in the
visible light range. The light from the phosphor screen of the
image intensifier is picked up on a television camera and
displayed as a fluoroscopic video image, or recorded onto
cineangiographic film (usually 35 mm). In modern “flat
panel” detectors, charge couple devices (CCDs) absorb the
electron and create a digital image.
The dimension of the image intensifier determines the
size of the field that can be imaged. Most image intensifiers
 corona ry a ngiogr a ph y
are bi- or trimodal, such that several field sizes can be imaged
from one large detector, allowing image magnification. In
the older image intensifiers, the entire cesium iodide crystal
face can be focused onto the phosphor screen or a smaller
portion can be imaged, ignoring photons from the periphery
of the crystal. Focusing on a smaller part of the input crystal
face increases the magnification of the image on the phos-
phor screen but decreases the signal intensity (fewer elec-
trons are focused onto the same size phosphor screen). This
is compensated for by increasing the x-ray dose, which
increases the number of x-ray photons and hence the number
of electrons emitted per area of the central crystal. The
increase in x-ray dose to the patient is mitigated by the
smaller field of radiation. Larger field sizes (9 to 11 inches)
are needed for ventriculography, and smaller sizes (4 to 5
inches) may be required for pediatric angiography. For coro-
nary angiography, the optimum size of image intensifier is 5
to 7 inches (13 to 18 cm).
In flat-panel detectors, magnification of the image is
accomplished digitally by restricting image acquisition to a
smaller portion of the CCD pickup. Since pixel density
(pixels per square centimeter on the CCD chip), the number
of pixels is smaller in a magnified image. Unlike the older
image intensifier design, image acquisition resolution is the
same for unmagnified and magnified images obtained on a
digital flat panel detector. Radiation exposure, however, is
reduced because the field of radiation is limited to the portion
of the detector used for the imaging.
Modern imaging equipment optimizes x-ray generation
by way of a feedback loop with the imaging chain. By mea-
suring the brightness of the center of the phosphor image of
the intensifier, the amount and energy of photons emitted
from the x-ray tube can be varied to obtain optimal image
brightness. Automatic brightness control systems adjust for
the radiodensity of the patient by varying kV and mA deliv-
ered to the x-ray tube, and by adjusting an iris between
the phosphor output screen and the imaging system (video
or film).
FLUOROSCOPIC DISPLAY
Images obtained from the imaging device are displayed on a
video system. The video image is composed of horizontal
lines. Modern displays show 1024 lines per image. Older
systems used an interlaced display mode that was used in
commercial television (NTSC standard). Using the interlaced
display, every other line on the video output is scanned every
1/60th of a second. By alternating the scans, a complete
image is displayed every 1/30th of a second. This interlacing
process eliminates the apparent image flicker that the eye
perceives when images are scanned at 30 frames/second.
Images of a rapidly moving heart, however, can be blurred
because motion has occurred between the first and second
interlacing scans that paint the entire image.
More recent systems use a progressive scan method where
the entire image is displayed line by line every 1/60th of a
second. This process permits better resolution of moving
objects. It also, however, leads to additional electronic noise
and some quantum mottle (see above). Most manufacturers
also employ systems that pulse the x-ray exposure. This
“pulse fluoro” approach can further improve image sharp-
ness. Radiation exposure is modestly reduced.
747
CINEANGIOGRAPHY
For cineangiography, an x-ray beam must be pulsed to provide
for adequate “stop motion” imaging and to limit x-ray expo-
sure. Thirty to 60 exposures/sec are needed to give the
appearance of a “live” continuous image, although 15 frames/
sec can produce a relatively smooth image if the software
eliminates flicker. Frame rates greater than 30/sec are needed
only in patients with rapid heart rates. The exposure duration
per frame should not exceed 5 to 8 ms to prevent motion
blurring.6 Exposure time control is achieved by pulsing the
current to the x-ray tube. Initially, this was accomplished by
pulsing the power to the high-energy transformer (“the gen-
erator”) leading to the x-ray tube. Modern switching systems
pulse the high-voltage side of the transformer output, yield-
ing relatively square pulse waves. Pulsing at 7.5 to 15 frames/
sec has now been applied to fluoroscopy with some reduction
in radiation exposure.7
DIGITAL PROCESSING, DISPLAY, AND STORAGE
Originally, a 35 mm film camera was used to record the
phosphor screen image as cineangiography. Nearly all newer
radiographic systems incorporate digital image processing of
the video pickup signal or obtain the image directly from
CCD chips. For coronary angiography, a pixel matrix of at
least 512 × 512 density and 256 gray levels (8 bits) per frame
are needed to give acceptable resolution and a 1024 × 1024
matrix is needed for diagnostic quality angiography. A variety
of pixel-processing algorithms are employed to enhance
image clarity.
Display monitors should be able to show all of the image
detail presented by the image chain. Monitors display at 525
or 1023 to 1049 lines per screen. The higher line rate provides
more resolution, but also decreases the signal-to-noise ratio.
Flat-panel liquid-crystal displays (LCDs) have been used
recently, but their reaction time and contrast ratio are still
inferior to cathode ray tube (CRT) displays.
Digitized cineangiograms contain an enormous amount
of information (typically 150 to 800 MB per study), making
storage and computer network transfer a challenge. Nearly
all digital images are stored using a DICOM (Digital Imaging
and COmmunication in Medicine) format that permits inter-
change of information between different manufacturers’
systems. In many labs, storage is done on compact discs or
DVDs. The discs are then filed similarly to the older 35 mm
film studies or placed into an automated jukebox, which is
attached to a computer network. These automated mass
storage devices, called picture archiving communication
systems (PACSs), can store huge numbers of angiograms that
can be retrieved over a computer network anywhere in the
hospital or over the Internet. Transmission speed of Intranet
and Internet connections remains a problem, so many of the
images are downgraded to a lower resolution to permit more
rapid transmission and to reduce storage costs.
IMAGE R ESOLUTION
The image quality can be defined by several methods. Overall
resolution of the digital image is limited by pixel density.
Although initial acquisition of 1024 × 1024 pixel matrix is
the rule, saved images are typically downgraded to 512 × 512
density to save storage space. Image resolution is measured
as the ability of the eventual image display (film or video) to
74 8 chapter
distinguish closely spaced lead wires and pixel density. To
provide adequate resolution of fine coronary detail, the cine-
angiographic film resolution should exceed 3.5 to 4.0 line
pairs per millimeter for a 6- to 7-inch image intensifier field.6
Image intensifier veiling glare is tested by filming a circular
lead disk. The contrast ratio of the disk to the surrounding
area should be at least 20 : 1.
Regardless of the display mode, image distortion occurs
for the following reasons: (1) Magnification of the image is
dependent on the distance between the x-ray tube, the patient,
and the image intensifier. Objects closer to the tube are more
magnified. (2) Images close to the x-ray tube and far from the
image intensifier are more blurred. (3) Photon scatter within
the image intensifier and subsequent phosphor display pickup
(veiling glare) can lead to a loss of contrast. In addition, in
older units the image intensifier is not entirely flat; it is
slightly curved like a pin cushion and increases the apparent
size of objects at the periphery.
Radiation Protection
Radiation protection is an important responsibility for all
catheterization laboratory personnel.8–19 To achieve adequate
imaging, the newer image detectors need to receive 10 to
40 μR/frame (varying inversely with image intensifier field
size in older units).19 For routine fluoroscopy using a 6- to 7-
inch field, this amounts to a skin entrance dose of approxi-
mately 3 to 10 R/min (increasing with angulation and patient
density) because most of the x-ray beam is absorbed or
reflected by the patient. Cineangiography increases the skin
entrance dose to approximately 20 to 70 mR/frame (0.6–2.1 R/
sec at 30 frames/sec, increasing with angulation and patient
density). The deep midline tissue dose is approximately one
tenth of the skin dose and it should be kept in mind that the
field of radiation is small, so that the average total body dose
is substantially smaller than the chest dose. Patient radiation
exposure can be minimized primarily by keeping the foot off
the x-ray on-off switch, by proper collimation of the x-ray
beam to prevent needless exposure of peripheral structures,
and by maintaining the radiographic equipment such that a
minimum x-ray dose is needed for adequate imaging.
Unless laboratory staff members place their hands in the
radiation path, they should receive very little direct radiation
exposure because by U.S. law all of the direct radiation emit-
ting from the collimator must land on the image intensifier.
However, only about 2% of the x-ray photons emitted from
the x-ray tube ever reach the image detector, the rest being
absorbed or reflected. Most of the radiation exposure to the
Eye exposure = 35 mR/hr Eye exposure = 110 mR/hr
4 4
3 3
2 25–50 mR/hr
50–100
1 100–200
200–300
0 >300
Scale (ft)
FIGURE 34.2. Radiation exposure to personnel during fluorography. Angulation of the x-ray tube toward personnel increases the
exposure.
34
laboratory personnel results from scatter radiation from the
patient (primarily internal reflection). Scatter radiation
increases directly with the size of the patient and the number
of photons in the x-ray beam and inversely with the energy
of the photons (higher kV energy photons are less likely to
be reflected).
The radiation exposure for personnel can be reduced by
attention to the patient exposure factors described above, by
having the personnel stay as far away as possible from the x-
ray source (the dose falls inversely with distance), and by
having the personnel wear radiation shielding.17,18 Most of the
reflected radiation is directed away from the beam direction
(i.e., away from the image intensifier). Physician exposure is
greatest when the image intensifier is pointed away from the
physician (Fig. 34.2).13,17 The brachial and radial artery
approaches to catheter insertion increases physician radia-
tion exposure by nearly 40% compared to the femoral
approach.9–11
All personnel should wear lead aprons with 0.5-mm lead
lining, a thyroid shield, and eye protection.9 Aprons with
0.5-mm lead shielding absorb 90% of the x-ray dose (70% for
0.25-mm lead lining) and leaded glasses reduce lens exposure
by approximately 40%. Leaded surgical gloves, however,
absorb only 10% of the radiation dose and have minimal
efficacy. A table shield is also effective in reducing scatter
radiation and should be used in all laboratories.
All personnel should also wear radiation detection badges
to quantitate their own exposure and identify faulty equip-
ment. The annual environmental radiation exposure (e.g.,
from radon and cosmic rays) is about 360 rem/year in most
parts of the United States. Current accepted limits (U.S.) for
radiation exposure for personnel are 30 to 50 rem/year super-
ficial skin dose, 50 to 75 rem/year for the hands and forearms,
5 to 15 rem/year for the lens, 5 rem/year (and <3 rem for any
3-month period) deep dose (under the lead apron), and a
cumulative dose of <1 rem/years of age.15,16
Physical Layout and Physiologic
Recording Equipment
A catheterization laboratory should provide at least 600
square feet of laboratory and control room space, and ade-
quate facilities for x-ray equipment (generator, etc.) and
storage.3,6 A physiologic monitor for recording the electrocar-
diogram (in multiple leads) and intravascular pressures
should be located outside the radiation field. It is important
that the pressure recording system be calibrated daily and
that optimal transducer damping is adjusted. Physiologic
2 25–50 mR/hr
50–100
1 100–200
200–300
0 >300
Scale (ft)
 corona ry a ngiogr a ph y
recorders digitize the pressure waveforms and computer-
analyze a variety of hemodynamic parameters (e.g., end-dia-
stolic pressures, systolic or diastolic pressure gradients
between two transducers, and waveform differentiation). It
is important to be familiar with the algorithms used to
derive these parameters before relying on the computer-
derived parameters for clinical decision making.
All catheterization laboratories should be equipped to
manage the complications of catheterization. This includes
a full stock of catheters and emergency drugs, the capability
for rapid defibrillation and right heart pacing, and the imme-
diate availability of an intraaortic balloon pump.
Personnel
In addition to the cardiologist performing the procedure, a
physiologic recording technician should be monitoring and
recording the electrocardiogram and pressure measure-
ments.6 A circulating nurse should be present during angiog-
raphy to administer drugs and fluids and to retrieve catheters.
A radiologic technician (or equivalent) should be available to
assist in operating the radiographic equipment and moving
the x-ray table. In many laboratories, a scrub nurse or techni-
cian is also available to assist in catheter preparation. Should
a complication develop, additional personnel should be
immediately available.
For percutaneous procedures that do not involve a
cutdown or prolonged catheter placement, the personnel in
the room should observe good principles of hygiene. The
same intensity of sterile practices performed in an operating
room is not supported for percutaneous catheterizations, pri-
marily because the rate of infection for these procedures is
extraordinarily low.20 Personnel at the site of catheter inser-
tion should wash their hands thoroughly and wear gloves. A
gown, mask, and protective eyewear should be worn to
protect the operator against blood-borne pathogens (e.g., HIV,
hepatitis). If vascular access is accomplished by cutdown,
sterile apparel (gown, glove, and mask) and limited room
access should be undertaken because the rate of infection is
approximately 10-fold that of percutaneous procedures.20
Techniques of Coronary Angiography
Technical History of Coronary Angiography
Nonselective angiography of the coronary arteries was
accomplished first in the 1920s and 1930s using an aortic
injection of radiographic contrast media and cut film
imaging.21 Coronary imaging was limited by the toxicity and
limited opacity of the di-iodinated contrast media, the
restricted rate of contrast injection through the needle or
small-lumen catheters used for intravascular access, and
poor radiographic imaging resolution. A variety of methods
were used subsequently to enhance coronary filling, includ-
ing acetylcholine-induced cardiac arrest and occlusion of the
distal aorta to limit peripheral arterial runoff.22 Although
normal proximal coronary anatomy could be discerned by
these methods, the structure of distal vessels and diseased
arteries was poorly defined.
Semi-selective coronary angiography was performed later
using a circular catheter with numerous side holes.23 When
74 9
placed in the aorta, some of the side holes opposed the coro-
nary ostia and contrast injection opacified these arteries.
Selective injection of contrast media into the coronary arter-
ies was limited by fear that the available radiographic con-
trast agents would cause ventricular fibrillation. This was
quite justified because in an era before direct current cardio-
version, fibrillation was a lethal complication.
The advent of selective coronary opacification was intro-
duced by Mason Sones, who inadvertently selectively injected
a right coronary artery during an attempted left ventricular
angiogram. The patient did not develop ventricular fibrilla-
tion and Sones went on to develop a selective coronary cath-
eter that could be deflected off the aortic valve into either
coronary ostium, whereupon contrast could be injected.24
Changes in contrast media and improvements in radiographic
imaging have led to better resolution of the coronary tree
with less toxicity and radiation exposure. Improvements in
radiographic positioning equipment enabled steep angulated
views of the coronary circulation that are needed to image
effectively the proximal left coronary vessels.
With the prior introduction of the Seldinger method of
peripheral vascular cannulation, Judkins, Amplatz, Abrams,
Schoonmaker and others invented preformed catheters that
could be passed with great ease from the femoral artery to
the coronary ostium.24–30 Since then an explosion of catheter
material and shapes has made possible nearly effortless can-
nulation of most coronary arteries and bypass grafts. As
Melvin Judkins is quoted as saying, “The catheter will find
the coronary ostium unless impeded by the operator.” The
technique of coronary cannulation and opacification is
important, however, because both the safety and quality of
coronary arteriography can be improved by rigorous atten-
tion to certain principles.
Patient Preparation
The evaluation of patients about to undergo coronary angi-
ography should emphasize a detailed history concerning
factors that affect the approach and risks of angiography, a
physical examination concentrating on the cardiovascular
system, and a frank discussion of the procedure and its antic-
ipated risks and benefits.
The history should include questions about prior experi-
ence with angiography, and prior or current vascular diseases
(e.g., stroke, transient ischemic attack, claudication) and pre-
vious vascular procedures (particularly aortic or iliofemoral
revascularization). Additionally, the presence of factors
increasing sensitivity to drugs used during catheterization
should be noted so that appropriate precautions can be taken.
This includes radiographic contrast materials (e.g., diabetes,
preexisting nephropathy, prior reaction to contrast), prot-
amine sulfate (e.g., α1-antitrypsin deficiency), narcotics, ben-
zodiazepines, and heparin or other anticoagulants (e.g.,
gastrointestinal disease).
The physical examination should concentrate on the vas-
cular system and elements that might change the approach
for the procedure. The quality of the pulses in both upper
(brachial, radial, and ulnar) and lower extremities (femoral,
dorsalis pedis, popliteal, and posterior tibia) should be
recorded because problems in obtaining vascular access
may necessitate a change in cannulation site and embolic
75 0 chapter
complications can occur in any vascular territory. In patients
where radial access is anticipated, an Allen test should be
performed to ensure patency of the ulnar artery. Particular
attention also should be paid to the quality of carotid artery
upstroke and the presence of carotid, abdominal (renal), or
femoral bruits. Although not always possible, it is better to
obtain arterial access in arteries without diminished pulse
or bruit. The presence of an abdominal aneurysm should be
assessed because aneurysms frequently contain thrombus or
other friable material that can be embolized during vascular
cannulation.
The physical examination should also concentrate on
the cardiovascular illness necessitating angiography. The
jugular venous pressure and waveform should be noted to
assess right heart filling pressure and possible tricuspid
regurgitation. The presence of left heart failure should be
assessed and the ability of the patient to lie flat for prolonged
periods should be ascertained (usually by observing the
patient supine for 15 to 30 minutes). If possible, patients with
severe left heart failure should undergo diuresis prior to
angiography.
After interviewing and examining the patient, the antic-
ipated procedure should be explained in sufficient detail to
give the patient an understanding of what will be done,
when it will be done, what will occur after the procedure,
and what the likely expected findings might be. The main
goal of this discussion is to ensure informed consent and to
allay anxiety on the day of the procedure. The procedural
description can be supplemented with written or video
format materials. It also can be quite useful to discuss the
implications of certain findings in order to lay the ground-
work for future recommendations for treatment. We find it
quite useful to involve a responsible family member in the
preangiography preparation.
After a discussion of the procedure itself, the potential
risks should be frankly discussed, and informed consent
should be obtained. A description of potential complications
should be tailored to the patient’s risk factors to provide
an estimate that is as accurate as possible (see below). It is
to no one’s advantage to minimize or exaggerate the risks of
angiography.
Before angiography, an electrocardiogram should be
obtained. The serum potassium and creatinine concentra-
tions and hemoglobin concentration should be measured to
ensure that special precautions need not be taken. Generally,
measurement of blood clotting time (prothrombin time or
partial thromboplastin time) is not required unless there is
a clinical suspicion that they might be abnormal (e.g., anti-
coagulant use, liver disease, severe right heart failure, bleed-
ing history).31 If the patient has had prior coronary bypass or
other heart surgery, the operative report should be read and
the position of bypass grafts noted. The patient’s report of
the operation or the brief notes of other physicians frequently
can be incomplete or inaccurate.
The day of the procedure, the patient should be instructed
to withhold oral intake for 6 hours before the procedure.
Medications should generally be continued, except for hypo-
glycemic agents. Oral hypoglycemic agents should be held
the day of the procedure. Doses of long-acting insulin [such
as neutral protamine Hagedorn (NPH) insulin] should be
halved and regular insulin should be held. Ultra–long-acting
34
insulin (such as Lantus) should be administered in the usual
dose. If insulin is given, a 5% glucose solution should be
infused until catheterization and supplemental oral glucose
can be given as needed. Metformin, an oral hypoglycemic
agent, should be held before and after angiography in patients
with increased risk of renal failure. The drug can lead to
lactic acidosis in the presence of renal failure.32
In all patients, a reliable intravenous access line should
be established prior to angiography. The infusion port should
be large enough to permit a rapid infusion of fluid, should
the patient develop reduced intravascular pressure (e.g., as a
result of increased vagal tone or nitrate induced veno-relax-
ation). Patients with renal dysfunction, particularly those
with diabetes, should be adequately hydrated before angiog-
raphy. Dehydration increases the risk of contrast induced
renal failure.32 There is little evidence to support the use of
mannitol or Lasix prior to angiography to reduce renal dys-
function. Maintenance of continuous urine flow during and
after angiography, preferably with alkalinized saline, is the
best deterrent to renal failure.33 In patients with preexisting
renal dysfunction (creatinine clearance less than 60 mL/min)
additional measures to reduce the incidence of contrast-
induced nephropathy should be taken (see below).
Proper sedation is also an important preparation of the
patient. Patients awaiting angiography are anxious. Treat-
ment with anxiolytic drugs can improve their perception of
the procedure, although elderly patients may have paradoxi-
cal excitation with benzodiazepines and other sedatives.
Before coming to the catheterization laboratory, the patient
should void urine and take a nonsoporific sedative (e.g., ben-
zodiazepine). Careful monitoring of respiration is important
during conscious sedation. If a long procedure is anticipated,
insertion of a urinary catheter may be useful in men with
prostatism or other patients who have trouble voiding.
Vascular Access
Access to the arterial vasculature can be accomplished by
cutdown and direct catheter insertion, or by the percutane-
ous Seldinger technique.34 For many years, the brachial
artery was exposed directly and incised with a blade to insert
Sones catheters into the central circulation. After arteriog-
raphy, the catheter was withdrawn and the artery was sutured
closed. The advantages of cutdown cannulation are control
of the artery and minimal bleeding after the completion of
the repair. The disadvantage is a higher risk of arterial throm-
bosis or injury (see below), infection, a scar on the arm, and
limited reuse of the same access site.
Introduction of a direct percutaneous needle puncture
method for angiography made possible the development of
femoral-approach angiography, the method used overwhelm-
ingly at present.34 The skin and subcutaneous tissues about
the artery are infiltrated with a local anesthetic (e.g., lido-
caine or the longer acting bupivacaine). The common femoral
artery is punctured with a thin walled needle. The site of
entry is important because an inferior puncture may enter
the smaller superficial femoral artery and a superior punc-
ture may pass through the peritoneal cavity or increase the
risk of retroperitoneal bleeding. The common femoral artery
can be located by finding the superior-anterior iliac crest and
the symphysis pubis (landmarks of the inguinale ligament).
 corona ry a ngiogr a ph y
The puncture site should be approximately 5 cm inferior to
the line at the site of the pulse. Particularly in obese patients,
the puncture site may be above the groin crease. Where land-
marks are difficult to ascertain, fluoroscopy can be used. In
97% of patients, a portion of the common femoral artery
overlies the medial femoral head.35
Once the artery is punctured, a 0.035- to 0.038-inch (0.88-
to 095-m) flexible guidewire with a “J” tip is passed through
the needle into the arterial lumen.36 Heparin coating on the
wire reduces platelet adhesion.37 Once the guidewire is in
place, a dilator is employed to enlarge the tract into the
artery, after which a catheter (with a tip tapered down to the
wire) or hemostatic sheath (a short tube with a one-way valve)
is advanced into the vessel. The angiographic catheters are
advanced through hemostatic valve in the sheath and up to
the ascending aorta with the aid of the J-tip guidewire. If a
hemostatic sheath is used, the outer diameter of arteriotomy
will be about 0.3 mm larger than the inner diameter of the
sheath, enlarging the puncture site by one French (F) size.
Although not preferred to a native femoral artery, vascu-
lar access can be obtained through prosthetic femoral artery
grafts (e.g., Dacron), provided that the grafts have been in
place long enough to develop extraluminal fibrosis (i.e., 2 to
4 months). Fears of uncontrollable bleeding, infection, and
disruption of the pseudointima within the graft, in general,
have not been realized 38,39 and catheter insertion into grafts
is usually safe. In our experience, however, it may take
slightly longer to achieve hemostasis after catheter with-
drawal, and dislodgment of the pseudointima within the
graft can occur very infrequently. It has been suggested that
catheters in vascular grafts be removed after straightening
with a guidewire.40
More recently, radial artery access has been used, partic-
ularly in patients with severe femoral or aortoiliac disease.41,42
After performing an Allen test to ensure that the ulnar
artery is patent, a small needle and guidewire is passed into
the radial artery. An intravascular sheath with a hydrophilic
coating is then passed into the artery. Vasospasm is common;
administration of intraarterial nitroglycerin, calcium
channel antagonist (e.g., nicardipine 200 μg), and heparin is
critical.
The advantage of radial access is that hemostasis after
the procedure can be obtained with simple wrist pressure
(several devices to apply pressure have been developed). This
allows the patient to ambulate quickly and avoids some of
the bleeding complications of femoral access, such as retro-
peritoneal hematoma. The disadvantage is that about 2% of
radial arteries are permanently occluded after the procedure
and catheters are usually limited to size 4F to 6F.42
After angiography, the extremity with the arteriotomy
site should be extended and held straight. The catheters
should be withdrawn from the artery, aspirating during with-
drawal to help avoid extrusion of thrombus. Immediately
after decannulation, the arterial puncture site should be
compressed by hand or, in the case of femoral puncture, with
the use of a device (e.g., a Femostop) to apply local pressure.
Some authors suggest that compression devices lead to a
higher complication rate, but there is little evidence to
support this view. An unwatched Femostop or other hemo-
static device, however, can be dangerous because changes in
patient position or muscle tone alter the pressure applied to
751
the artery and may lead to bleeding, total vessel occlusion,
venous thrombosis, or pressure injury of the femoral nerve
or soft tissue. The Femostop is meant to save the hands,
not time.
Several vascular closure devices have been developed
recently. They are divided into percutaneous suture devices
(e.g., Perclose) and devices that apply a hemostatic material
(collagen or thrombin) to the puncture site (e.g., Angioseal).
These devices allow patients to ambulate quickly, usually
within an hour or less. They do not, however, reduce the
bleeding complications of arteriotomy. The incidences of
bleeding, femoral pseudoaneurysm, retroperitoneal hema-
toma, and surgical repair are similar in patients treated with
manual compression and those in whom a closure device
is used.42
Regardless of the method used for hemostasis, the distal
pulse should be monitored frequently until pressure is with-
drawn and for at least several hours thereafter (e.g., every 15
minutes for 1 hour after hemostasis, then every 30 to 60
minutes). The patient should avoid actions that increase arte-
rial pressure (e.g., coughing, straining to urinate, sitting up)
for 2 to 6 hours. The precise duration of bed rest needed after
arterial puncture is not clear but probably decreases with
smaller diameter catheters.43
Coronary Catheters
The essential features of a coronary angiographic catheter
are an adequate lumen area, shape retention, torque control,
radiographic opacity, and safety. Catheters used to cannu-
late the coronary arteries were initially constructed of a
woven Dacron or hydrocarbon polymers. Polymers, pre-
dominantly polyurethanes and polyethylenes, are advanta-
geous because they can be extruded and easily shaped. Their
drawbacks are that they also can soften when inserted into
the body and frequently do not transmit torque to the cath-
eter tip. To improve shape retention and torque transmis-
sion, most manufacturers use wire braiding within the
catheter wall. Improved polymers have allowed a reduction
in the thickness of the catheter wall, preserving the caliber
of the inner lumen, without a significant loss in handling
characteristics.
After Sones developed catheters for brachial approach an-
giography, Judkins and Amplatz designed a series of coronary
catheters for cannulation from the femoral approach.24–30
Each design has a primary and secondary curve, and tapers
at the tip to hug the guidewire (Figs. 34.3 and 34.4).24–30
Catheter caliber is measured in French (F) size (French
size = circumference in millimeters). In the 1990s, catheter
construction improved remarkably, allowing the manufac-
ture of sizes 4F to 6F. The smaller arteriotomy required by
size 4F to 6F catheters has reduced the time needed for hemo-
stasis and bed rest after catheter withdrawal, and may prevent
peripheral vascular complications.40,43 However, smaller
catheters (particularly less than 5F) can have insufficient
lumen area to inject contrast adequately into the coronary
artery (leading to contrast streaming), poor torquing charac-
teristics, and instability within the coronary lumen.44 Rapid
injection through a small catheter end-hole orifice can lead
to damage of the coronary wall.45 The likelihood of coronary
injury is related directly to the energy content of the contrast
75 2 chapter
A B C eter in the orifice, a test injection should be done. Free-
small normal enlarged
aorta aorta aorta
FIGURE 34.3. Cannulation of the left coronary artery using a
Judkins curve catheter. The catheter is passed to the proximal aorta
(A) using a guidewire (not shown). It is then advanced to the coro-
nary ostium while pressure is monitored from the catheter tip (B
and C). The tip should be coaxial with the artery. The length of the
catheter between the primary and secondary curves should increase
with the diameter of the aorta (lower panel).
jet. A single report also describes an increase in catheter-
induced coronary artery dissections associated with 6F cath-
eter use by less experienced operators.46 Newer small
catheters have a remarkably large lumen area and may be
safer than earlier versions. In general, however, newer cath-
eters of size 4F to 6F produce acceptable angiography, par-
ticularly when used with a mechanical injector.
Cannulation of the Coronary Ostia
Cannulation of the coronary ostium is the most important
step in angiography. Catheters should be advanced to the
ascending aortic root with the use of a guidewire. Inserting
catheters without a guidewire can lead to retrograde periph-
eral arterial dissection. After aspirating the catheter to
ensure that any debris or air has been removed, the catheter
should be filled with contrast and connected to the pressure
transducer. Left Amplatz and Judkins catheters can be
advanced to the coronary ostium directly and usually require
little manipulation (Figs. 34.3 and 34.4).25,27 Right coronary
Amplatz and Judkins catheters should be advanced to the
aortic valve, withdrawn 1 to 1½ cm and rotated clockwise
until the ostium is engaged (Fig. 34.4).
When cannulating a coronary ostium, fluoroscopy in the
40- to 45-degree left anterior oblique (LAO) projection can be
useful because the coronary ostia are nearly perpendicular
to the view. Alternatively, when the coronary origin is rotated
posteriorly (e.g., with left ventricular hypertrophy) or anteri-
orly (e.g., with lung disease), a right anterior oblique (RAO)
45-degree projection can help significantly. If the coronary
cannot be cannulated, a different catheter shape should be
used, keeping in mind the shape of the aorta, the angle of the
coronary origin, and the rotation of the heart. If a coronary
ostium cannot be found, the possibility of an aberrant origin
should be considered (see below).
34
After cannulation, the pressure at the catheter tip should
be observed. Pressure damping implies that the catheter has
burrowed into the wall of the artery, that there is catheter-
induced vasospasm, or that there is an organic ostial steno-
sis. If present, injection of contrast should be avoided because
it could cause a coronary dissection. The catheter should be
withdrawn slowly. If the pressure normalizes with the cath-
flowing contrast without staining of the arterial wall should
be observed before angiography. Since contrast emerges from
the catheter as a jet, it is important that the catheter tip is
coaxial with the proximal artery to avoid contrast-jet–
induced injury to the ostial wall.
Pressure damping from an improper catheter position or
vasospasm is common in the right coronary artery, but in
the left coronary it should alert the angiographer to the pos-
sibility of stenosis in the left main coronary, a particularly
dangerous problem. A test injection below the artery or use
of a “cusp” catheter can define the coronary ostium and
permit selection of the best catheter shape. Administration
of nitroglycerin can reduce the tendency for catheter-induced
ostial vasospasm, although it is not always effective.
BYPASS GRAFT A NGIOGRAPHY
Coronary artery bypass graft angiography is usually straight-
forward if the grafts are in their usual position. The common
aortic anastomosis sites of bypass grafts are shown in Figure
34.5. Left coronary vein grafts are usually located on the
anterolateral portion of the aorta and can be cannulated with
a left vein bypass curve catheter or with a variety of other
coronary catheters (e.g., Judkins right 4 curve, Amplatz right
1 or left 1 curves). A small number of surgeons pass the
A B C
small normal enlarged
aorta aorta aorta
FIGURE 34.4. Cannulation of the right coronary artery using a
Judkins curve catheter. The catheter is passed to the proximal aorta
(A) using a guidewire (not shown). It is then advanced to the level
of the coronary ostium and rotated clockwise while pressure is
monitored from the catheter tip (B and C). The tip should be coaxial
with the artery. The length of the catheter between the primary and
secondary curves and the angle of the primary curve should increase
with the size of the aorta (lower panel).
 corona ry a ngiogr a ph y
FIGURE 34.5. Typical locations of coronary artery vein bypass
grafts. The vein graft to the circumflex marginal branch is usually
the most superior and leftward vein aortic anastomosis. The vein
graft to the left anterior descending artery typically arises inferior
and anterior to the circumflex graft. The right coronary graft arises
lowest on the aorta and in an anterior-rightward position.
circumflex vein graft through the transverse sinus and anas-
tomose it to the right-posterior aorta (to minimize graft
kinking). If the circumflex graft cannot be found, the poste-
rior aorta should be searched with a left vein bypass graft or
Amplatz left catheter.
The right coronary vein grafts usually arise at a very
shallow angle from the aorta and can be cannulated easily
with a right vein graft curve catheter. Other catheters (e.g.,
Judkins right 4 curve, Amplatz right 1 or left 1 curves) may
also be successful, particularly when the aortic root is
enlarged or if the aortic anastomosis is more horizontal.
Internal mammary artery grafts are best cannulated with
an internal mammary curve catheter, although a Judkins
right 3.5 or 4 curve may suffice. If the internal mammary
cannot be engaged selectively, patency can be established
with a subclavian artery angiogram performed after inflation
of a blood pressure cuff to reduce peripheral runoff into the
ipsilateral arm. Injection of contrast material into the inter-
nal mammary artery can be painful if the artery still per-
fuses the chest wall. Low osmolality contrast media is better
tolerated.
75 3
The most common problems in bypass graft angiography
are failure to determine graft patency, failure to fully opacify
the graft and distal coronary, and failure to define a stenosis
at the coronary anastomotic site. It is of paramount impor-
tance that the angiographer know the origin and destination
of each bypass graft. The only reliable source for such infor-
mation is the operative report. If a convincing aortic vein
graft stump is not found and the recipient coronary dose not
fill via collaterals, the vein graft is probably patent. An aortic
root injection with dense aortic opacification should be done
to find the graft or its stump.
Vein bypass grafts are often much larger in caliber
than the native coronary arteries they perfuse, leading to
slow velocity within portions of the graft lumen. Large-
caliber grafts can be difficult to fully opacify, and layering
of contrast within the graft can be confused with a stenotic
lesion or intraluminal thrombus. Better injection (often
using an angioplasty guiding catheter) will minimize the
effects of streaming. The coronary anastomosis may also be
difficult to define because of overlapping bypass graft or
native arteries. It is important that at least one view be
obtained in a radiographic angle that is nearly normal to the
anastomosis.
Radiographic Contrast Material
PREPARATIONS
Iodine, an element that absorbs x-ray photons, is the essential
constituent of angiographic contrast material. In all biologi-
cally compatible angiographic contrast agents, the iodine is
organically bound to a benzene carbon ring (Fig. 34.6). The
compounds are highly water soluble, stay within the extra-
cellular space, and are excreted primarily by renal glomeru-
lar filtration (with minimal biliary, salivary, and small bowel
excretion). An iodine concentration of at least 320 mg/mL
is required for adequate definition of the coronary arterial
tree and higher concentrations (i.e., 350 to 370 mg/mL) are
desirable.
In all modern contrast media, three iodine atoms are
bound to a benzene ring (Fig. 34.6). In so-called ionic contrast
media the ring is a benzoic acid derivative and in solution it
dissociates into two charged particles.47 Each cationic iodin-
ated benzene ring has a corresponding anion (usually meglu-
mine and sodium in a ratio of 6.6 : 1). The ionic nature of
contrast increases its osmolality (osmolality = number of
particles/volume), which can have profound physiologic
effects.
Many other constituents of contrast solution are impor-
tant. In the past, a high or low concentration of sodium
cations led to increased ventricular arrhythmias, but now
almost all contrast media used for coronary angiography has
a sodium concentration between 150 and 190 mmol/L.48 Eth-
ylenediaminetetraacetic acid (EDTA) is added to nearly all
preparations to remove heavy metal contaminants. Addi-
tionally, the acidic pH of diatrizoate is neutralized with a
variety of bases (e.g., NaOH, sodium citrate). Citrate and
EDTA can bind calcium, reducing the ionized calcium con-
centration in the blood and interstitial space, which pro-
motes ventricular fibrillation.49–52 Agents with added calcium
(e.g., calcium edetate) and those without citrate cause fewer
ventricular arrhythmias and are preferred.49,50,52
75 4 chapter 34

Contrast Media

Ionic Nonionic Iso-osmolar

monomer dimer monomer
O O– (+cation) O O– (+cation) R
C R C R R
I I I II I I I I II I
R R R R R R R R R R
I I I I I I
Preparations Diatrizoate salt Ioxaglate Iopamidol Iodixanol
lohexo
lopromide
loversol
Cation Meglumine and None None None
sodium
Osmolality (mOsm/kg) 1570–2020 600 790–840 290
Viscosity (cp@37°C) 4.2–8.5 7.5 9.0–10.4 11.8
Density (g/mL) 1.34 1.32 1.33–1.41 1.36
FIGURE 34.6. Structure and characteristics of radio-
LD50 (g I/Kg) 7.5 15–17 10–24 15–20 graphic contrast agents. LD50, median lethal dose.

Many of the unwanted effects of contrast material are
related to the high osmolality of the contrast solution needed
to obtain an adequate iodine concentration. To reduce the
osmolality, an ionic dimer (ioxaglate, Hexabrix) was devel-
oped (Fig. 34.6). This compound has only one cation for every
two benzene rings (six iodine atoms/three particles), reduc-
ing osmolality by 30% over the diatrizoate salts. Ioxaglate is
better tolerated than the ionic monomer preparations.53
“Nonionic,” lower osmolality solutions have been devel-
oped by creating an iodinated benzene ring that does not
dissociate, resulting in yet lower osmolality and the absence
of toxic effects associated with the cations. Even these solu-
tions, however, still have an osmolality much greater than
blood and are quite viscous. Although the nonionic, lower
osmolar solutions are more expensive, they confer signifi-
cant advantages, particularly in patients with severe coro-
nary artery disease, reduced ventricular function, or a history
of sensitivity to ionic contrast media.54–57
Recently, a nearly iso-osmotic, nonionic contrast medium
(iodixanol) has been developed. This agent appears to further
reduce the risk of angiography, particularly due to its minimal
effects of ventricular compliance, resulting in little effect on
hemodynamics and little reflex bradycardia. Preliminary
studies suggest it may also reduce the risk of renal failure.
Ventricular dP/dt falls within seconds after contrast
injection followed by a reduction in systemic blood pres-
sure.63,64 A reflex-mediated rebound increase in blood pres-
sure often occurs 8 to 10 seconds later. Ventricular compliance
decreases, causing end-diastolic pressure to rise.65–67 The
negative inotropic response is more pronounced and lasts
longer in the presence of coexistent left ventricular dysfunc-
tion or myocardial ischemia (up to 20 minutes).68,69 Nonionic,
low osmolar and iso-osmolar contrast media have substan-
tially less deleterious effect on ventricular function and
should be used in patients with acute ischemic syndromes,
heart failure, severe aortic stenosis, and left main coronary
artery disease.54,56,63,64,70 In these patients, the additional cost
of nonionic media may be offset by the lower incidence of
costs related to complications.71
Contrast significantly reduces the rate of sinoatrial node
depolarization, and prolongs the action potential and repo-
larization. Intracoronary contrast injection causes an increase
in QRS voltage and a lengthening of the QRS and QT inter-
4
Renografin
Iohexol
Δ CBF (× resting)

3 Saline
PHYSIOLOGIC EFFECTS OF CONTRAST M ATERIAL 8 mL i.c.
Injection of contrast material initially causes a brief (<5-
second) fall in coronary blood flow caused by passage of the 2
viscous solution through the microcirculation (following
Poiseuille’s law, Fig. 34.7). Immediately thereafter, blood
flow increases by 2.5- to 4.0-fold basal blood flow and returns 1
to normal within about 15 to 20 seconds.58,59 The cause of
the hyperemic response appears to be related in part to the
high osmolality of contrast media since a similar response
is seen after injection of hyperosmolar dextrose solution.60,61 10 20 30 40 50 60 70 80
Stimulation of chemoreceptors in the myocardium may con- Time (sec)
tribute to coronary (and peripheral) vasodilation through the FIGURE 34.7. Changes in coronary blood flow velocity (ΔCBFV)
Bezold-Jarisch reflex60 and a direct effect on the microcircula- after intracoronary (i.c.) injection of ionic contrast media (Renogra-
fin), nonionic contrast media (Iohexol), and saline. An initial fall in
tion cannot be excluded. The hyperemic response after non- coronary blood flow velocity after contrast injection (but not saline)
ionic contrast media is less than that seen after ionic contrast is followed by a hyperemic response that is more marked after ionic
injection (Fig. 34.7).62 contrast injection.
 corona ry a ngiogr a ph y
vals, in addition to ST-segment shifts.63 The effects on the
QT interval may be exacerbated by local hypothermia
induced by use of room temperature contrast material. These
effects are short lasting (<2 minutes).
The bradycardia and reduced atrioventricular node con-
duction is caused by a direct effect of contrast material on
conduction tissue and indirectly by stimulation of afferent
chemoreceptors in the ventricle. Chemoreceptor discharge
causes a reflex-mediated increase in vagal tone and peripheral
sympathetic withdrawal (the Bezold-Jarisch reflex).60,61,72 The
vagally mediated bradycardia can be blocked by atropine,
although in most patients its brief duration does not merit
treatment. Prophylactic pacemaker placement to avoid bra-
dycardia is not recommended because its routine use
increases the frequency of ventricular arrhythmias, includ-
ing fibrillation, without significant benefit.73,74
Contrast media also alters blood coagulation by multiple
mechanisms.75–78 High concentrations of diatrizoate salts
reduce activation of platelets and increase the thrombin
time, which may prevent clotting within the coronary cath-
eter and thromboembolic complications. Nonionic contrast
media has less effect on coagulation. Iopamidol (a nonionic
agent) decreases platelet surface charge, which may facilitate
platelet aggregation, but it also prevents fibrin monomer
assembly and prolongs the thrombin time (although less than
ionic salts).76,77 The high osmolarity of contrast media also
causes transient shrinkage of red blood cells and endothelial
cells, increasing vascular permeability.76 It has been sug-
gested that ionic contrast media (diatrizoate salts) be used in
patients with thrombotic coronary syndromes (e.g., infarc-
tion or unstable angina), but in clinical studies the overall
incidence of thrombotic complications is very low when non-
ionic agents are employed.79
INJECTION OF CONTRAST M EDIA
Contrast media can be injected into the coronary arteries
with the use of a motorized injector or by a handheld syringe.
Hand injection is accomplished with a syringe attached to
Hand syringe and manifold
Pressure transducer
and
Catheter to patient d u cer
s ge
tran pur
s s ure g for
pre ba
To a ste n t ras
w yc o
To x-ra
To
FIGURE 34.8. Left panel: One variation of the manifold and syringe system used to inject the coronary arteries by hand. Right panel: A
variable injection speed semiautomated injector for coronary and ventricular angiography.
75 5
the coronary catheter via a manifold of stopcocks (Fig. 34.8).
The setup varies widely among laboratories but the essential
elements are a clear syringe (to ensure that bubbles can be
seen prior to injection) connected to a stopcock manifold.
Using clear tubing, the manifold is connected to a contrast
media container, a pressure transducer (for monitoring pres-
sure at the catheter tip), and a pressurized bag of saline to
facilitate connecting the coronary catheter to the injection
manifold without the introduction of air. The paramount
importance of keeping the entire injection system free of air
cannot be overemphasized. This can be accomplished by a
thorough purging of the manifold and tubing system with
contrast or saline during the setup and vigilance during the
procedure. It should be kept in mind, however, that all liquids
contain microbubbles that can cause transient microcircula-
tory obstruction.80
Motorized injectors permit the injection of specified
amount of contrast material at a specified constant injection
rate. Typically, the left coronary is injected with 5 to 12 mL
of contrast material at 3 to 5 mL/sec and the right coronary
with 2 to 5 mL at 1 to 4 mL/sec. The rate should be adjusted
for the size of the perfusion field and the rate of blood flow
in the recipient artery or bypass graft. For each contrast injec-
tion, most angiographers prefer to progressively increase the
initial injection rate by using a ramp (a specified rate of rise
in injection speed) to prevent the injection jet from causing
the angiographic catheter to “kick” out of the artery. It is
important that the ramp not be too slow, because a good
initial injection of contrast media reduces coronary blood
flow transiently and enhances the angiographic image (Fig.
34.7). A slow injection results only in contrast hyperemia,
which further dilutes the injected contrast. The advantage of
motorized injectors is consistency, the ability to deliver large
contrast volumes at high flow rates (e.g., to hypertrophied
hearts), and the ease of injection. The disadvantage is an
inability to adjust the flow rate during injection. Recently, a
semiautomated injector with variable injection rate control
has been developed for coronary angiography.81
Automated injector
ush
in eb
sal
ttle
t bo
Hand syringe
75 6 chapter 34

Anticoagulation sclerotic and normal coronary arteries dilate after nitroglyc-

erin, but proximal vessels exhibit less dilation than distal
Catheterization itself is associated with platelet activation
epicardial vessels (9% vs. 34% diameter increase).94 Stenotic
and a rise in thromboxane A 2 metabolite excretion.82 The
lesions also relax after nitroglycerin, although severely nar-
presence of catheters within the vascular lumen causes endo-
rowed segments usually dilate little.95 Removal of tone by
thelial denudation and combined with the foreign body of
nitroglycerin permits an assessment of maximal coronary
the catheter is a stimulus for intravascular thrombosis.
caliber, effectively eliminates vasospastic coronary lesions,
Several, but not all, studies suggest that systemic anticoagu-
and facilitates assessments of stenosis severity.
lation with heparin reduces the incidence of thrombotic
Nitroglycerin primarily affects the large-diameter epicar-
complications of angiography (primarily thrombosis at the
dial portion of the coronary artery, and dilation in these
site of catheter insertion),83–85 although heparin has also been
vessels lasts for 10 to 20 minutes. When administered by the
reported to cause additional activation of platelets.86 Antico-
intracoronary route, only small doses of nitroglycerin (100 μg
agulation is not necessary for patients undergoing routine
in the right coronary, 150 μg in the left coronary artery) are
diagnostic angiography from the femoral approach. There is
needed to effect maximal epicardial coronary dilation, and
uniform agreement, however, that heparin (e.g., 2000 U into
these doses have a minimal impact on systemic hemody-
the artery and 3000 U intravenously) should be given to all
namics.94 A 400-μg sublingual dose of nitroglycerin also
patients in whom the brachial or radial approach is used,
causes maximal dilation of the conduit coronary arteries.
because of the higher incidence of thrombosis at the catheter
Nitroglycerin administered into the coronary ostium also
insertion site. In patients undergoing femoral approach angi-
has very brief effects on the microcirculation (usually causing
ography, the risk of thrombotic complications probably
a 1.5- to 2.5-fold increase in coronary blood flow lasting less
increases with the duration of the procedure, a smaller
than 2 minutes), but causes negligible changes in blood flow
femoral artery, or larger catheter, and the presence of periph-
when given by intravenous infusion or by mouth.96,97
eral vascular disease. Patients at higher risk of thrombosis
It should be remembered that the nitrate response in the
should be anticoagulated (3000 to 5000 U intravenously)
large coronary arteries is not complete for 2 minutes after
unless a contraindication exists.
intracoronary administration and 4 minutes after a sublin-
The optimal dose of heparin may vary among patients
gual dose. Additionally, patients undergoing angiography are
because plasma antithrombin III and platelet factor four
often intravascular volume depleted because oral intake has
(which binds heparin) concentrations affect heparin efficacy
been withheld for some time. This can lead to an increased
and availability, respectively.87 Heparin pharmacokinetics
sensitivity to nitrate-induced venodilation and transient
are not affected by the type of contrast media selected.88
hypotension. Since coronary caliber is dependent on distend-
Aspirin decreases platelet activation caused by angiography,
ing pressure, the reproducibility of coronary angiographi-
but its efficacy in reducing complications has not been
cally defined measurements of coronary diameter over time
evaluated.82
is dependent on maintenance of arterial pressure. In patients
At the end of the procedure, the anticoagulant effects of
without heart failure, saline is often given prior to nitroglyc-
heparin can be reversed by administering protamine.89 Prot-
erin administration to blunt the fall in arterial pressure.
amine is a polycationic compound derived from fish sperm
In some patients and particularly in radial artery bypass
(primarily from salmon and herring) that binds to heparin.
graft conduit, nitroglycerin may not entirely reduce arterial
One milligram of protamine binds approximately 100 U
tone. Intracoronary or graft calcium channel blocking agents
(1 mg) of heparin.12 Since heparin is essentially eliminated by
(e.g., nicardipine 100 to 400 μg) may be effective.
first-order kinetics, the amount of protamine needed is a
function of the initial heparin dose and the time since
administration. For a 5000-U heparin dose, the initial prot- Special Situations
amine dose should be 50 mg if less than 20 minutes have
OSTIAL CORONARY STENOSIS
passed and progressively less thereafter (e.g., 30 mg if 60
Coronary angiography in patients with ostial stenosis, par-
minutes has elapsed).9 If insufficient protamine is given, a
ticularly stenosis of the left main coronary artery, is associ-
phenomenon known as “heparin rebound” can occur.13 After
ated with significantly higher incidence of complications.98,99
initial normalization of clotting times from the first
Left main stenosis occurs in 2% to 11% of patients undergo-
protamine dose, protamine degradation by proteinases
ing angiography, but accounts for a significantly greater frac-
leads to release of free heparin and a rebound increase in
tion of mortality associated with the procedure.99 A procedural
clotting time.90,91
mortality rate of 0.75% was found in patients with left main
Protamine should be administered cautiously to patients
coronary stenosis in the Coronary Artery Surgery Study.100
with a prior exposure to the drug (such as NPH insulin, or
Myocardial infarction, persistent angina, profound hypoten-
protamine sulfate or chloride) or patients with a fish allergy,
sion, and ventricular fibrillation also can occur during or
and should not be given to patients with α1-antitrypsin defi-
immediately following angiography in patients with left
ciency (see below).92,93 Very large protamine doses (>4.0 : 1
main coronary stenosis. The likelihood of complications is
protamine/heparin concentration) can have an anticoagulant
greater in patients with angina within 24 hours of catheter-
effect, although it is rarely observed in a clinical setting.12
ization and if the stenosis is in the proximal left main coro-
nary (within 6 mm of the angiographic catheter tip).98
Management of Epicardial Coronary Artery Tone
Complications can be minimized by rapidly identifying
The lumen caliber of epicardial coronary arteries measured the presence of left main stenosis, which occurs more often
at angiography reflects a variable degree of tone. Both athero- in patients with widespread, severe atherosclerosis and may
 corona ry a ngiogr a ph y
be associated with pressure damping on left coronary can-
nulation. When left main stenosis is suspected, a “cusp”
injection about the ostium may identify its presence and
morphology. When a significant left main stenosis is present,
nonionic contrast should be used and the number of angio-
grams should be limited to only those views required to
identify the vessels needing bypass grafts. A catheter tip
shape that will not deeply cannulate the ostium should be
used. If the pressure at the catheter tip always damps on left
main cannulation, the catheter may need to be withdrawn
between injections, although repeated cannulation of a ste-
notic left main may increase the possibility of catheter-
induced injury. If adequate filling can be obtained, a
nonselective “cusp” injection should be used. The pulmo-
nary capillary wedge pressure monitoring during angiogra-
phy can be important in patients with severe stenosis or
reduced left ventricular function because contrast material
may precipitously reduce left ventricular function. If the
wedge pressure rises significantly, angiography should be
stopped until hemodynamics are controlled.
Coronary cannulation causes endothelial denudation,
which may be responsible in part for the ischemic complica-
tions of angiography in this patient group. After angiography,
patients with a significant (>50%) left main stenosis should
be monitored because of the higher frequency of ischemia
and hemodynamic deterioration over the following 24 hours.
Semi-urgent revascularization should be considered after
angiography in patients with severe left main stenosis (>90%),
particularly if the lesion is in the proximal left main.
HEART FAILURE AND A BNORMAL L EFT
VENTRICULAR FUNCTION
Coronary angiography always causes a transient increase in
ventricular filling pressure, due mostly to contrast-mediated
transient increases in diastolic ventricular stiffness. Dia-
stolic stiffness increases for up to 20 minutes after contrast
injection. In contrast, any reduction in systolic contraction
is usually brief (<60 seconds). Patients with preexisting ele-
vated filling pressures may develop frank pulmonary edema
during or shortly after angiography because of the reduction
in compliance and the concomitant volume load from hyper-
tonic contrast material and other fluids given during angiog-
raphy. In patients with marked left heart failure or an inability
to lie flat because of high left atrial pressure, diuresis should
be accomplished prior to angiography if possible.
Nonionic, low-osmolar contrast agents have a less pro-
nounced effect on myocardial function and intravascular
volume than ionic agents and should be used in patients with
significantly elevated left heart filling pressures. Iodixanol,
an iso-osmolar contrast agent, has minimal effects on left
ventricular diastolic stiffness and may be safer in patients
with severe LV dysfunction. Additionally, in patients with
poor compensation, some angiographers monitor pulmonary
artery wedge pressure during angiography. If the mean wedge
pressure rises above 20 mm Hg, angiography should be
stopped and appropriate steps should be taken to reduce the
filling pressures (e.g., nitrates, afterload reduction, diuretics,
intraaortic balloon pump). A recent study suggest that mea-
suring pulmonary artery pressures in patients with acute
coronary syndromes is associated with increased mortality,
but patient selection might have significantly biased the
75 7
results.101 Whatever the monitoring methods, assiduous
attention to heart failure can avoid pulmonary edema and
emergency intubation.
SHOCK
Coronary angiography in patients with cardiogenic shock is
challenging. In most patients, placement of an intraaortic
balloon pump before angiography is important for stabiliza-
tion and to prevent hemodynamic collapse during angiogra-
phy. The balloon pump increases diastolic coronary blood
flow in addition to improving systemic blood flow.102 Iso-
osmotic contrast media should be used routinely and the
minimal number of contrast injections necessary to plan
treatment should be obtained. Special care should be taken
in cannulation of the left main coronary artery because of
the increased frequency of left main stenosis in patients with
cardiogenic shock.
AORTIC DILATION
Aortic root dilation, common in patients with aortic valve
disease, prolonged hypertension, and Marfan’s syndrome,
presents a particular challenge for coronary cannulation
(Amplatz, Judkins). Large curve left coronary catheters
are required (e.g., Judkins left 5 to 7 curve, Amplatz left 3
curve).
Right coronary cannulation can be especially problem-
atic because the root is enlarged, elongated, and horizontal.
Catheter manipulation can be difficult because of associated
tortuosity of the descending aorta and peripheral vessels.
Occasionally, an Amplatz left curve or a specially steamed
catheter may be needed to cannulate the right coronary. The
rapid coronary blood flow associated with hypertrophy from
aortic valve disease or hypertension makes it essential to use
a catheter of adequate caliber to deliver a rapid injection of
contrast material (which should be warmed to 37˚C to reduce
viscosity and the effects of cold contrast–induced hypother-
mia on the myocardium).
T RANSPLANTATION
After transplantation, the majority of patients undergo
annual surveillance angiography to detect transplant-related
vasculopathy. Several factors are unique to transplanted
hearts.103 The aortic anastomosis causes a ridge in the ascend-
ing aorta, making it important to pass the Judkins left coro-
nary nearly to the sinus of Valsalva to avoid the catheter
being hung up on the ridge as it is advanced to the left coro-
nary ostium. The transplanted heart is usually clockwise
rotated (from the diaphragmatic perspective) and the left
coronary ostium is more posterior and the right ostium more
anterior than usual. Additionally, the ascending aorta is
often longer and more horizontal in its more proximal
segment. Frequently, the right coronary is better cannulated
from a right anterior oblique projection and may require a
catheter that can reach more anteriorly, such as a Judkins
right 5 curve or Amplatz right 2 or left 1 curve.
Outpatient Angiography
Although once performed exclusively as an inpatient proce-
dure, the majority of angiography is now be performed in the
outpatient setting.104–108 Outpatient angiography generally
75 8 chapter 34

has a 25% lower hospital cost, but it places some strains on
preangiography patient preparation.104,108 It also imposes more
responsibility on the patient for precatheterization medica-
tion and site preparation, and postangiography catheter inser-
tion site observation.
Outpatient angiography requires selection of patients
who are expected to have a low risk of late complications.
Patients with acute ischemic syndromes (unstable angina,
infarction) should not go home immediately after angiogra-
phy because of the risk of recurrent ischemic episodes.107
Patients with left main or severe three-vessel coronary
disease, severe heart failure, bleeding diathesis, and severe
aortic valve stenosis generally should be observed longer
after contrast angiography.107 Many patients undergoing out-
patient angiography are admitted to the hospital after the
procedure, 1% to 2% for observation after a complication,
and the remainder for a surgical procedure (e.g., angioplasty
or bypass surgery).104,105,108
More recently, coronary angiography has been performed
in mobile truck trailers stationed at smaller hospitals.109,110
With the exclusion of higher risk patients through proper
patient selection, the complications of “mobile angiography”
appear not to be increased and patient satisfaction may be
improved.110 Several logistical problems remain. Since a sig-
nificant fraction of patients undergo a revascularization pro-
cedure based on the information gained from the angiogram,
many patients (if not the majority) will need to travel to a
larger hospital anyway, obviating the advantages of mobile
angiography. Additionally, patients who subsequently have
angioplasty may need to have two procedures (at two hospi-
tals) instead of proceeding with angioplasty in the same
procedure as the angiogram. More information will be needed
to know if catheterization in mobile structures is cost
effective.
Complications of Coronary Angiography
Coronary arteriography is generally a safe procedure, but
serious complications can occur. The overall incidence of
complications and mortality (Table 34.1) increases directly
with the extent of coronary artery disease (particularly left
main coronary stenosis), the presence of coexistent sig-
nificant valvular disease, a reduced ventricular ejection
fraction, reduced functional state, and advancing age.100,111–114
The complications fall into several groups: those resulting
from arterial cannulation, embolization from the aorta, cath-
eter-induced coronary arterial spasm or dissection, arrhyth-
mias, allergic-type reactions from drugs and radiographic
contrast material, and angiography-induced deterioration in
hemodynamics.
Complications of Arterial Cannulation
Peripheral Vascular Complications
Arterial cannulation performed by the Seldinger method
usually causes endothelial denudation at the site of catheter
or sheath insertion. During arterial puncture the needle also
may pass into or through the posterior wall of the artery, and
advancement of a guidewire into the posterior wall can result
in arterial dissection. Fortunately, the arterial flap proceeds
against the flow of blood and usually is sealed rather than
propelled down the vessel by the arterial pulse. Dissection,
along with endothelial injury, however, may promote local
thrombosis and arterial occlusion. Perforation of peripheral
arteries by a guidewire or catheter is uncommon, but proba-
bly occurs more frequently in patients with tortuous vessels
and when stiff wires or catheters are used.

TABLE 34.1. Incidence of complications following elective coronary angiography

Bourassa et al.111 Davis et al.100 Kennedy et al.112 Noto et al.113
Year 1970–74 1975–76 1979–80 1990

Route Femoral Femoral Brachial F or B F or B

Number of patients 5,250 6,328 1,187 53,581 59,972
Death (%) 0.23 0.15 0.50 0.14 0.11
Myocardial infarction (%) 0.09 0.22 0.42 0.07 0.05
Vascular complication (%) 0.85 0.36 2.8 0.57* 0.43*
Thrombosis (%) 0.68 0.2 1.9 0.23 ns
Dissection/perforation (%) 0.17 0.1 0.9 0.04 ns
Stoke/TIA (%) 0.13 0.02 ns 0.07 0.07
Embolic complication (%) 0.07 0.08 0.17 ns ns
Arrhythmia (%) 1.23 0.63† ns 0.56 0.38
Ventricular fibrillation/ 0.40 ns ns 0.44 ns
tachycardia
Asystole/severe bradycardia 0.25 ns ns 0.09 ns
Contrast reaction (%) ns ns ns ns 0.37
Hemodynamic deterioration 0.1 ns ns ns 0.26
* True incidence probably underestimated because only “in laboratory” complications reported.
† All patients.
F, femoral artery approach.
B, brachial artery approach.
ns, not specified.
 corona ry a ngiogr a ph y
The development of a hematoma, arterial pseudoaneu-
rysm, or arteriovenous fistula formation after arterial cathe-
ter removal remains an important and probably underreported
complication. The importance of immediately obtaining
adequate hemostasis cannot be overemphasized. Once a
small perivascular hematoma has formed it becomes more
difficult to apply effective pressure to the puncture site
because applied force is spread equally throughout the hema-
toma. Conversely, prolonged overcompression of the site can
occlude the vessel, leading to vascular stasis and thrombosis.
The affected extremity should be immobilized for at least 4
hours and a catheter of size ≥6F is used. Sandbags applied
over the arteriotomy site are ineffective in preventing com-
plications. A collagen plug device, implanted into the punc-
ture site above the artery, has been developed and appears to
markedly reduce the time needed for hemostasis.115
The incidence of arterial cannulation site complications
is higher in women, the elderly, in the presence of peripheral
vascular disease, when blood flow is reduced (e.g., low cardiac
output state or catheter occlusion of the vessel) and with
brachial access or a low femoral puncture site, probably
related to the smaller size of these vessels.112,116–119 Although
common sense suggests that arterial complications would be
less frequent if smaller catheters were used and arterial
access time was minimized, an increase in vascular compli-
cations has been shown only for catheters >8F (>2.5 mm
outer diameter) in size.117 Patients with synthetic (e.g.,
Dacron) femoral artery grafts may also have a higher inci-
dence for cannulation-related complications, although the
reported experience suggests that cannulation of grafts that
have been in place for at least several months is safe. 38,39
Heparin anticoagulation during the catheterization reduces
the incidence of arterial thrombosis and the need for surgical
embolectomy, but may increase the incidence of hematoma
formation.84,85,117
Septic complications (access site infection and bactere-
mia) are very uncommon and associated almost exclusively
with prolonged cannulation or repeated instrumentation of
the same site within a short time period.20,120 The most
common organism is Staphylococcus aureus, although other
staphylococcal species, streptococci, gram-negative organ-
isms, and anaerobic species can occur.120 The mortality asso-
ciated with bacteremic episodes can be significant.
The development of Doppler echocardiographic methods
for imaging these complications has revealed that small
femoral artery pseudoaneurysms are more common after
femoral angiography than clinically suspected. Additionally,
incidence of pseudoaneurysms and arteriovenous fistulas
may have increased with the more frequent use of aspirin,
anticoagulants, and thrombolytic drugs. Many close sponta-
neously within 1 to 2 months.121 Until recently, all persistent
femoral artery pseudoaneurysms were repaired surgically
because late enlargement and rupture can occur. It has been
shown more recently that prolonged (average 30 minutes)
compression during ultrasound imaging can be used to close
over 90% of pseudoaneurysms and small arteriovenous
fistulas.122,123
EMBOLIZATION
Embolization of arterial circulation can occur from injection
of air, catheter-induced dislodgment of atherosclerotic plaque
75 9
or vascular thrombus (e.g., clot in an abdominal aneurysm),
dislodgment of left ventricular thrombus (e.g., in a ventricu-
lar aneurysm or recently infarcted ventricle), and debris or
clot extruded from an improperly aspirated angiographic
catheter. Catheter-induced embolization can lead to a variety
of complications, depending on the target organ and makeup
of the embolus.124–133
Systemic embolization is more likely when the aorta has
severe atherosclerosis or mural thrombus, when a large
abdominal aortic aneurysm is present (typically containing
thrombus), and in elderly patients. In patients undergoing
cardiopulmonary bypass, transesophageal echocardiographic
identification of atheroma protruding into the aorta may
identify patients at risk for embolic complications, and
pedunculated, mobile aortic masses may be a source of cath-
eterization-related embolism.134,135 The brachial approach is
preferred in patients predisposed to peripheral embolization
unless significant disease in the aortic arch or upper extrem-
ity vessels is present.
The sequelae of systemic emboli vary widely, from no
symptoms to severe tissue necrosis. Thrombotic embolism
frequently results in a loss of the peripheral pulse and occlu-
sion of larger branch arteries that can be treated by embolec-
tomy, anticoagulation, and in some cases thrombolytic drugs.
Cholesterol emboli affect vessels 58 to 800 μm in diameter,
and the syndrome is characterized by skin changes of livido
reticularis, tissue ischemia with intact peripheral pulses,
renal dysfunction, eosinophilia, and an elevated erythrocyte
sedimentation rate.124–131 The renal insufficiency associated
with cholesterol embolization can cause immediate anuria,
but more frequently leads to delayed oliguria. It can be dif-
ferentiated from contrast-induced renal failure by its minimal
reversibility (contrast nephropathy usually is reversible),
associated skin findings of embolization, and eosinophilia.
Embolization of the splanchnic bed can cause abdominal
pain, ileus, or bowel or spleen infarction, usually with onset
of symptoms within hours of catheterization. Treatment for
cholesterol embolization consists of supportive care. Antico-
agulation is ineffective.
Large peripheral air embolization can occur after acci-
dental injection of air or, more commonly, from inspissation
of air through a central venous access catheter in the jugular
or subclavian venous systems. Venous air embolisms over 50
to 100 mL can cause acute pulmonary hypertension and
hypoxemia.136 Arterial air embolism can lead to profound
transient tissue ischemia, including stroke, myocardial isch-
emia and cardiac arrest.137 The immediate treatment is to tilt
the patient head-down (Trendelenburg position) and on the
left side to prevent air from rising to the head or passage from
the venous system to the left atrium via a patent foramen
ovale. Venous air can pass to the arterial circulation without
a clear defect connecting the two circulations, presumably
though the pulmonary arteriovenous shunts.137 Aspiration of
air with a catheter in the right atrium or ventricle may be
partially effective.138 Breathing 100% oxygen may help treat
hypoxemia associated with pulmonary artery flow obstruc-
tion. For large emboli, a hyperbaric chamber may be useful
if employed promptly.139
Selective coronary injection of air can occur when the
catheter or injection tubing is not completely flushed with
fluid. Tuohy-Borst Y connectors are a notorious source of air,
76 0 chapter
as are tubing connectors. Small bubbles may result in tran-
sient ischemia without consequence. Larger selective air
injections (>1 to 2 mL), however, often result in ventricular
fibrillation and cardiovascular collapse.
Neurologic Complications
Neurologic complications of coronary angiography include
local brachial nerve injury from brachial artery cannulation,
ulnar nerve compression during prolonged procedures, tran-
sient central ischemic attacks, and stroke. Significant neuro-
logic events are uncommon, although they probably are
underreported (Table 34.1) because the vast majority resolve
within 24 to 72 hours after the procedure.140–142 Most isch-
emic central neurologic events occur in the posterior distri-
bution, although any territory can be affected.140–143 In one
careful series, transient visual disturbance occurred in 1%
of patients.142 Women and patients with an anginal syndrome
and normal coronary angiograms were more commonly
affected.142 The most likely mechanism of central neurologic
events is embolism of clot or atheromatous debris from the
aorta or cardiac chambers, although vasospasm and transient
hypotension during angiography may also be operative in
some patients.
Transient cortical blindness can result from contrast
administration. This syndrome lasts for 1 to 2 days and
resolves spontaneously. Brain imaging (computed tomogra-
phy or magnetic resonance imaging) is normal.144
Coronary Artery Complications and
Myocardial Infarction
Catheter-induced spasm is common in the right coronary but
very uncommon in the left.145–148 For the most part, the spasm
occurs at the catheter tip and may be related to mechanical
traction on the artery. Rarely, catheter-induced spasm distal
to the catheter tip has been observed. There is no proven
significance of catheter-induced spasm, although some
authors have postulated that patients with catheter-induced
spasm may be more prone to spontaneous spasm.145,148 Cath-
eter-induced spasm usually can be prevented by administra-
tion of nitrates and by using an angiographic catheter that
does not tent the artery.
Myocardial infarction is usually caused by catheter-
induced coronary injury, or embolization from the catheter
or left ventricular thrombus. Catheter-induced arterial injury
is usually caused by the tip of the catheter burrowing into
the arterial plaque or media, raising an arterial flap that can
be extended further by blood flow or by contrast injection
through the catheter into the arterial wall.149,150 The most
common and important sites of catheter-induced injury are
the coronary arterial ostia or the internal mammary artery,
where dissection can lead to thrombosis, spasm, or an exten-
sive spiral dissection down the vessel.151
Normal coronary arteries and arteries with ostial lesions
or acute angle origins are more likely to suffer catheter-
induced injury. The occurrence of catheter injury can be
reduced by careful ostial cannulation with “soft tip” cathe-
ters, monitoring the pressure at the catheter tip (pressure at
the catheter tip will be damped if the catheter has burrowed
into the wall), and advancing the catheter to the ascending
aorta using a flexible guidewire (to prevent the tip from
34
shoveling into the vessel wall). Ostial coronary stenosis is a
rare complication of coronary cannulation.152
Coronary artery embolization usually results from injec-
tion of air or debris from within the catheter. Small air
emboli typically cause ischemia for 5 to 10 minutes. On
angiography, blood flow to the embolized segment is slow,
but the epicardial arteries appear to be intact and no filling
defect is seen. Thrombotic emboli, however, almost always
lead to occlusion of an artery visible on angiography. Infarc-
tion is common, and rapid reperfusion with angioplasty can
be effective in limiting injury. Coronary cholesterol embo-
lism can cause a picture similar to either thrombotic or air
embolism, but the effects are usually not reversible. In one
series, cholesterol emboli were seen at autopsy in 26% of
patients undergoing coronary angiography, but most emboli
were in the myocardium.130,132,133 This underscores the impor-
tance of aspirating the coronary catheter and discarding the
aspirate prior to intracoronary injection. Aspiration of shim-
mering cholesterol crystals is not rare.
Drug Reactions and Toxicity
Radiographic Contrast Material
Although usually well tolerated, iodinated contrast material
can have deleterious consequences related to its normal
physiologic effects and from allergic-type reactions. The
negative inotropic effects on ventricular function and intra-
vascular volume expansion can lead to hemodynamic decom-
pensation, primarily in patients with reduced ventricular
reserve (either diastolic or systolic) and ischemic syn-
dromes.54,56,69,153 The effects on the conduction system can
cause transient severe sinus bradycardia or heart block, and
the effects on ventricular repolarization can cause ventricu-
lar fibrillation (see below).
R ENAL DYSFUNCTION
Contrast agents can also cause renal dysfunction, which is
usually transient but can be severe. A transient increase in
glomerular filtration, an osmotic diuresis, and proteinuria
all occur soon after contrast administration.154 Clinically
evident renal dysfunction with increased serum creatinine
concentration and reduced urine output, however, occurs 48
to 72 hours later. The etiology of contrast-induced renal
failure is unclear, but transient renal ischemia, physical
obstruction of the renal tubules, superoxide radical release,
and endothelial injury have been proposed.
Patients with diabetic nephropathy, preexisting renal dys-
function, dehydration, low cardiac output, and possibly mul-
tiple myeloma are predisposed to develop contrast-induced
renal failure, which ranges from an asymptomatic increase
in serum creatinine concentration to frank anuria.155–158
The likelihood probably rises with the amount of contrast
media administered, although renal dysfunction is very
uncommon in patients with a serum creatinine concentra-
tion <150 μmol/L (<1.7 mg/dL).156 In diabetics with preexist-
ing renal insufficiency (serum creatinine concentration
>150 mmol/L), Parfrey et al.156 found the risk of a 25% increase
in creatinine concentration was 7.2%. In nondiabetic patients
with mild renal insufficiency (creatinine 150 to 250 mmol/L),
there was no significant reduction in renal function after
 corona ry a ngiogr a ph y
angiography using small to moderate contrast volumes
(<200 mL). The reported incidence of renal failure after con-
trast exposure varies widely, but nearly all investigators find
that the likelihood of a transient increase in creatinine and
oliguria rises sharply in patients with a creatinine concentra-
tion >250 mmol/L.155–159
The primary prevention of contrast-induced renal failure
is to limit the amount of contrast used to the minimum that
is required to obtain an adequate study and to avoid admin-
istering contrast media to dehydrated patients. Patients
should be well hydrated with 0.9% saline prior to and after
angiography (except for patients with heart failure and ele-
vated left atrial pressure at rest). Nonionic media probably
reduces the risk of contrast nephropathy, but the degree of
protection offered is relatively modest.54,56,159 Iso-osmolar
media (iodixanol) may confer greater protection.160
Recently, two additional methods have been reported to
offer some degree of protection from contrast nephropathy.
N-acetylcysteine (600 mg every 12 hours for four doses, two
before and two after angiography) and hydration with bicar-
bonate buffered saline both result in slightly higher glomeru-
lar filtration rate (GFR) after angiography and may reduce the
incidence of dialysis.161–163
Several prior studies suggested that a number of other
agents might confer protection from contrast nephropathy,
including mannitol (e.g., 25 g in 250 mL of 155 mM saline) to
increase urine flow prior to and during angiography,164,165
simultaneous administration of the loop diuretic furose-
mide,166 dopamine receptor stimulation with fenoldopam,167
and theophylline. In general, however, there is no convincing
evidence that any of these agents reduce the incidence of
renal failure after contrast administration.
A LLERGIC-T YPE R EACTIONS
Contrast material can also give rise to allergic-type reac-
tions, but the mechanisms are poorly understood. Nonspe-
cific mast cell degranulation and activation of complement
have been implicated, but true immunoglobulin E (IgE)-
related allergy is rare. Contrast reactions vary from simple
urticaria to nausea to an anaphylactoid reaction character-
ized by hypotension and bronchospasm. Patients with a prior
history of contrast reaction or multiple allergies (including
seafood) and patients who receive ionic contrast media (espe-
cially with a high sodium content) are more likely to have a
contrast reaction.55,168,169
Patients with a history of allergic-type reactions should
be treated with corticosteroid drugs the day before the pro-
cedure.168 We typically give prednisone (60 mg orally) the
night before the procedure, and before the angiography give
another dose (30 mg prednisone orally or 250 mg hydrocorti-
sone intravenously) and an antihistamine (e.g., hydroxyzine,
50 mg intravenously). In patients predisposed to a contrast
reaction, administration of prednisone at least 12 hours prior
to angiography reduces the incidence of mild to moderate
reactions by half. Treatment only on the day of angiography
has no effect.168 An additional reduction in risk of less severe
reactions (e.g., bradycardia, mild hypotension, brief angina)
will occur if nonionic contrast media is utilized.169 Although
H 2 histamine receptor antagonists (e.g., cimetidine) have also
been used to prevent reactions, their efficacy is unclear and
probably minimal.170
761
Treatment of a reaction is tailored to the symptom. Urti-
caria is treated with intravenous antihistamines. Nausea,
possibly related to intestinal mast cell release, can be less-
ened with antiemetic compounds. Hypotension is treated
with vasopressor drugs, large doses of corticosteroid drugs
(e.g., 1 g methylprednisolone), and antihistamines. Broncho-
spasm is treated with theophylline, inhaled β2-adrenorecep-
tor agonists, and corticosteroids.
Anticoagulants
Heparin can result in thrombocytopenia, which can be
dependent on the type of heparin used (bovine, porcine,
etc.).171 Arterial aggregation and thrombosis can also be
caused by heparin, although reactions from brief exposure
are rare.172
The second most frequent important source of allergic
reactions occurs in association with the anticoagulation
used during angiography. Protamine sulfate, given to bind
heparin and reverse its effects prior to decannulation, can be
associated with several adverse reactions, including urti-
caria, severe hypotension, bradycardia, bronchospasm, and
noncardiogenic pulmonary edema.173 Severe reactions can
require vasopressor drug support for several days. The etiol-
ogy of protamine reactions may vary among patients. Immu-
noglobulin E and IgG antibodies, complement activation,
direct myocardial depression, increases in endothelial per-
meability due to interaction with membrane-bound heparan
sulfates, and protamine-stimulated nitric oxide release from
the endothelium have been postulated.92,174,175 Immunoglobu-
lin G antibodies are the predominant mechanism in patients
without prior protamine exposure.92 In one series, protamine
given after catheterization reduced white blood cell count by
an average of 23% ± 4%.176
Patients with recent protamine exposure or a fish allergy,
diabetic patients exposed to neutral protamine zinc (NPH)
insulin, and patients with α1-antitrypsin deficiency are par-
ticularly sensitive to protamine.173 Additionally, protamine,
when given rapidly to any patient, transiently reduces vascu-
lar resistance and can cause hypotension (possibly related to
protamine stimulated nitric oxide release from the endothe-
lium).175 To minimize complications, a small test dose of
protamine can be given into the arterial cannula. If the
patient has local erythema or hypotension, the drug should
be avoided.
Anesthetics
True allergies to local “-caine”-type anesthetics are very rare.
Patients sometimes claim to be allergic to “novocaine” as a
result of a syncopal episode during a prior procedure (usually
neurally mediated syncope) or a complication related to rapid
or excessive lidocaine administration (seizure, dysarthria,
etc.). These “reactions” are not allergic in nature and, based
on the exceptionally low incidence of true lidocaine allergy,
we usually continue to administer lidocaine local anesthesia
unless the patient gives a clear history consistent with an
IgE-mediated reaction. To date, no patient with a “lidocaine
allergy” has had an adverse reaction. The maximal subcuta-
neous dose should not exceed 5 mg/kg, and solutions con-
taining epinephrine should not be used. In patients with a
bona fide allergic reaction or local sensitivity to lidocaine,
76 2 chapter
the offending agent is usually the preservative methylpara-
bate. In these patients lidocaine without the preservative
(intravenous use lidocaine) or bupivacaine (0.25 to 0.5 mg/
mL) can be substituted.
Arrhythmias
Arrhythmias during angiography can occur from abrasion of
the conduction system by catheters, contrast media–induced
changes in repolarization, reflex-mediated changes in neural
traffic to the heart, and transient myocardial ischemia from
hemodynamic deterioration. The left bundle branch of the
conduction system courses near the surface of the left ven-
tricular septum and can be injured transiently during can-
nulation of the left ventricle.177,178 The right bundle branch is
located near the tricuspid annulus and can be rendered dys-
functional by a right heart catheter (particularly if the cath-
eter is rubbed against the superior annulus repeatedly). In a
patient with a preexisting contralateral bundle branch block,
complete heart block can occur.177,178 In these patients, the
immediate availability of cardiac pacing (external or by cath-
eter) should be ascertained prior to catheterization.
Contrast media can induce sinus bradycardia, sinus node
block, and atrioventricular node block by two mechanisms.
The hyperosmolar and chemical properties of contrast cause
activation of ventricular afferent chemoreceptors, which
reflexively trigger a parasympathetic surge, reducing sinus
and atrioventricular (AV) node repolarization.60,61,72 The reflex
is blocked partially by muscarinic receptor blockade with
atropine. Iso-osmolar contrast media significantly reduce or
eliminate vagally mediated bradycardia.
Neurally mediated syncope can also complicate angiog-
raphy, particularly when the patient is dehydrated and experi-
ences pain. Contrast material may also directly depress
conduction tissue repolarization and transiently slow heart
rate. Vigorous coughing can maintain blood pressure but
does not hasten clearance of contrast material from the coro-
nary circulation.179
Prolongation of the ventricular refractory period by con-
trast media can initiate ventricular fibrillation. Fibrillation
occurs more commonly after right compared to left coronary
injection. The incidence is less with nonionic or iso-osmolar
contrast material and with ionic contrast with a physiologic
calcium ion content.49–52,57 The probability of ventricular
fibrillation also is higher if an excessive volume of contrast
material is injected in a single dose.
Hemodynamic Deterioration
Although catheterization of the coronary arteries does not
by itself change ventricular function, injection of contrast
media causes a reduction in diastolic ventricular compliance
and a brief reduction in systolic function. These effects
appear to be mediated by the osmolarity of the contrast agent
because iso-osmolar contrast has only minimal effects of
ventricular function.180
In patients with normal or near-normal ventricular
function, the ventricular effects of contrast are not impor-
tant clinically. Patients with markedly reduced systolic
function (ejection fraction <35%) or elevated ventricular
filling pressure (regardless of systolic function), however,
34
must be approached with caution, for these are the patients
who develop pulmonary edema after contrast injection.54,56,69
We often ascertain the left ventricular end diastolic or pul-
monary artery wedge pressure prior to angiography in
patients with a prior history of congestive left heart failure,
pulmonary edema, or severe left ventricular dysfunction,
particularly if they are decompensated. If the pulmonary
wedge pressure is more than 20 mm Hg, it should be reduced
prior to contrast injection and the pulmonary wedge or
mean pressure should be monitored during the angiogram.
Iso-osmolar contrast should be used. If the pressure rises
significantly, contrast injections should be withheld. Intra-
venous nitroglycerin or nitroprusside infusion during angi-
ography can be used to rapidly reduce filling pressures and
facilitate angiography. It is important to remember that con-
trast can affect ventricular diastolic function for up to 20
minutes.
Coronary Anatomy and
Radiographic Evaluation
Angiographic visualization of the heart, great vessels, and
coronary arteries is fundamental to the accurate diagnosis
of the wide spectrum of cardiovascular diseases that are
characterized by morphologic abnormalities. Whereas the
angiographic evaluation of the past several decades was based
solely on a visual assessment of the anatomy, today this
visual assessment is frequently aided by computer-assisted
quantitation of vessel dimensions and physiologic informa-
tion, allowing assessment of the functional effects of the
anatomic abnormalities.
Coronary Anatomy
Coronary Ostia
In humans as well as all birds, reptiles, and mammals, the
arterial supply to the heart arises from two ascending aortic
branches. The position of these branches that transverse the
atrioventricular and interventricular sulci in the shape of a
crown led early anatomists to designate the vessels as coro-
nary (or “crown”) arteries.181–183
The coronary ostia normally are located in the right and
left aortic sinuses of Valsalva. The ostia originate at the
center of each sinus, close to the free edge of the aortic cusp
and just below or no more than 1 cm above the superior edge
of the aortic cusp. Ostia located more than 1 cm above the
cusp edge are abnormal, occurring in less than 3% of
patients.184 Although two coronary ostia (one in each sinus)
are the rule, three or four separate ostia are considered
normal variants. In up to 30% of cases, the artery to the
pulmonary conus (conal artery) originates from a separate
ostium rather than its usual position as a branch from the
proximal right coronary. Absence of a left main coronary
trunk resulting in separate aortic origins for the left anterior
descending and circumflex arteries occurs in 0.5% to 1% of
patients.184 Most commonly these two ostia are closely jux-
taposed with the dual ostia existing as a “double barrel.”
Widely separated left anterior descending and circumflex
ostia are uncommon.
 corona ry a ngiogr a ph y
Orientation of Coronary Trunks
The anatomic configuration of the aortic-coronary junctions
has made careful quantitative measurements of the normal
coronary-aortic branching angles difficult. Using corrosion
casts obtained by injecting casting material through the
aorta under physiologic perfusion pressure, Zamir and Sin-
clair185 measured coronary-aortic branching angles in both
horizontal and vertical planes in normal hearts obtained at
autopsy. The mean horizontal branching angle was 25 degrees
(range 0–55 degrees) for the left main coronary and 35 degrees
(range 0–88 degrees) for the right main coronary. The mean
vertical branching angle was 102 degrees (range 77–145
degrees) for the left main and 69 degrees (range 34–110
degrees) for the right main coronary. These measured branch-
ing angles correlate poorly with what would be considered
optimal on theoretical grounds. Such data suggest that this
geometry reflects more the anatomy of the aortic root rather
than the fluid dynamic principles that usually govern arte-
rial branching.
Left Main Coronary Artery
The left coronary artery has a single initial trunk in 92% to
96% of autopsy cases.181,182,186 The length of the left coronary,
as derived from pathologic examinations, is 1.0 ± 0.3 cm.187
Pre- and postmortem angiographic studies have reported that
patients with bicuspid aortic valves have a higher incidence
of short left main arteries188 and left coronary dominance,189,190
although the findings have been refuted by some187,191 and
affirmed by others.192 Although angiographic measurements
of coronary diameter are probably more accurate than post-
mortem pathologic studies (due to changes inherent in the
postmortem state), angiographic measurements of coronary
length are probably less accurate due to underestimation of
the effects of rotation, angulation, and foreshortening.
Virmani et al.187 found no correlation of left main coronary
length with age, sex, heart weight, extent of coronary disease,
or left ventricular wall thickness.
The left main coronary consists of three portions: the
ostium or origin from the aorta; the midportion; and the
distal portion, which includes the bifurcating segments. His-
tologically the left main ostium lacks adventitia and has a
larger proportion of elastic tissue than any other area in the
coronary tree. These anatomic and histologic features may
account for some of the differences in the response of the left
main coronary to interventional procedures. Since the
left main ostium lies within the wall of the aorta it is vulner-
able to diseases primarily affecting the aorta: syphilitic
aortitis, rheumatoid arthritis, radiation-induced aortitis, and
Takayashi’s aortitis.193
Left Anterior Descending Artery
The left anterior descending artery is a direct continuation
of the left main coronary with its course along the anterior
interventricular sulcus. Several normal variations of the
length and distribution of this vessel have been recognized.
It is not essential for the anterior descending artery to reach
the cardiac apex or to have well-defined septal or diagonal
branches to qualify as the anterior descending artery,
although both are usually true.184 The number and promi-
76 3
nence of diagonal branches are variable. The diagonal branch
in its proximal portion may give rise to septal perforating
branches. This is especially likely in cases of chronic isch-
emic disease with anterior descending occlusion. Hence, the
angiographic recognition of a septal branch thus does not
conclusively identify the left anterior descending artery. The
cardiac apex is usually perfused by the anterior descending
artery but may be supplied by an unusually long diagonal
branch or right posterior descending artery.
Left Circumflex Artery
The circumflex artery is also a continuation of the left main
artery. Its initial course is in the left posterior atrioventricu-
lar groove, circumscribing the mitral valve. The extent and
distribution of the circumflex artery and right coronary
artery are generally reciprocal. If the circumflex artery is
extensive in its supply to the posterior and inferior walls of
the heart, the right coronary will usually be small with fewer
branches to these regions. The variability of this reciprocal
arrangement is great, with some hearts exhibiting a dual
vascular supply to the same anatomic regions (e.g., the infe-
rior septum) from both the right and circumflex arteries.
Ramus Intermedius Branch
In some hearts, the left main coronary exhibits a trifurcation
at its origin instead of the usual bifurcation. This third
artery, termed ramus intermedius (or diagonalis), acts func-
tionally as a circumflex branch, supplying a portion of the
obtuse margin of the heart. In a pathologic study of 150
hearts, Baptista and coworkers192 found that the left coronary
artery exhibited a bifurcation configuration in 55%, trifurca-
tion (with the ramus branch) in 39%, and a quadrifurcation
(ramus intermedius and a separate diagonal branch) in 7%.
A trifurcation pattern was most commonly found (60%) in
the hearts of female non-Caucasians. The length of the ramus
varied from 20 to 50 mm, and its relative length varied from
21% to 50% of the length of the left ventricle.
Right Coronary Artery
The right coronary runs in the anterior atrioventricular
groove and circumscribes the tricuspid valve. The first branch
of the right coronary artery is usually to the right ventricular
outflow tract (the conal branch), although this artery often
arises separately or from a common aortic ostium with the
right coronary. In midcourse, the right coronary normally
supplies branches to the right ventricle, which usually reach
the acute margin of the heart (so-called acute marginal
branches). In a small number of cases the right coronary may
have an anomalous intraatrial subendocardial course.194 This
unusual condition has no known adverse clinical outcomes
and is usually recognized only at autopsy. The anatomy of
the distal right coronary artery, particularly its size and
course over the left ventricle, is quite variable. In 50% to
60% of patients, the right coronary bifurcates at the crux of
the atrioventricular groove and the interventricular septum,
giving rise to the posterior descending branch (which runs
in the posterior interventricular sulcus to meet the anterior
descending artery coming from the anterior sulcus) and pos-
terior lateral branches (which perfuses the posterior lateral
76 4 chapter
left ventricle). In other cases, however, the posterior descend-
ing branch may arise before the crux, either at the acute
margin (13%) or at an intermediate position (19%).195 In 10%
to 20% of patients, none of the left ventricular branches arise
from the right coronary artery, coming instead from the ter-
minal portion of the circumflex artery (see Coronary Domi-
nance, below).186,196
Sinus Node Artery
In 51% to 70% of humans, the sinus node artery arises from
the right coronary artery.195,196 In contrast, the sinus node
artery of swine and dogs almost always (90–100%) arises
from the right coronary.186,197 The sinus node artery arises
from the circumflex artery in the remainder of patients. The
sinus node artery is usually the second branch of the right
coronary artery (excluding the conal branch) and is generally
the first and largest atrial branch. When the sinus node does
not originate from the right coronary artery, it usually is a
branch of the circumflex artery. In an anatomic study of 300
human hearts, Nerantzis and Avgoustakis198 found that the
sinus node artery arose from the circumflex in 37% of cases.
Although this circumflex sinus node artery usually arises
near the origin of the circumflex, in 21% of patients with a
circumflex origin the artery is an S-shaped vessel that origi-
nates from the posterior-lateral branch of the circumflex.
This S-shaped sinus node artery can function as a bridge
between the right and left coronary trunks in the case of
proximal coronary occlusions.
Atrioventricular Nodal Artery
The atrioventricular nodal artery in nearly 90% of humans
arises from the right coronary artery in the area of the crux.
In the remainder this artery is a branch of the circumflex
artery. This pattern of vascular supply is similar to that seen
in swine, but differs greatly from the dog.197 In canines,
because of a small nondominant right coronary, the AV nodal
artery arises from the left circumflex artery in almost
100%.186,197
Vascular Supply to the Interventricular Septum
In over 99% of patients the blood supply to the anterior
interventricular septum is from the left anterior descending
coronary.199 In the majority of patients, there is no dominant
septal artery; rather, the proximal septal vessels are of equal
caliber. In 38%, a large dominant septal perforator occurs,
and this is usually but not always the first septal. Septal
perforators may exhibit bifurcation or trifurcation. The
branching pattern is unordered (i.e., tertiary branches may
arise from the primary vessel).200
Septal branches from the posterior descending artery,
arising from either the right coronary or left circumflex
artery, are the usual vascular supply to the posterior septum.
In rare instances, the posterior descending may originate
from the first septal branch of the anterior descending or
from an obtuse marginal branch of the circumflex artery.
A more common variant that occurs to differing degrees
is the “wrap-around” left anterior descending. In such
cases, the posterior septum is supplied by the anterior
descending artery. Distal left anterior descending occlusion
34
can result in an inferior wall ischemic pattern on the
electrocardiogram.
Coronary Dominance
The term coronary dominance was introduced by
Schlesinger201 in 1940. The “dominant” coronary artery is
the one that gives rise to the posterior descending artery,
traversing the posterior interventricular sulcus and supply-
ing the posterior part of the ventricular septum and often the
posterolateral wall of the left ventricle as well.202 The right
coronary artery is dominant in approximately 70% of
humans.203 If the circumflex artery terminates in the poste-
rior descending artery, left dominance is present. This is seen
in 15%. In the remaining 15%, the posterior septum is sup-
plied by branches arising from both the right coronary and
left circumflex artery. In this situation the circulation is said
to be “balanced” (or codominant) and the posterior descend-
ing is either dual or absent,202 being supplied by a network of
small branches. It should be noted that anatomic dominance
does not imply physiologic dominance. Although the right
coronary artery is usually dominant, the left coronary almost
always supplies a greater myocardial mass.204
Standard Nomenclature
To facilitate clinical studies and communication between
clinicians, several systems of coronary nomenclature have
been developed. These clinical systems often apply slightly
different names to arterial segments than are used in the
anatomy literature. The most commonly used system was
developed for the Bypass Angioplasty Revascularization
Intervention (BARI) trial.205
Angiographic Views
The importance of obtaining adequate angiographic views of
the coronary arteries cannot be overemphasized. Since the
orientation between the planes of the major cardiac grooves
and septum are different from the standard anteroposterior
(AP) and lateral projections utilized for chest roentgenology,
oblique views must be used to obtain optimal angiographic
visualization of the coronary arteries. An understanding of
the orientation of these structures and the coronary vessels
in the oblique positions can be difficult for the novice, but
several teaching models have been developed to facilitate
understanding.206–208
We have utilized the schematic diagram shown in Figure
34.9, in which the eyes represent the line of sight of the
viewer. In the LAO projection the viewer is sighting down the
interventricular and interatrial septum. All left-sided cardiac
chambers appear to the viewer’s right. In the LAO projection,
the anterior and posterior descending coronary arteries are
seen coursing vertically in the middle of the cardiac silhou-
ette, following the path of the interventricular septum. In the
RAO projection, the viewer’s line of sight is the atrioventricu-
lar groove plane. In this projection the two atria and the two
ventricles are superimposed. The proximal circumflex and
proximal right coronary arteries are well visualized as they
follow their course in the atrioventricular groove.
The angiographer must evaluate the entire vessel in
several different views to avoid the effects of vessel foreshort-
 corona ry a ngiogr a ph y
Transverse Plane
Posterior
LA
Right Left
RA LV
Lateral View
RV
Anterior
RAO View LAO View
Frontal (PA) View
FIGURE 34.9. Schematic depicting cardiac chamber locations as
viewed in the four standard radiographic projections: Frontal (pos-
teroanterior, PA), lateral, right anterior oblique (RAO), and left ante-
rior oblique (LAO). The eyes represent the viewer’s line of sight.
ening that can hide a stenotic lesion and because coronary
lesions are frequently eccentric. Although the severity of a
coronary stenosis is often reported as the most severe appear-
ance measured in any of the views, physiologic studies show
that an integration of lumen stenosis from many views more
accurately predicts the degree of blood flow impairment
imparted by the lesion.209 In truth, if the lesion can be well
visualized, all views are contributory toward assessing ste-
nosis severity. Additionally, when quantitative angiographic
methods are employed, coronary lesions are best evaluated
in at least two orthogonal projections (e.g., LAO 60 degrees
and RAO 30 degrees) in which the lesion can be seen well in
both projections without foreshortening or overlap.210
In 1981 Paulin211 proposed that radiographic projections
be named by following the course of the x-ray beam as it
passes through the heart. The x-ray gantry can be angled in
the horizontal and coronal planes. The position of the imaging
device defines the projection. In the LAO projection, the x-
ray beam is angled in the horizontal plane such that it is
projected from under and to the right of the patient (right
posterior) to the image intensifier, which is anterior and to
the patient’s left. Similarly, the x-ray beam of the RAO view
originates in the left posterior aspect and passes to the image
tube, which is anterior and rotated to the patient’s right. In
caudocranial views the x-ray beam is angled in the coronal
(frontal) plane. In the “cranial” view, the x-ray beam origi-
nates caudally and passes through the heart to the image
intensifier, which is angled cranially. Conversely, in a caudal
projection the x-ray tube is angled cranially and projects the
x-ray beam caudally to the image tube. The use of multiple
oblique views in the anterolateral projection in conjunction
with angulation in the caudocranial plane has greatly
facilitated optimal visualization of coronary lesions and
76 5
minimized the problem of foreshortening of the coronary
arteries.
The use of a standard set of optimal projections for coro-
nary angiography is at best only a guide, since variations in
normal coronary anatomy are the rule rather than the
exception. The following suggestions may be of some help.
The left main coronary artery, which under most circum-
stances should be visualized first and with great care, can
be seen best in the posteroanterior (PA) (Fig. 34.10) or in a
very shallow oblique projection (either RAO or LAO) so that
the left main coronary is just off the spine. The circumflex
artery and its marginal branches can be defined in the RAO
projection (20- or 30-degree angulation) with 20 to 30
degrees of caudal angulation (Fig. 34.10). A second less steep
RAO or PA view coupled with marked cranial angulation
(30 degrees) (Fig. 34.10) may be helpful in delineating the
course of the anterior descending artery, avoiding overlap
by other branches. A steep LAO view (40 degrees) with
severe cranial angulation (40 degrees) (Fig. 34.10) is essential
in viewing the left anterior descending and diagonal branch
bifurcation. An additional LAO caudal view (LAO 40
degrees, caudal 30 degrees, the so-called spider view) (Fig.
34.10) may be of use in visualizing the bifurcation of the
left main, the proximal circumflex, and left anterior
descending and at times the distal left anterior descending.
The proximal and mid-right coronary arteries are usually
seen well in a 30- to 45-degree LAO projection. A moderate
LAO view with cranial angulation (LAO 20 degrees, cranial
20 degrees) (Fig. 34.11A) may be ideal for viewing the bifur-
cation of the distal right coronary into the posterior descend-
ing and posterior lateral branches. One view of the right
coronary in the RAO view is necessary. At times visualiza-
tion of the distal right coronary is helped by adding cranial
angulation (sometimes up to 60 degrees) to the RAO view
(Fig. 34.11B).
A common series of initial projections are as follows:
Left coronary
1. LAO 5
2. RAO 30, caudal 20
3. PA, cranial 40
4. LAO 40–45, cranial 30–40
5. LAO 40, caudal 30
Right coronary
1. LAO 40, cranial 20
2. RAO 45
3. PA, cranial 35 if bifurcation not seen
Rotational Angiography
The development of rapidly rotating x-ray gantries and digital
imaging makes it possible to image the coronaries from a
180-degree arc during one coronary contrast injection, reduc-
ing the number of angiographic runs needed to image the
coronaries from multiple projections. In one study, the con-
trast dose using this rotational method was reduced by 27%
and the x-ray dose by 40%, although there was a learning
curve for adopting the method.212 The accuracy of coronary
lesion interpretation appeared to be similar to planar imaging,
but the method is still in its infancy.
76 6 chapter 34

FIGURE 34.10. Angiographic projections of a normal left coronary

artery. (A) Selective left coronary angiogram viewed with 30-degree RAO
and 20-degree caudal angulation. (B) Same vessel viewed with 30-degree
RAO and 30-degree cranial angulation. (C) Same vessel viewed in the PA
projection with 35-degree cranial angulation. (D) Same vessel viewed
with 40-degree LAO and 30-degree cranial angulation. (E) Same vessel
viewed with 30-degree LAO and 30-degree caudal angulation. LAD, left
anterior descending; Cx, circumflex; RI, ramus intermedius; LM, left
main.
 corona ry a ngiogr a ph y
FIGURE 34.11. Angiographic projections of a normal right coro-
nary artery. (A) Selective right coronary angiogram viewed with
30-degree LAO. (B) Same vessel viewed with 45-degree RAO. RCA,
Coronary Artery Dimensions
Normal Dimensions in Humans
It has become recognized increasingly that measurements of
coronary artery dimensions at autopsy do not correlate well
with in vivo angiographic measurements of coronary diam-
eter.213–217 The importance of accurate measurements of
normal coronary caliber is underscored by the understanding
that coronary atherosclerosis is primarily a diffuse disease
process that may be difficult to recognize angiographically.218
Thus, without knowing the “true” caliber of an artery it is
often difficult to conclude whether a given coronary segment
that appears normal angiographically is normal anatomi-
cally.219 The importance of recognizing diffuse coronary nar-
rowing is underscored by studies in patients with advanced
atherosclerosis showing that angiographic measurements
based on lesion percent stenosis (as a fraction of the diameter
of the adjacent normal segment) correlate poorly with physi-
ologic measurements of the effect of a given focal stenosis
on coronary blood flow.220,221 The rationale for expressing
lesion severity as percent stenosis has recently been rendered
even more tenuous by the findings that in atherosclerosis,
compensatory coronary enlargement precedes the process of
luminal narrowing, and often compensates for any narrow-
ing until this narrowing reaches 40% of the intimal lumen222
(Fig. 34.12).
Dodge and coworkers223 used computer-based quantita-
tion of angiograms to measure coronary lumen diameter at
96 points in 32 defined coronary segments or major branches
in normal arteriograms carefully selected from over 9000
consecutive studies. In these angiograms, absolutely smooth
lumen borders were used to indicate likely freedom from
atherosclerotic disease. For these normal arteries, a round
767
right coronary artery; PDA, posterior descending artery; PLA, pos-
terolateral artery.
cross section was assumed, and the cross-sectional area was
estimated to be: (Coronary diameter)2 ÷ (π · 4).
The summed cross-sectional areas of the main right
coronary, the proximal left anterior descending, and proxi-
mal circumflex arteries were called the total coronary area.
A summary of these results is given in Table 34.2 and
Figure 34.13. In men with a large dominant right coronary
distribution, the total coronary area was 32.1 ± 7.3 mm2
with the right coronary contributing 38% of the total area,
the circumflex 29%, and the left anterior descending 33%.
The total coronary area was not statistically different
between patients with small right coronary, balanced, and
dominant left coronary distributions (33.5 ± 9.3, 26.8 ± 5.2,
and 30.7 ± 5.5 mm2, respectively.223 Using these measure-
ments and those of others224,225 it is usually possible to esti-
mate “normal” coronary segment diameter in men and
women to within ±25% (coefficient of variation). Unfortu-
nately, nitroglycerin was not given in these studies so that
the effects of differences in coronary vasomotor tone were
not standardized.
Muscularis
Diameter Plaque
Lumen
Time
FIGURE 34.12. Concept of compensatory coronary dilation as ini-
tially proposed by Glagov et al.222 The early atherosclerotic plaque
development is associated with a compensatory increase in lumen
area. No decrease in lumen caliber is seen until the stenosis reaches
nearly 40%.
76 8 chapter 34

TABLE 34.2. Diameter of the main coronary arteries in normal Coronary dilation and increased coronary tone is also seen
men, normal women, and men with left ventricular hypertrophy in long-distance runners.234 Coronary dilation can also result
or dilated cardiomyopathy
from fistulous connections between the artery and a cardiac
Men Women, chamber or vein.
RCA dominant Men with Men with
Location dominant RCA DCM LVH
Effects of Gender, Weight, Age, and Tortuosity on
LM mid 4.5 ± 0.5 3.9 ± 0.4 4.8 ± 0.3 4.9 ± 0.4 Coronary Caliber
Proximal 3.6 ± 0.5 3.2 ± 0.5 3.8 ± 0.5 3.9 ± 0.5
The evidence suggests that females have higher morbidity
LAD
and mortality resulting from attempts at coronary revascu-
Distal LAD 1.7 ± 0.5 1.6 ± 0.4 2.0 ± 0.4 2.1 ± 0.5
larization either with angioplasty235 or bypass surgery.236,237
Proximal Cx 3.4 ± 0.5 2.9 ± 0.6 3.3 ± 0.7 3.6 ± 0.6 Speculation as to reasons for apparent differences in results
Distal Cx 1.6 ± 0.6 1.4 ± 0.4 2.1 ± 1.0 1.7 ± 0.6 has focused on differences in coronary size between men and
Proximal RCA 3.9 ± 0.6 3.3 ± 0.6 4.5 ± 0.5 4.6 ± 0.7 women. In one report, the proximal coronary lumen diame-
Distal RCA 3.1 ± 0.5 3.0 ± 0.5 3.7 ± 0.3 4.1 ± 0.5 ter of women with normal arteries and a right dominant
RCA, right coronary artery; LCA, left coronary artery; R, right coronary coronary circulation was 9% ± 8% less than in similar men.
artery; LM, left main; L, left anterior descending; C, circumflex. Values are In the same study, women had 15.3% smaller main coronary
mean ± SD.
branch areas when normalized for body surface area. In a
collaborative study involving multiple institutions in north-
ern New England, O’Connor et al.237 recorded prospectively
body weight and the luminal diameter of the mid-left ante-
rior descending (LAD) branch in 1325 patients undergoing
Influence of Coronary Artery Length and
coronary artery bypass surgery. Vessel size was strongly
Dominance on Coronary Caliber
The normal diameter of a coronary artery is proportionately
related to the length of the vessel. Although the diameters
of the left main and the left anterior descending segments
are unaffected by anatomic perfusion field size, the left cir-
cumflex artery or right coronary artery is usually signifi-
cantly larger when dominant.223 The diameter of the posterior
descending artery, however, is similar regardless of whether
it arises from the right or circumflex arteries.223
The epicardial distribution, characterized by the arterial
length relative to the distance from its origin to the left
ventricular apex is the principal determinant of branch
diameter. There is a close correlation between the lumen
area of a coronary artery at each point along its length and
the corresponding summed distal branch lengths and regional Lm
myocardial mass, in patients with and without coronary
artery disease.226
C1
R1
Effects of Other Physiologic and Pathologic
Variables on Coronary Caliber
Multiple other physiologic and pathologic processes affect L1
coronary caliber. Acute changes in perfusion pressure mark-
edly alter coronary diameter by changing the distending
force.226 Increased blood flow from heightened myocardial
C3
oxygen demand (e.g., increased heart rate) or drug adminis-
tration lead to coronary relaxation 227–229 by an endothelial- L3
dependent mechanism that affects coronary smooth muscle
vasomotor tone.230 The effects of intraluminal pressure and
endothelial-mediated dilation on coronary caliber can be
altered significantly by vascular pathology.
Other conditions lead to anatomic coronary dilation via
a chronic increase in coronary blood flow. Hypertension and R3
the wide range of conditions resulting in left ventricular
hypertrophy231–233 result in marked increases in epicardial
vessel size.231 When body surface area is used to normalize FIGURE 34.13. Diagram of coronary artery segment nomenclature
for a right coronary dominant circulation. LM, left main; R1, proxi-
for differences in body size, men with left ventricular hyper- mal right coronary; R3, distal right coronary; L1, proximal left
trophy or dilated cardiomyopathy have 37% or 31% larger anterior descending; L3, distal left anterior descending; C1, proxi-
coronary segment areas, respectively, than normal men.223 mal circumflex; C3, distal circumflex (see Table 34.2).
 corona ry a ngiogr a ph y 76 9
related to both gender and body size (body surface area, mass Relationship Between Angiographic Coronary
index, height, and weight). Within each quartile of body size Anatomy and Myocardial Perfusion Field
measurements, the mid-LAD diameter in men was greater (Risk Region)
than that in women with a mean difference range of 0.14 to
There is considerable experimental data relating myocardial
0.23 mm. The smaller LAD diameter in women was also
infarct size and consequent clinical outcomes to the mass of
associated with increased risk of mortality from coronary
myocardium perfused by an infarct-related coronary
bypass surgery. Differing results were found when Kornowski
artery.204,246,247 Calculation of the infarct/risk area ratio is
et al.238 compared coronary cross-sectional area luminal nar-
critical to the assessment of interventions aimed at limiting
rowing, plaque quality, plaque calcium, and lumen location
infarct size. Relating coronary anatomy as viewed from the
in 549 men and 169 women with chronic stable angina using
coronary arteriogram to the myocardial perfusion volume or
intravascular ultrasound. These investigators found that
risk area, however, has proven difficult to accomplish in the
when corrected for body surface area, no differences in these
clinical setting. Quantitating these relationships in patients
parameters of atherosclerosis between men and women could
with atherosclerosis is difficult because of complexities
be identified.
introduced by the presence of diffuse luminal narrowing and
Age, if considered separately from an increased possibil-
vessel occlusion.
ity of the presence of diffuse atherosclerosis, is thought gen-
Experimental studies in normal animals have shown
erally to increase coronary caliber.239 Dodge et al.,223 however,
that geometric characteristics of the arterial tree relate
found no age-related trend toward increased total coronary
directly to regional myocardial perfusion volume. Koiwa’s
area in normal men when the coronary diameter was nor-
group248 has shown in dogs that the maximally dilated
malized for body surface area. Total coronary area in men
coronary artery luminal cross-sectional area is related lin-
with apparently normal coronary arteries was virtually con-
early to the volume it perfuses. The cumulative length of
stant at 15.2 ± 3.6 mm2/m2. Of note, however, in the LAD
arterial branches is also related to the myocardial perfusion
artery a positive correlation was found between age and
volume.249
vessel tortuosity, but not between tortuosity and lumen
In humans, radioisotopic techniques have been used to
diameter. In contrast, Leung et al.240 found a progressive age-
measure the region at risk. Using a method initially vali-
related decrease in the cross-sectioned area of each proximal
dated in the pig,250 technetium-99m–radiolabeled albumin
coronary and reduced total coronary cross-sectional area.
microspheres were injected directly into both coronary arter-
These authors speculate that such changes may be due to
ies of patients presenting with acute infarction during the
decreased coronary flow requirements, attenuated endothe-
period of total coronary occlusion and again following
lial vasodilatory responses, or age-related changes in myo-
achievement of lumen patency after intracoronary throm-
cardial composition.
bolysis.204 Delayed scanning revealed perfusion deficits that
could be quantitated as the area at risk and correlated with
Effects of Normal Variations in Coronary the exact site of coronary occlusion determined with acute
Vasomotor Tone on Coronary Caliber coronary angiography (Fig. 34.14). Data from a limited number
of patients studied with these techniques revealed that infe-
The importance of coronary vasomotor tone on measure-
rior infarcts secondary to right or circumflex coronary artery
ments of coronary caliber, though widely acknowledged, is
occlusions were associated with areas of risk ranging from
often ignored. Normal proximal epicardial coronary caliber
10% to 26% (mean 18%) of left ventricular mass. In contrast,
can increase up to 30% after administration of nitroglycerin,
anterior infarctions resulting from left anterior descending
if coronary perfusion pressure is maintained.241 Angiographic
artery occlusions had risk areas of 14% to 49% (mean 39%).
studies show striking variations in coronary tone depending
Two patients who subsequently expired had risk regions of
on time of day242 and psychological stress.243 In atheroscle-
over 40% of the left ventricular mass. Importantly, the area
rotic monkeys, coronary vasomotor responses can be modu-
lated by estrogen treatment.244 Despite the acknowledgment
of the importance of coronary vasomotor tone, quantitative
studies of atherosclerosis progression or regression too
frequently are performed with this important variable 70
Successful reperfusion (16) N = 29
uncontrolled. 60 Unsuccessful reperfusion (11)
Although vasodilation in response to nitroglycerin is Patient died
seen in normal coronary segments of all sizes, the response 50
% Area at risk

varies in magnitude.95 Those epicardial coronary segments

40
with the smallest basal diameter show the greatest relative
change in dimension.95 Since most coronary stenoses have a 30
portion of the vascular circumference that is relatively
normal, even severe stenoses may dilate in response to nitro- 20
glycerin. However, if stenosis severity is calculated as percent 10
stenosis (comparing lesion diameter to the diameter of the
adjacent normal segment), the stenosis may artifactually 0
RCA LAD CX
RCA
appear to worsen after nitroglycerin administration because + CX
of a comparatively greater dilatory effect on the adjacent FIGURE 34.14. Relationship between site of coronary occlusion
normal segment.245 and the size of the risk area.
770 chapter
of the region at risk could not be predicted by careful visual
assessment of the coronary angiogram.
Intravenous technetium-99 m sestamibi has also been
used to measure the area at risk in patients with acute infarc-
tion.251,252 The lack of redistribution with this radiopharma-
ceutical permits imaging to be done with single photon
emission computed tomography up to 6 hours after injection.
Using this technique, quantitative measurements of the
infarct risk area in patients with an initial acute infarction
correlated poorly with the “best estimate” of two experi-
enced angiographers.252 These data emphasize again the vari-
ability of risk areas that are not predictable by the anatomic
site of coronary occlusion, and the inability of angiographers
to predict the risk area in individual patients.
Leung et al.240 and others253 developed a semiquantitative
method for determining the myocardial territory supplied by
a nutrient vessel based on the relative size of the vessel as
judged by the summed length of the terminal vessel segment.
Although this method is easy to use and has acceptable
interobserver variability, it has not been validated in an
animal model.
Congenital Coronary Anomalies
Embryology
Although a thorough description of the genesis of the coro-
nary circulation is beyond the scope of this chapter, a few
important considerations are appropriate. There are at least
three major anatomic components important in the develop-
ment of the coronary arterial bed: the myocardial sinusoids,
the in-situ vascular network, and the coronary anlage184 (Fig.
34.15). The myocardial sinusoids are an elongation of the
trabeculae into the developing myocardium. The sinusoids
are the earliest sites of metabolic exchange between the
blood contained in the cavities and the cardiac mesenchyma
FIGURE 34.15. Schematic illustration of three major components
responsible for development of the coronary arterial bed: myocardial
sinusoids, in-situ vascular network, and coronary anlage (buds).
34
TABLE 34.3. Incidence of coronary artery anomalies, detected by
angiography
Author (ref.) Total no. of patients Anomalies Incidence (%)
Liberthson 289 Not stated 21 0.6
Engel 257 4,250 51 1.2
Chaitman 285 3,750 31 0.83
Baltaxe258 1,000 9 0.9
Kimbiris 7,000 45 0.64
Hobbs297 9,153 601 1.55
Wilkins256 10,661 83 0.78
Yamanaka 254 126,595 1,686 1.3
(myocardial jelly). The in-situ vascular endothelial network
develops separately in the subepicardium 31 days after ovula-
tion. The coronary anlage (buds) sprout from the wall of the
aorta-pulmonary trunk as septation is proceeding. After
completion of aortopulmonary septation these latter two
components fuse and a normal coronary circulation begins.
Although the coronary ostia are formed quite early, the distal
coronary branching pattern remains as a variable inter-
branching network until the cardiac chambers develop.
The size and distribution of the coronary arteries are
related to and dependent on subsequent myocardial chamber
development. According to Angelini,184 a true mismatch
between the dependent myocardium and its related coronary
arteries is embryologically improbable. Therefore, on physi-
ologic grounds, the finding of coronary atresia or hypoplasia
is unlikely. Instead, either the dependent myocardium is also
hypoplastic or, more commonly, the opposite coronary is
relatively oversized. Thus, at birth the coronary circulation
is usually effectively normal in global physiologic terms and
the angiographic finding of a coronary artery that appears
hypoplastic is usually only an infrequently occurring coro-
nary arterial pattern. Some coronary anomalies still occur,
however, and are well recognized to be associated with major
adverse clinical consequences.
Incidence and Classification
Tabulations of coronary angiograms suggest that coronary
anomalies occur in the adult population with an incidence
ranging from 0.6% to 1.3%254–258 Yamanaka and Hobbs254
reported the Cleveland Clinic experience from 1960 to 1988
reviewing data from 126,595 angiograms. Coronary artery
anomalies were found in 1686 patients, an incidence of 1.3%.
Of the coronary anomalies, 87% involved the origin and
distribution of the vessel, and 13% were coronary artery fis-
tulas. Table 34.3 shows the incidence for various coronary
anomalies from the Cleveland Clinic study. Since the angio-
grams were obtained primarily to assess coronary atheroscle-
rosis in adults, congenital coronary anomalies resulting in
early or sudden death are not represented.
A variety of classification schema for congenital coro-
nary anomalies has been proposed.259 Although each has its
attributes, the most clinically useful classification divides
congenital coronary anomalies into those that are usually
associated with a benign outcome, and those whose natural
history is associated with adverse events. Most adverse out-
comes appear to result from decreased myocardial perfusion,
 corona ry a ngiogr a ph y 7 71
although the mechanism of such an ischemia is speculative.
Coronary atherosclerosis does not seem to occur with
increased incidence in anomalous vessels nor is the presence
of coronary anomalies protective against coronary artery
disease.254

Congenital Coronary Anomalies, Often Benign

MYOCARDIAL BRIDGES
That portions of the conduit coronary arteries may take a
short intramural course and be covered by a muscle “bridge”
has been part of the anatomic literature since 1737.260 However,
the clinical significance of such anatomy is more recent in
origin. Muscular myocardial bridges are recognized angio-
graphically by the characteristic narrowing of the coronary
lumen that is seen during systole and that is absent during
diastole. Although most cases of angiographic systolic nar-
rowing correspond with anatomic myocardial bridges, this
finding occasionally may be caused by other mechanisms
A
such as pericardial fibrosis, tumors, or foreign bodies.261
Coronary arterial location in mammalian hearts has
been classified into three main types: type A (hamster, squir-
rel, rat, guinea pig, and rabbit), in which the coronary arteries
are entirely intramyocardial; type B (goat, sheep, dog, cat,
macaque, and humans), in which the coronary arteries are
predominantly epicardial but myocardial bridging is fre-
quent; and type C (horse, cow, pig), in which the coronary
arteries are entirely epicardial and bridging is rarely if ever
seen.262 In humans and other type B mammals, myocardial
bridges are found most frequently in the left anterior descend-
ing artery. Table 34.4 details the incidence of muscular
bridges in the experience of four groups of investigators.
When the results of eight separate autopsy studies were
pooled, myocardial bridges were found in 449 of 1652 cases
(27%).263 This high frequency coupled with the comparative
anatomic data suggest that myocardial bridging is often a
“normal” finding.
The most frequent site of bridging is the mid-segment of B
the left anterior descending artery (Fig. 34.16). A typical mus- FIGURE 34.16. Selective coronary angiogram showing a distinct
cular bridge in this artery is 10 to 20 mm long and 2 to 4 mm muscular bridge in the left anterior descending artery. (A) Selective
thick.261 Portions of other arteries that are located in the coronary angiogram showing a muscular bridge in the left anterior
atrioventricular groove (such as the proximal–middle right descending artery. In diastole, the artery (arrows) is normally dis-
tended. (B) In systole, the artery is compressed by a muscle bridge
and circumflex arteries) are frequently surrounded by scat- (arrows).

TABLE 34.4. Anatomic incidence of muscular bridges (MBs)* tered muscular fibers continuous with the atrial myocar-
262 278
dium and may also exhibit systolic narrowing. These are
Source Polacek Edwards
referred to as myocardial loops. As another variant, arteries
No. of cases 70 270 such as the obtuse marginal branch and ramus intermedius,
Male/female NS NS which are located over the free wall of the left ventricle, may
Incidence of MB (%): plunge into the myocardium at some point in their course.
LCA + RCA 85.7 5.4 These arteries frequently do not resurface. Anatomic studies
LCA 77.7 5.1 suggest that the prevalence of myocardial bridging involving
LAD 60.0 4.7 major coronary veins is less than 5%.262
DIAG 18.5 NS Angiographic studies of myocardial bridging in humans
have shown a much lower prevalence than seen in autopsy
CX 40.0 NS
studies, usually ranging from 0.5% to 7.5%.261,264,265 In one
OM 14.2 0.4
series, however, the occurrence was 16%.266 For systolic nar-
RCA 41.4 0.4
rowing to occur, the external muscular compressive force
* Incidence of muscular bridges. Percentage of patients with muscular bridges must exceed the arterial pressure and the intrinsic arterial
in different locations.
wall stiffness. During angiography, the increased intralumi-
LCA, left coronary artery; RCA, right coronary artery; LAD, left anterior
descending; DIAG, diagonal; CX, circumflex; OM, obtuse marginal; NS, not nal pressure resulting from the pressure of contrast injection
stated. may act to diminish recognition of lesser intramyocardial
772 chapter
bridges than might be detected in anatomic studies. In one
study, the mean maximum corrected length of artery involved
in the muscle bridge was 15 mm (range 9 to 44 mm) and the
maximum percent reduction in diameter during systole was
56% (range 30–100%).264 Long myocardial bridges, often
referred to as tunnels, have been described.
Although scattered reports have attributed chest pain in
patients with normal coronary arteries to the finding of a
myocardial bridge, these two conditions are not frequently
related causally. Patients with equal degrees of systolic nar-
rowing do not exhibit a similar clinical or pathophysiologic
response. Since coronary flow is predominantly diastolic and
some animals have wholly intramyocardial arteries, luminal
compression during systole is unlikely to play a frequent role
in causing myocardial ischemia. Experimental studies in
dogs have shown that systolic myocardial contraction does
not limit coronary flow at heart rates less than 160 beats/min
or unless coronary compression extends into early diastole.267
Doppler flow studies in one patient with myocardial bridging
and normal arteries have confirmed these findings.117 The
use of intracoronary Doppler measurements of coronary flow
and intravascular ultrasonography (IVUS) may help in defin-
ing the clinical significance of coronary bridging.268
Delayed diastolic relaxation in the bridged segment in
humans has been reported 269,270 using intravascular ultra-
sound. Rapid atrial pacing with marked shortening of the
coronary diastolic perfusion time, especially if combined
with left ventricular hypertrophy, may rarely result in myo-
cardial ischemia in patients with bridging.271 Thus it is pos-
sible that certain myocardial bridges, especially those of long
length that course deeply within the myocardium,272 may be
responsible for sudden unexpected cardiac death following
tachycardia-related ischemia. These occurrences are likely
quite rare, although this anomaly has been reported as the
sole cardiac anomaly in young patients with sudden unex-
pected death.273
Several anatomic studies have reported a protective effect
of myocardial bridging.261,274–276 In rabbits whose proximal
coronary arteries are exclusively intramural, cholesterol-
induced atherosclerosis spares these arteries even when
severe lesions develop in the subendocardial arteries.261 The
mechanism of such a protective effect is unknown but may
involve protection from systolic wall stress. In humans, myo-
cardial bridges may slightly increase the chances of proximal
coronary atherosclerosis, while protecting the bridged
segment and the distal artery. Postmortem human morpho-
metric studies have shown that when proximal myocardial
bridging is present, intimal thickening and macroscopic
raised atherosclerotic lesions are increased just before the
bridge. Under the bridge, eccentric plaques and raised lesions
are absent, although there is often concentric intimal thick-
ening.277,278 There are isolated case reports of acute myocar-
dial infarction associated with muscle bridges.279,280 However,
when carefully examined, the overall frequency of myocar-
dial infarction is the same in patients with and without
myocardial bridges.
Myocardial bridges have been recognized with increased
frequency following cardiac transplantation. Review of the
angiograms of 64 cardiac transplant patients revealed a 33%
incidence of myocardial bridging, a much higher angiograph-
ically detected incidence than would be expected in the
34
normal population.281 Administration of nitroglycerin accen-
tuated the degree of systolic narrowing.282
There is a well-described association between left ven-
tricular hypertrophy (as seen in aortic stenosis, hypertrophic
cardiomyopathy and hypertension) and an increased inci-
dence of myocardial bridges.274,283 This may relate to a greater
contractile force generated by the myocardium. Although
angiographically detected systolic compression occurs rarely
in normal intramural septal arteries, septal “twinkling” or
“squeeze” resulting from prominent widespread systolic
septal compression is commonly seen in patients with aortic
stenosis (71%) and hypertrophic cardiomyopathy (74%).283
ORIGIN OF THE L EFT CIRCUMFLEX FROM THE R IGHT
CORONARY SINUS
In the United States the origin of the left circumflex artery
from the right aortic sinus or from the right coronary
artery is the most common anomaly of coronary arterial
origin.284–286 Most patients have no other associated anoma-
lies and no deleterious effects resulting from this congenital
anomaly. The anomalous circumflex courses posterior to the
aortic root and the noncoronary sinus to enter the left atrio-
ventricular groove and ultimately perfuse its usual territory
(Fig. 34.17). The size and variation of the perfusion field is
similar to that of the normal circumflex artery.
An anomalous origin of the circumflex artery should be
suspected when contrast injection into the left coronary
artery reveals what appears to be an unusually long left main
coronary or flush occlusion of the circumflex (Fig. 34.18).284
The anomalous circumflex origin is often missed during
right coronary angiography since deep seating of the right
coronary catheter may prevent sufficient reflux of contrast
to opacify the aberrant origin (Fig. 34.19). If suspected, the
catheter should be withdrawn slowly and repositioned poste-
riorly in the right sinus of Valsalva and the injection repeated
(Fig. 34.20). A right vein bypass curve catheter can be useful
in cannulating the circumflex ostium, which often is directed
inferiorly.287
In this anomaly, the proximal circumflex invariably runs
a retroaortic course and does not cross between the great
vessels. It has no clinical significance unless the angiogra-
pher assumes the vessel is occluded or a significant stenosis
in the artery is not identified.
SEPARATE ORIGINS OF THE L EFT A NTERIOR DESCENDING
AND L EFT CIRCUMFLEX FROM THE SINUS OF VALSALVA
In this common anomaly the left anterior descending and
circumflex arteries arise from separate but adjacent ostia and
FIGURE 34.17. Views of the aortic (left) and pulmonary (right)
valves showing normal origin of the coronary arteries (left) and
anomalous origin of the circumflex artery from the right coronary
artery and its usual course posterior to the aorta.
 corona ry a ngiogr a ph y
FIGURE 34.18. Selective left coronary artery angiogram in a patient
with anomalous origin of the left circumflex from the right coro-
nary artery. Note the apparent very long left main coronary caused
by the absence of a circumflex branch.
a common left main trunk is absent (Fig. 34.21).288 The dis-
tribution pattern of both arteries is otherwise normal. The
anomaly is associated with aortic valve disease and left coro-
nary dominance.289 At angiography it can be difficult to
determine whether the left main is truly absent or very short,
or if a common ostium is present. Occasionally, different
catheter curves are needed to inject contrast into the separate
left anterior descending and circumflex branches (Fig. 34.22).
If unrecognized at catheterization, one of the major left
FIGURE 34.19. Selective right coronary angiogram from the same
patient as in Figure 34.18. Note that the catheter is positioned deeply
into the ostium of the vessel so that no contrast reflux into the sinus
is seen. No anomalous circumflex artery is demonstrated.
773
FIGURE 34.20. Repeat selective right coronary angiogram from the
same patient as in Figure 34.19. The catheter has been pulled back
and the anomalous circumflex is now apparent.
coronary branches may be misinterpreted as being totally
occluded.
A NOMALOUS CORONARY A RTERY ORIGIN A BOVE THE
SINOTUBULAR R IDGE
In this anomaly either the right (most frequent) or occasion-
ally the left coronary ostium is located 1 to 2 cm above the
sinotubular ridge. The distribution of the affected coronary
is otherwise normal. This common anomaly should be
FIGURE 34.21. Separate ostia for the left anterior descending and
left circumflex arteries from the left sinus of Valsalva.
 7 74 chapter
A postulated that exercise results in kinking or in some way
B Although coronary angiography, if carefully done, can often
FIGURE 34.22. Selective left coronary angiogram in a patient with
separate ostia for the left anterior descending and left circumflex
arteries. (A) Selective injection reveals only the left anterior descend-
ing artery. (B) Catheter reposition now reveals a large dominant cir-
cumflex vessel; the left anterior descending artery is now not seen.
suspected when the angiographer is unable to visualize either
coronary ostium using standard angiographic catheters and
usual techniques. An aortic root angiogram may be neces-
sary to identify the anomalous origin and facilitate selective
catheterization.
A NOMALOUS CORONARY A RTERY ORIGIN FROM POSTERIOR
SINUS OF VALSALVA
Either the right coronary artery or the left main coronary
can take its origin from the posterior sinus of Valsalva (the
usual noncoronary sinus). Both of these variants are rare,
although an ectopic right coronary origin is more common.
Except for the anomalous origin, the anatomic course is
normal and no significant clinical complications have been
reported.290
A BSENT L EFT CIRCUMFLEX
In this rare anomaly, a large “superdominant” right coronary
artery crosses the crux of the heart, ascending the atrioven-
tricular groove to perfuse the posterior and lateral wall of the
heart. The left anterior descending artery is normal.
34
Coronary Arterial Anomalies Associated with
Adverse Outcomes
A NOMALOUS ORIGIN OF EITHER M AJOR CORONARY A RTERY
WITH A PROXIMAL INTERARTERIAL OR SEPTAL COURSE
It is the course of an anomalous coronary artery, rather than
the location of the coronary ostium that is the major deter-
minant of whether the anomaly is benign or has associated
clinical consequences (e.g., angina, ventricular arrhythmias,
syncope, or sudden death).254,291–293 These adverse outcomes
usually occur when the anomalous coronary artery passes
between the aorta and the pulmonary artery, or less com-
monly via a septal pathway. Clinical events, particularly
sudden death, are usually seen during exertion in young
individuals in the absence of coronary atherosclerosis. It is
causes transient limitation in coronary flow because of the
orientation of the vessel at its origin or because it is com-
pressed during its anomalous course.294
It is often difficult to delineate angiographically the prox-
imal course of an anomalous vessel. Although some angiog-
raphers have suggested that performing coronary angiography
in a lateral projection after passing a pulmonary artery cath-
eter localizes the course of the vessel, this technique is of
limited value since in the lateral view both a septal and
interarterial course (between the aorta and pulmonary artery)
will appear posterior to the pulmonary artery and anterior
to the aorta if the septum is caudal to both great vessels. A
ventriculogram or aortic angiogram performed in the RAO
projection is needed.295 Serrota and colleagues295 have devel-
oped a clever “dot and eye” recognition pattern technique for
localization of the initial pathway, which may be helpful.
define the cause of the anomalous vessel, the concomitant
use of computed tomography (CT) [or, to a lesser extent,
magnetic resonance imaging (MRI)] coronary angiography
has recently been shown to be especially helpful.296
Several coronary variants sharing a common physiology
appear at greatest risk:
1. Origin of the right coronary artery from the left sinus
of Valsalva. When the right coronary artery arises from the
left coronary cusp or proximal left main coronary artery, it
almost invariably (>99%) follows one path.254 This course
runs between the aorta and pulmonary artery, placing the
patient at risk for adverse events (Fig. 34.23).297 This variant
should be suspected when the right coronary ostium is
unable to be cannulated in the right coronary sinus or above
the sinotubular ridge, yet collateral vessels are absent. This
is the most common variant associated with adverse clinical
events.
2. Origin of the left anterior descending coronary artery
from the right sinus of Valsalva. If the right aortic cusp or
right sinus gives rise to the left anterior descending artery,
the artery may initially follow a septal or an anterior free
wall course. The anterior free wall path is associated with
tetralogy of Fallot. If unrecognized, it can lead to catastrophic
complications at the time of surgical repair. Although the
septal pathway occurs less commonly, only patients with a
septal course are at risk for sudden cardiac death.295
3. Origin of the entire left coronary artery from the right
sinus of Valsalva, arising separately or sharing a common
 corona ry a ngiogr a ph y 7 75
years and despite the lack of surgical treatments, there were
no deaths directly related to the anomalous coronary origins.
Syncope (14%) and aortic regurgitation (21%) were the most
common adverse events.

ORIGIN OF A CORONARY A RTERY FROM THE

PULMONARY A RTERY
Origin of the left coronary artery from the pulmonary artery,
sometimes referred to as the Bland-White-Garland syn-
drome,299 results in perfusion of the left ventricle via collater-
als from the right coronary and a shunt into the pulmonary
artery (Fig. 34.25).300 It generally results in myocardial isch-
emia and is characterized clinically by wheezing, tachypnea,
failure to thrive, and angina. Ninety percent of these patients
die in infancy and very few survive to adult life.301
Survival is occasionally permitted by the development of
intercoronary collaterals, although collateral blood flow
from the contralateral artery is drained partially into the
low-pressure pulmonary artery via the aberrant coronary.
FIGURE 34.23. Schematic diagram illustrating origin of the right This steal phenomenon can permit identification of the aber-
coronary from the left sinus of Valsalva. The usual course of this rant artery when the contralateral vessel is injected with
vessel is between the aorta and pulmonary artery (see text).
contrast media. Undiagnosed adults may present with angina,
mitral regurgitation, a continuous murmur, heart failure, or
ostium with the right coronary artery. In this anomaly the
sudden death. If such patients receive a premortem diagnosis,
left main coronary artery may follow one of the four path-
surgical treatment (coronary reimplantation into the aorta)
ways shown in Figure 34.24; the septal pathway is the most
is advised.302
frequent. The low incidence of this anomaly makes assess-
ment of the risk difficult. If unrecognized, any of these
L EFT M AIN CORONARY ATRESIA
anomalous courses may be associated with complications at
Left main coronary atresia is a very rare coronary anomaly
the time of cardiac surgery.297
in which there is no left coronary atrium. The proximal left
4. Single coronary artery. There are multiple patterns of
main trunk ends blindly and blood flows via small collater-
the single coronary artery, although this anomaly is rare in
als into at least one of the left-sided arteries.303 Pediatric
the absence of other abnormalities of the heart and great
patients are overtly symptomatic early in life. This condition
vessels. The Lipton classification schema as modified by
can occur in the adult population secondary to gradual ath-
Yamanaka and Hobbs,254 designates the anomalous coronary
erosclerotic obstruction and is occasionally compatible with
by the ostium of origin, its anatomic course, and the relation-
normal resting global left ventricular function.304,305 Origin
ship to the great arteries. In the type I pattern, a single coro-
of the right coronary artery from the pulmonary artery is
nary artery from a single ostium perfuses the entire heart.
extremely rare.
This extremely rare anomaly generally has a benign clinical
course. In the type II single coronary pattern, the anomalous
coronary arises from the proximal part of the normal coro- A B
nary. The greatest adverse risk would be expected to occur
in those cases in which the anomalous vessel passes between
the great vessels.
Although the association between the abnormal inter–
great vessel or septal course of the coronary artery and
adverse clinical events is well documented in the Western
medical literature, a recent investigation from Japan raises
interesting questions. Kaku et al.298 report the clinical fea- D
tures of 56 patients (0.33%) with anomalous origins of the C
coronary arteries after review of 17,000 patients with angio-
grams taken between 1968 and 1994, mean age 56 years.
Despite a similar overall incidence of anomalous origin of
the coronary artery in Japan and the United States, the most
frequent anomalous coronary course in the Japanese popula-
tion was the right coronary originating from the left sinus
of Valsalva and coursing between the great vessels (79%). An
anomalous posterior course of the left circumflex, which FIGURE 34.24. Variations in the course of the left coronary artery
(LCA) when it arises from the right sinus of Valsalva. (A) Interarte-
occurs most frequently in the U.S., was seen in only 11%. rial course of the LCA. (B) Transseptal course of the LCA. (C) Course
The left main coronary arising from the posterior sinus of the LCA posterior to the aorta. (D) Course of the LCA anterior to
occurred in 7%. During a mean follow-up period of 5 ± 4 the aorta.
7 76 chapter
Coronary Artery Fistula
Although fistulas are relatively common congenital anoma-
lies that have the potential to alter myocardial perfusion,
more than half of patients with a fistula are entirely asymp-
tomatic. Small coronary fistulas are quite common and are
seen in 0.1% to 0.2% of all patients undergoing coronary
angiography.306 Most arise from a small coronary branch and
drain into a single cardiac chamber. The majority of small
fistulas originate from the left anterior descending artery
and drain into the pulmonary artery.307 These are angio-
graphically identifiable by contrast swirling as “smoke” in
the otherwise unopacified pulmonary artery. Most are not
associated with detectable intracardiac shunting, or with
auscultatory abnormalities (e.g., a continuous murmur). The
clinical course is usually benign. Patients with small asymp-
tomatic fistulas should be managed medically.
Although the majority of coronary artery fistulas are
congenital,308,309 many are acquired and have been reported
secondary to deceleration accidents, coronary angioplasty,
repeated endomyocardial biopsies in heart transplant
patients, permanent ventricular pacing leads, and cardiac
surgery. These acquired forms of coronary fistulas have been
increasing in frequency over the past several decades.308
FIGURE 34.25. Origin of the left coronary artery from the pulmo-
nary artery resulting in a steal phenomenon (aorta left, pulmonary
artery right). Arrows represent direction of coronary flow.
34
FIGURE 34.26. A large fusiform aneurysm (arrow) of the left ante-
rior descending artery in a patient with coronary atherosclerosis.
Large congenital fistulas may occasionally persist unde-
tected into adult life. These abnormalities may be asymp-
tomatic, detected only by a continuous murmur, or may
present with complications such as endocarditis, heart
failure, ischemia, or infarction.310 Large fistulas are associ-
ated with the development of very tortuous ectatic coronary
arteries proximal to the origin of the fistula (Fig. 34.26) and
may empty into any cardiac chamber. About 50% of fistulas
arise from the right coronary, 42% from the left coronary,
and 5% from both.307 The right atrium, pulmonary artery,
and coronary sinus are the most common sites for emptying.
The decision as to which fistulas should necessitate therapy
is at present difficult.311 If therapy is undertaken, the treat-
ment should obliterate the fistula yet maintain antegrade
coronary flow.312 In the past this usually entailed coronary
artery bypass grafting with coronary reimplantation. More
recently, percutaneous transcatheter embolization tech-
niques have been used. Although these techniques are
usually successful and have a low morbidity and mortality,
the obliteration of arterial perfusion to the distal bed makes
these techniques unsuitable for large congenital fistulas.
Another variant is the occurrence of diffuse coronary to
ventricular chamber fistula, which resembles an unusually
prominent Thebesian drainage system.313–315 In these patients,
coronary injection results in diffuse endocardial opacifica-
tion and filling of the ventricular cavity. Either or both coro-
nary artery branches can be affected. Symptoms consistent
with ischemia and abnormal thallium scintigraphy can
occur, but are uncommon.316,317 Acquired fistulas to the ven-
tricular cavity can also occur at myocardial biopsy sites.318
Coronary Atherosclerosis
For over a quarter-century, selective coronary angiography
has remained the ultimate diagnostic test for assessing the
significance of atherosclerotic lesions in the coronary circu-
lation of humans. Despite criticism regarding interpretation
and the development of many noninvasive techniques
 corona ry a ngiogr a ph y
designed to detect myocardial ischemia, the coronary angio-
gram has maintained a preeminent position for the evalua-
tion of coronary atherosclerosis.
Angiographic Assessment of Stable
Coronary Atherosclerosis
Atherosclerosis is a disease of the arterial wall that can
encroach on the vessel lumen and limit blood supply to the
myocardium. In interpreting coronary angiograms, it is
important to understand the nature of the atherosclerotic
process as it relates to coronary dimensions and the angio-
graphic appearance of atherosclerosis.
Coronary Changes of Atherosclerosis
COMPENSATORY CORONARY DILATION
Glagov et al.,222 in a seminal observation, using pressure-
perfused postmortem hearts, demonstrated that early in the
atherosclerotic process coronary arteries undergo a compen-
satory increase in outer diameter of the artery. Although
different segments of the same artery may respond differ-
ently, this compensatory dilation acts to maintain lumen
caliber despite thickening of the wall. These investigators
found that coronary arterial lumen encroachment does not
begin until the atherosclerotic plaque occupies about 40% of
the original lumen area, as determined by the internal elastic
lamina (Fig. 34.12). Only at this point is angiography able to
detect the presence of disease. This is an extremely impor-
tant observation that may explain the frequent discrepancy
between pathologic and angiographic assessments of experi-
mental atherosclerosis.
Clarkson et al.319 studied the pathology of coronary arter-
ies in monkeys with diet-induced atherosclerosis and in
humans (men and women). These investigations found that
as plaque intimal area enlarged, so did the artery size as
judged in the internal elastic laminar area. However, there
was large individual variability. Although the intimal area
was significantly associated with lumen area, it was a poor
predictor, explaining only 7.5% of the variability. In humans
a lack of compensation (decreased lumen size as plaques
enlarged) and a history of coronary heart disease were sig-
nificantly correlated. Mohiaddin et al.,320 using cardiomag-
netic resonance in the aorta of asymptomatic human subjects
with fibrous plaque, showed that after 2 years, total plaque
volume increased significantly, although there was no change
in total lumen volume.
CORONARY CALCIFICATION
It has been known for decades that calcification of the ath-
erosclerotic plaque is a common occurrence, is associated
with an advanced disease state and is easily detectable in the
coronary arteries by fluoroscopy or angiography. Recent evi-
dence derived from electron beam computed tomography
(EBCT) has challenged the old dogma that coronary plaque
calcification is mainly a marker of end-stage plaque degen-
eration, but instead has demonstrated that intramural
calcium can be observed in all degrees of a atherosclerotic
involvement.321 Recent investigations have proposed using
EBCT as a noninvasive screening test for coronary athero-
sclerosis. Janowitz and colleagues322 have shown that regard-
777
less of gender, the prevalence and extent of coronary
calcification increases with age with an epidemiologic
pattern similar to that known for coronary atherosclerosis.
The total area of coronary calcification detected by EBCT
correlates linearly with histologically determined coronary
plaque.323 However, the total area of coronary plaque calcifi-
cation significantly underestimates the total associated coro-
nary plaque area. Calcium may be absent or undetectable in
small plaques, and the location of coronary calcification may
not correlate with the most significant atherosclerotic nar-
rowing. Studies using intravascular ultrasound have con-
firmed this general premise showing that coronary
calcification correlates with total plaque burden, but not
with the degree of luminal compromise.324
Absence of detectable coronary artery calcification on
EBCT is highly unlikely in the presence of a severe luminal
coronary obstruction, and has been proposed as a screening
tool to identify patients at low risk (80% chance of having
angiographically normal arteries). Schmermund et al.,325
using EBCT in patients who had recently diagnosed coronary
disease and had undergone angiography, found that quantita-
tion of coronary artery calcification was comparable to coro-
nary angiography in measuring the effect of established
cardiovascular risk factor on coronary atherosclerosis.
A NGIOGRAPHICALLY INAPPARENT
DIFFUSE ATHEROSCLEROSIS
Pathology studies demonstrate consistently that atheroscle-
rosis is more widespread than angiograms depict.213,326
Although early pathology studies were flawed because they
measured the size of coronary vessels in an undistended state
(leading to overestimation of stenosis), two independent
techniques have recently reconfirmed the essential findings.
Using high-frequency epicardial echocardiography, the coro-
nary vessels of living human hearts have been evaluated at
the time of cardiac surgery.219 The ratio of coronary artery
lumen diameter to the thickness of the coronary wall was
used to quantify the severity of coronary lesions. In patients
without atherosclerosis, the mean coronary lumen to wall
thickness ratio was 5.9 ± 0.3 (± standard error of the mean,
SEM). In patients with atherosclerotic disease at the site of
examination the mean ratio was markedly reduced (2.3 ±
0.2), consistent with the marked wall thickening at the site
of obstruction. In angiographically normal arterial segments
of patients with atherosclerosis elsewhere, however, the
mean ratio (4.1 ± 0.3) was also reduced, suggesting diffuse
wall thickening. Thus, in patients with atherosclerosis else-
where, even normally appearing epicardial segments showed
significant unrecognized thickening of the arterial wall.326
Davies,327 in a series of autopsy studies on both men and
women, showed a positive relationship between percent cor-
onary stenosis, percent plaque burden, percent remodeling,
and an inverse relationship between percent plaque burden
and percent remodeling. The increase in lumen size in an
atherosclerotic coronary artery may vary widely between
different plaques, even in the same artery. High-grade steno-
ses are often associated with a total failure of remodeling,
thus the use of the calculation of percent stenosis (comparing
the lumen size to the apparently normal cross-sectional area)
is greatly flawed. This calculation, on average, overestimates
the diameter of stenoses by 30% when compared to an
778 chapter
“angiographic equivalvent” calculation of an adjacent arte-
rial segment without plaque.328
Intravascular ultrasound techniques have demonstrated
similar findings and have confirmed the insensitivity of coro-
nary angiograms to detect early atheromatous changes.329,330
Using intravascular ultrasound, abnormally high intimal/
medial thickness measurements have been found in the coro-
naries of majority of young donor hearts prior to cardiac
transplantation—all of which appeared angiographically
normal.331 The lack of angiographic sensitivity to early,
diffuse vascular disease is also demonstrated compellingly
in cardiac transplant recipients.332
In one study of 60 patients studied 1 year or more after
transplantation, all had at least minimal intimal thickening
and 63% had moderate or severe intimal thickening even
though 70% of the patients had arteries that appeared
normal angiographically. Postmortem examination of one
cardiac transplant patient who died of severe left ventricular
dysfunction 2 weeks after normal coronary angiography
showed severe, diffuse accelerated coronary vasculopathy.333
Several IVUS examinations showed that early after trans-
plantation, a large proportion of coronary segments show
compensatory dilation of the vessel wall. However, a sub-
stantial number (22%) show no compensatory dilation, but
rather luminal shrinkage. These findings of inapparent
diffuse disease in angiographically normal coronary arterial
segments are an additional reason why conclusions of ste-
nosis severity based on relative measurements of percent
luminal narrowing, either area or diameter, are often in
error.
DIABETES AND CORONARY ATHEROSCLEROSIS
The problem of coronary atherosclerosis in diabetes mellitus,
both types 1 and 2, are especially vexing. Not only is diabetes
a highly potent risk factor in the pathogenesis of atheroscle-
rosis and the major cause of death in this population, the
typical symptoms of this condition are atypical and often
absent. Angiographically the frequent widespread presence
of diffuse disease makes calcification of percent stenosis as
a marker of disease severity in this patient population most
unreliable. “Normal” lumen diameters necessary for a refer-
ence segment value in this calculation are often impossible
to determine. Diabetics have accelerated progression of
disease after diagnosis, a condition also worsened by renal
failure and need for dialysis, which may accompany diabetic
renal disease.334 A decreased ability to exhibit compensatory
luminal enlargement has been found in patients with diabe-
tes, which may contribute to the diffuse nature and acceler-
ated course of this condition.335 Diabetics also have a lesser
degree of coronary collateral circulation associated with
severe stenotic lesions. 336
Visual Assessment of Coronary Arterial Stenosis
Data obtained from analysis of the coronary arteriogram are
traditionally expressed in anatomic terms, describing the
vessel narrowing as a percentage reduction of the adjacent
apparently normal lumen caliber. Reams of studies obtained
from over 20 years of investigations relate the number, sever-
ity, and distribution of coronary obstructive lesions, assessed
by visual analysis of the angiogram to a host of clinical out-
34
Studies in the Dog Studies in Man
Maximal Coronary Peak Velocity/
Dilator Response Resting velocity ratio
5 10
4
3 6
2 4
1 2
0 0
0 20 40 60 80 100 0 25 50 75 100
Percent Stenosis Normal Percent Stenosis
FIGURE 34.27. Relationship between maximal coronary blood
flow or blood flow velocity and percent stenosis in an experimental
study337 and a clinical study. Left: In the animal experiment, a short
concentric stenosis was placed on a normal coronary artery in an
awake, chronically instrumented dog. Resting coronary blood flow
(dashed line) was not significantly decreased until the percent diam-
eter stenosis was >85%. In contrast, maximal hyperemic coronary
blood flow (solid line) was limited when percent diameter stenosis
was in the 50% to 60% range. Right: In the clinical study, maximal
coronary blood flow (expressed as a ratio of peak velocity to resting
velocity) was measured after transient ischemia. The range of
normal responses in humans is shown by the black bar on the right.
Each open circle represents a study in one patient. In contrast to the
close relationship between percent diameter stenosis and maximal
coronary blood flow in dogs, angiographically determined percent
diameter stenosis was unrelated to hyperemic blood flow impair-
ment in humans with widespread atherosclerosis.
comes. The effect of a given stenosis in limiting coronary
blood flow and thus effecting myocardial ischemia is gener-
ally assumed and rarely assessed directly.
The clinical maxim that a coronary stenosis does not
become functionally significant until it causes a >50% diam-
eter narrowing is an outgrowth of studies in animals by
Gould,337 showing that maximally augmented coronary flow
is not limited until the stenosis is >50% (Fig. 34.27). Although
these studies were performed in animals using externally
applied constrictors, it was assumed that similar findings
would apply to human atherosclerotic lesions.
SOURCES OF ERROR IN VISUAL ASSESSMENTS OF
L ESION SEVERITY
Although visual assessment of the severity of luminal nar-
rowing remains the standard for patient care today, many
investigators over the past decade have realized increasingly
the inadequacy of this approach.222,338–341 Marked intra- and
interobserver variability in interpretation of lesion severity
has been documented repeatedly. Visual intraobserver vari-
ability (±1 standard deviation) ranges from 7% to 18%,
depending on technique.342–345 The lower value was obtained
from analyses of individual cine frames rather than
unselected cine runs. Disagreements of 30% to 35% have
been reported when maximal stenosis severity has been
assessed using either a 50% or 70% diameter criterion.345
Factors increasing observer variability include lesion loca-
tion (left main346 or distal lesion345), recent angioplasty,347
and poor quality angiograms.345 Variability is lessened by the
use of manual or electronic calipers or a calibrated magnify-
ing eyepiece.348,349
It is widely known that visual interpretation usually
overestimates the severity of relatively high-grade lesions350
and underestimates or totally overlooks low-grade lesions.
 corona ry a ngiogr a ph y
Although visual interpretation has been reported to under-
estimate lesions >50% based on necropsy data, such conclu-
sions may be somewhat inaccurate because pathologic
assessment of the coronary stenosis was carried out in
“deflated,” non–pressure-fixed specimens, exaggerating the
degree of luminal compromise.351 Ex-vivo autopsy studies
have also shown a high incidence of severely eccentric or
slit-like coronary lumina; however, such lumen shapes are
rarely seen angiographically.
Although it has been suggested that observer variability
improves with angiographic experience, frequency of reading,
and the use of consensus panels, the superiority of using a
group of experienced angiographers to quantitatively grade
angiograms does not withstand careful scrutiny.342 There is
very high (95%) agreement regarding lesion severity when
determined by panel consensus352; however, the standard
deviation of these interpretations of percent stenosis was ±
14%. No improvement in correlation between three individ-
ual observers and a three-member consensus panel has been
found.353 Fortunately, quantitative methods for determining
stenosis severity (see Quantitative Coronary Angiography,
below) have today gained ascendancy in research investiga-
tions, and digital methodologies are frequently used in clini-
cal angiographic evaluations.
Quantitative Coronary Angiography
Since the visual interpretation of coronary angiograms is
inherently flawed, numerous computer-assisted systems to
aid in the geometric assessment of epicardial coronary lesions
have been developed.354–357 Although quantitation of coro-
nary stenoses is a giant step forward (compared with visual
assessment), it must be remembered that quantitative angi-
ography is an anatomic but not a physiologic measurement
tool. The coronary angiogram is a two-dimensional represen-
tation of the lumen of the artery under investigation. Changes
in the size or configuration from an assumed normal vessel
may not be sufficient to understand either the physiology
involved or to recognize the anatomic extent of the athero-
sclerotic process (see Physiologic Assessment of Coronary
Arterial Stenosis). Despite these limitations, the develop-
ment and implementation of quantitative methods for analy-
sis of stenosis severity has improved evaluation of coronary
artery lesions.
CALIPER M ETHOD
In 1971 Gensini et al.358 described an electronic caliper
system in which the borders of the arterial lesion could be
manually defined using moving cursors. Errors related to
visual parallax, systematic underestimation of severe
obstructions (>75% diameter stenosis) and overestimation of
less severe obstructions make this method an imprecise sub-
stitute for computer-based methods. 354,359,360
BROWN-DODGE M ETHOD
Development of quantitative coronary angiography by Brown
and colleagues208 at the University of Washington, provided
the seminal advance in the assessment of coronary angio-
grams. Images obtained from standard 35mm cine film are
projected at 5× magnification onto a grid. The vessel edges
of the lesion and the adjacent proximal and distal “normal”
779
segments are traced manually. The angiographic catheter is
used as a scaling device to correct for magnification. The
drawn arterial outlines from two orthogonal angiographic
views are manually digitized. The outlines are corrected for
magnification and distortion using a previously entered
record of each angiographic laboratory’s x-ray beam diver-
gence and pin-cushion distortion and using the actual
diameter of the angiographic catheter. The outlines are com-
puter-matched at the minimum diameter or another stan-
dard point of reference visible in both views. Two orthogonal
views are then combined to form a three-dimensional repre-
sentation, assuming an elliptical lumen contour.
From this composite image, lesion minimum diameter
and cross-sectional area are determined in absolute (mm2)
and relative (lesion percent diameter and percent area steno-
sis) terms. This method has been used for many research
applications and is highly accurate and reproducible. The
standard deviation of repeated measurements of arterial
diameter (±0.12 mm) and percent diameter stenosis (±3%) are
small.208 However, the method is time-consuming and labor-
intensive. For these reasons it has not seen widespread clini-
cal utilization.
AUTOMATED EDGE DETECTION SYSTEMS
Reiber and colleagues361–363 developed a semiautomated
method for detecting the edges of coronary artery segment
of interest and of the calibrating catheter (coronary artery
analysis system, CAAS). Similar methods have been devel-
oped by others, but all use a digitized image obtained from
a cineangiographic film frame or video signal. Nearly all
techniques detect the arterial edge by videodensitometric
methods, usually employing a weighted average of the first
and second derivatives of the density change across the artery
to identify the edge.364
Unlike the early Brown-Dodge system, these methods do
not match orthogonal images and thus give only lumen
diameter rather than cross-sectional area measurements.
Manual matching of the data obtained from orthogonal
views using the Reiber-CAAS system, however, correlates
highly with cross-sectional area measured using the Brown-
Dodge system.365
OTHER M ETHODS —VIDEODENSITOMETRY
A number of other investigators have developed other systems
for computer-assisted quantitative coronary angiography366,367
or have made important contributions to the field.368–375
Although most of these methods assess stenosis severity
using geometric methods, considerable research has been
directed toward nongeometric methods. Videodensitometry
has been most commonly used. This technique is based on
the Lambert-Beer law, which states that the logarithmic
attenuation of the x-ray beam is proportional to the thickness
of the column of contrast within the vessel. This approach
is fundamentally different from others previously described
because it requires minimal assumptions regarding the
geometry of the lesion being examined. With this approach,
the operator performs an analysis at the site of the narrowest
portion of the vessel as well as at a smooth proximal “normal”
reference segment. The diameter of the adjacent normal
segment is determined geometrically using the catheter as a
scaling device. The normal lumen is assumed to be circular.
780 chapter
Using a previously determined density calibration curve, the
gray scale level along the arterial segment is converted to an
optical density profile that is corrected for the optical density
of a corresponding background point. An integrated optical
density across the diameter of each arterial segment is cal-
culated. The minimum integrated optical density of the
coronary lesion is divided by the density of the normal
segment and the quotient is multiplied by the normal segment
area. The resulting value is the minimum cross-sectional
area of the artery.
Under very carefully controlled circumstances and in a
small number of patients, one videodensitometric approach
appeared to correlate well with minimal luminal area mea-
sured using Brown-Dodge quantitative coronary angiography
as well as measurements of coronary flow reserve.375 However,
there are many theoretical and practical limitations to the
use of videodensitometric techniques. Theoretically, densi-
tometric techniques are less sensitive to variations in imaging
system resolution, quantum noise, and stenosis cross-sec-
tional shape than are edge detection techniques.376 However,
densitometry is also much more sensitive than edge detec-
tion to densitometric nonlinearities, overlapping structures
(e.g., bone, diaphragm), and a nonperpendicular relationship
between the vessel and the x-ray beam. The frequent occur-
rence of vessel foreshortening in many of the radiographic
views results in artifactual increases in density and greatly
limits the clinical utility of this technique. At present, the
usual error with densitometric angiography appears between
5% and 20%, but can approach 50%.376 For these reasons and
despite initially promising results, videodensitometric
approaches to lesion quantitation have not yet seen wide-
spread application.
PROBLEMS IN QUANTITATIVE A NGIOGRAPHY
Technical Problems. Although under ideal circum-
stances quantitative angiography can be a reliable and highly
accurate measurement technique, many potential pitfalls
exist. Blurring of the vessel edges, the penumbra effect, and
cardiac motion can lead to a widened vessel edge, making
edge detection less accurate.354 Compared to visual assess-
ment, quantitative angiography requires greater attention to
optimal angiographic technique. Vessel overlap and unrecog-
nized lesion foreshortening may produce major errors because
single film frames are examined.
Inaccurate calibration from the angiographic catheter can
be a major problem for quantitative angiography.377–379 The
use of small catheters (5F or 6F) as the calibration source can
lead to significantly less accuracy in the calculation of abso-
lute diameter measurements.380 Nylon catheters are also
poorly suited for quantitation because they are less radi-
opaque (some newer nylon catheters are impregnated with
radiopaque material). Even catheters of the same size from
various manufacturers can vary by as much as 25% in diam-
eter. Inaccuracies in angiographic measurement of the true
catheter size of up to 35% also can occur due to inaccurate
determination of the outer catheter edge (i.e., tracing of the
contrast-filled inner lumen rather than the outer contour of
the catheter).361 Some authorities suggest catheter calibration
should be based on a catheter empty of contrast, before begin-
ning the coronary injection, although this is not a widely
34
held view.381 Reference tables for the true size of a variety of
angiographic catheters, together with a comparison of their
angiographic measurements as calculated by two different
algorithms, are available.378
Variations in Lesion Geometry. Most quantitative
angiographic systems calculate only one lumen diameter
measurement and assume a cylindrical shape if a lesion area
measurement is calculated. The true geometry of a coronary
lesion may vary widely. The Brown-Dodge system assumes
an elliptical lesion shape and uses integration of two orthogo-
nal views to obtain lumen area. Although major deviations
from an elliptical shape occur rarely, the use of orthogonal
views and the assumption of an elliptical geometry do not
solve all geometric problems. Two acceptable truly orthogo-
nal views are obtainable in only about 50% of lesions exam-
ined.356 The maximal error for two arbitrary orthogonal
views is small (<25%) only for mild degrees of ellipticity
(major/minor axis <2).377,382 The error increases as the angle
between views becomes less orthogonal and as lesion ellip-
ticity increases.
For angioplasty patient populations, quantitative mea-
surements of vessel diameters taken from only one view in
which the lesion appears worst, compare quite closely with
the average of two diameter measurements from nearly
orthogonal views (minimum diameters of the two views
within ±5% in 90% and within ±10% in all but 2.7%).383
From these data one could conclude that quantitative mea-
surement of one view is adequate for routine clinical pur-
poses. However, for research purposes, orthogonal views may
sometimes be required. Our experience comparing angiogra-
phy to Doppler flow reserve measurements has led to the
conclusion that integration of lesion diameters as seen in all
views appears to relate best to physiologic measures of lesion
severity.
Variations in Vasomotor Tone. Day-to-day changes in
coronary smooth muscle motor tone increase the interstudy
variability of angiographic measurements and reduce the
power of angiographic methods to detect small changes in
coronary caliber in sequential studies. Removal of tone by
nitroglycerin permits an assessment of maximal coronary
caliber during similar conditions between studies.
Physiologic Assessment of Coronary
Arterial Stenoses
The inaccuracies inherent in even the most sophisticated
methods of anatomic assessment have led to the develop-
ment of physiologically based methods to assess coronary
stenosis severity. In 1939 Katz and Lindner384 described the
coronary reactive hyperemia response that has subsequently
become the gold standard for the physiologic assessment of
stenosis severity. In normal coronary arteries, myocardial
blood flow is primarily regulated by the resistance of the
arteriolar vessels (≤400 μm diameter); the epicardial coro-
nary arteries provide little resistance to coronary blood flow
under physiologic circumstances. As a stenosis progresses in
an epicardial vessel, a transstenotic pressure gradient devel-
ops. The microvessels dilate to compensate for the reduced
distal perfusion pressure, thus maintaining normal resting
blood flow to the myocardium.
 corona ry a ngiogr a ph y 7 81

Anatomy Physiology occlusion or drugs) to resting blood flow is termed coronary

vasodilator reserve (or coronary flow reserve).
Normal 4x The ratio of the intracoronary pressure distal to a stenosis
Flow to the proximal coronary or aortic pressure during condi-
tions of maximal hyperemia is termed the fractional flow
x
Epicardial Artery
Time reserve. These two physiologic measurements (coronary flow
Arteriolar Vasodilation (Papaverine) reserve and the fractional flow reserve) have provided impor-
4x tant clinical techniques to assess limitations in hyperemic
blood flow imparted by a stenosis.
Flow

Epicardial Stenosis x CORONARY FLOW R ESERVE

Time
Arteriolar Vasodilation (Papaverine)
4x
Flow
x the epicardial surface of a coronary vessel.386 These experi-
Microvascular Disease Time
Arteriolar Vasodilation (Papaverine)
FIGURE 34.28. The effects of an epicardial stenosis on coronary
flow reserve. Top panel: Dilation of a normal microvasculature with
papaverine causes blood flow to increase fourfold. Middle panel: An
epicardial stenosis causes partial microvascular dilation, and papav-
erine has little additional effect. Flow reserve is reduced. Bottom
panel: Microvascular disease prevents normal arteriolar dilation,
reducing flow reserve.
Studies in animals have shown that resting coronary
blood flow can be maintained at normal levels until more
than 75% of the arterial cross-sectional area (50% of the
diameter if the obstruction is concentric) is obstructed. At
this point the vasodilator reserve of the arterioles is
exhausted, and further vasodilation is impossible. 337 Resting
blood flow does not decrease until 90% of the lumen is
obstructed. Coronary stenoses that limit myocardial blood
flow during maximal arteriolar vasodilation are termed
physiologically significant (Fig. 34.28).385 The ratio of
maximal hyperemic blood flow (e.g., induced by coronary
Utilization of Doppler methods for measuring blood flow
velocity has provided the major principles for clinical inves-
tigation of coronary flow reserve. Initial studies in humans
were performed using a Doppler crystal applied at surgery to
ments showed that the reactive hyperemic response in
normal human coronary arteries was similar to that obtained
in anesthetized animals. However, they failed to confirm in
humans the relationship between luminal stenosis and flow
impairment previously observed in normal animals (Fig.
34.27). In patients with multivessel coronary atherosclerosis
and isolated discrete coronary lesions varying in severity
between 10% and 95% stenosis, measurements of the ana-
tomic stenosis severity were not correlated significantly
with the reactive hyperemic response (r = −.25).386 Underes-
timation of lesion severity occurred in 95% of vessels with
>60% diameter stenosis by angiography. Both overestimation
and underestimation of lesions with <60% stenoses were
common.
The development and validation of small Doppler cathe-
ters387 and subsequently Doppler guidewires388 made possible
the subselective measurement of coronary blood flow veloc-
ity in individual coronary vessels at the time of angiography
(Fig. 34.29). Subselective techniques for measuring flow
velocity were necessary for clinical usefulness of this

Percent area stenosis = 95 Translesional gradient = 52mmHg Percent area stenosis = 68 Translesional gradient = 12ml

Phasic
CBFV
(kHz shift) 0–v
peak velocity 1.5 5.0
Mean resting velocity
CBFV
(kHz shift) 0
200
Arterial
Pressure
(mm Hg)
0

ECG

1sec
6 mg papaverine
FIGURE 34.29. A record obtained from patient undergoing right
coronary artery angioplasty. The top tracing shows phasic coronary
blood flow velocity (CBFV), the second tracing mean coronary blood
flow velocity, and the bottom two panels the arterial pressure and
electrocardiogram. Before angioplasty (left), the lesion produced
95% area stenosis with an associated translesional pressure gradient
of 52 mm Hg. Six milligrams of intracoronary papaverine produced
30 sec
6 mg papaverine
only a 1.5–fold increase in blood flow velocity. After angioplasty
(right) the percent area stenosis was decreased to 68% and the trans-
lesional pressure gradient was reduced to 12 mm Hg. Six milligrams
of intracoronary papaverine resulted in a 5.0–fold increase in
blood flow velocity, demonstrating that physiologically significant
obstruction to coronary blood flow had been removed.
782
methodology since coronary atherosclerosis had a heteroge-
neous distribution throughout the coronary tree. Since coro-
nary occlusion is not practical during angiography,
pharmacologic vasodilators were given to create a maximal
hyperemic response. The original studies utilized intracoro-
nary papaverine, which results in maximal increases in coro-
nary flow comparable to those achieved with intravenous
transient coronary occlusion or dipyridamole.389 Although
the short half-life coupled with little effect on systemic
hemodynamics made papaverine a useful drug for this
purpose, occasional QT prolongation and rare but potentially
serious transient arrhythmias can occur.390 For this reason,
intracoronary adenosine, which has an even shorter half-life
than papaverine, has now generally replaced papaverine as
the drug of choice for physiologic studies of the coronary
circulation under hyperemic conditions.391
In contrast to measurements obtained in patients with
severe coronary atherosclerosis studied at cardiac surgery,386
flow reserve measurements obtained in the catheterization
laboratory in patients with only single-vessel disease show a
curvilinear relationship between percent stenosis and flow
reserve, similar to that found in animals with normal coro-
nary vessels (Fig. 34.30).209
Lesions causing <70% area stenosis did not cause a sig-
nificant reduction of hyperemic blood flow. The disparate
results seen in patients with limited versus those with more
widespread coronary atherosclerosis probably relates to the
unrecognized presence of diffuse luminal encroachment.
Percent stenosis measurements of a focal lesion in an artery
with diffuse luminal narrowing leads to underestimation of
lesion severity based on an inaccurate determination of the
“normal” adjacent lumen reference segment. Since the coro-
nary angiogram is a “lumenogram,” it is impossible to know
whether a segment of a vessel appearing angiographically
“normal” has inapparent diffuse disease. As the degree of
diffuse narrowing increases, lesser focal stenoses are required
to impair maximal hyperemic blood flow.392 As shown in
Figure 34.31, a 50% stenosis has greatly different effects on
8 fractional flow reserve (FFR), this technique in reality com-
7
6 flow.394 A ratio of proximal to distal intracoronary pressure
Δ CBFV (× resting)
5
4 ologic significances of coronary stenoses of moderate sever-
3 to correlate highly with noninvasive tests of myocardial
2
± 1SD
1 r = 0.82
0
0 20 40 60 80
Diameter stenosis (%)
FIGURE 34.30. Relationship between the most severe diameter
stenosis measure in the left or right anterior oblique projection and
coronary flow reserve. The open bar represents the range of coronary
flow reserve measured in 13 patients with normal coronary vessels.
The shaded area along the regression line represents l standard
deviation (SD) above and below the mean.
chapter 34
Normal Obstructive Diseased Superimposed
vessel lesion vessel obstruction
2.5 mm 1.25 mm
Diameter stenosis = 50% Diameter stenosis = 50%
CSA = 4.9 mm2 CSA = 1.43 mm2
FIGURE 34.31. The effects of a 50% diameter stenosis in a normal
vessel (left) and a diffusely diseased vessel (right). A 50% stenosis
in a “normal” artery leaves significantly greater residual cross-
sectional area than does a 50% stenosis in an artery that is already
diffusely narrowed. Since the amount of diffuse coronary narrowing
cannot be assessed well from a visual analysis of a coronary angio-
gram, a focal 50% stenosis on the angiogram may have vastly dif-
ferent effects on coronary blood flow.
limiting flow depending on the true area of the normal
segment.
Absolute measurements of the coronary caliber can
provide important information that is independent of diffuse
luminal narrowing. A minimum lesion cross-sectional
area ≥2.5 mm2 (≥3.5 mm2 in the proximal left anterior descend-
ing artery) almost always indicates the absence of flow
impairment by the lesion, regardless of the adjacent arterial
diameter.
One should not conclude from these studies that moder-
ate inapparent diffuse coronary atherosclerosis alone impairs
the vasodilator reserve.351 In a study from our laboratory,
hyperemic blood flow was normal in atherosclerotic vessels
perfused by bypass grafts as long as the graft perfused a non-
stenotic coronary vessel subserving normal myocardium.392
This occurred despite the fact that cross-sectional area of the
bypassed artery is diffusely narrowed (40% smaller than a
similar site in matched normal vessels).
FRACTIONAL FLOW R ESERVE
Intracoronary pressure measurements can also provide
important physiologic information regarding the functional
significance of coronary stenoses.393 Commonly termed the
pares the intracoronary pressure measured proximal and
distal to a stenosis under conditions of maximal hyperemic
measured with a fiberoptic pressure-monitoring guidewire
during adenosine infusion has been used to assess the physi-
ity (40–50%). In 45 patients an FFR of >0.75 has been shown
ischemia. The overall sensitivity, specificity, positive and
negative predictive values, and accuracy were 88%, 100%,
100%, 88%, and 93%, respectively.395
Such FFR measurements can be used to assess the results
of balloon angioplasty.396 Using a pressure monitoring wire
100
to replace a standard angioplasty guidewire, Bech and col-
leagues396 showed that an FFR >0.90 stratified patients into
an optimal post–percutaneous transluminal coronary angio-
plasty (PTCA) result. A small amount of additional stratifica-
tion value was obtained when a quantitatively determined
residual percent on diameter stenosis of <35% was combined
with the FFR.
 corona ry a ngiogr a ph y
In addition to assessing the efficiency of angioplasty,
physiologic measurements assessing the functional signifi-
cance of intermediate coronary lesions has been used to
make a decision not to dilate non–flow-limiting lesions.397,398
These data indicate that deferral of a coronary intervention
based on a normal coronary flow reserve or an FFR ≥0.75 is
associated with a lower clinical event rate than would be
expected if the procedure had been performed as originally
planned.399
L IMITATIONS IN THE USE OF PHYSIOLOGIC FLOW AND
PRESSURE M EASUREMENTS: DUAL ROLES OF THE CORONARY
EPICARDIAL AND M ICROCIRCULATIONS
Although attractive in concept there are many limitations
in utilizing coronary flow or pressure reserve measurements
to define the physiologic significance of a given atheroscle-
rotic lesion. Inherent in understanding these limitations is
the fact that the coronary circulation can be regulated by
two distinct vascular components connected in series: the
epicardial vessels and the microcirculation. Coronary ath-
erosclerosis affects primarily the epicardial vessels, and the
microcirculation subserved by any given epicardial artery
may be normal or abnormal. A variety of pathophysiologic
conditions (e.g., anemia and polycythemia, diabetes, hyper-
trophy, infarction, vasculitis, wall motion abnormalities, and
other conditions involving the coronary microcirculation)
can reduce flow reserve in myocardium supplied by anatomi-
cally normal epicardial vessel, or by one containing athero-
sclerotic lesions.400–404 Hence, a reduction in the coronary
flow reserve (CFR) of a coronary artery with a stenosed vessel
cannot be taken as prima fasciae evidence that blood flow is
limited by the stenosis.
The coronary flow reserve is altered by the hemodynamic
conditions existing at the time of study.405 Increases in heart
rate or preload reduce flow reserve because these conditions
increase resting blood flow without changing hyperemic
flow. In contrast, acute changes in mean arterial pressure
within the autoregulatory range do not alter the flow reserve
ratio because resting and hyperemic blood flow are increas-
ing proportionately as arterial pressure rises. It has been
suggested that flow reserve measurements be obtained during
atrial pacing to eliminate the confounding effects of heart
rate. Despite these limitations, serial measurements of flow
reserve are highly reproducible over time in the absence of
conditions known to alter resting or hyperemic coronary
blood flow.406 Repeated measurements of flow reserve sepa-
rated by 1 year, performed on patients under these conditions
showed a very high degree of correlation (r = 0.95).
Unlike CFR, FFR has been shown to be independent of
loading conditions.407 Although the clinical outcome can
suggest that deferral of revascularization in stenotic vessels
with FFR >0.75 is a better approach, these studies were per-
formed prior to drug-eluting stents.
L IMITATIONS OF AN OPTIMAL HEMODYNAMIC EVALUATION
OF A CORONARY L ESION
Despite the importance of determining the hemodynamic
impact of individual coronary lesions, the pathophysiologic
consequences of non–flow-limiting lesions must not be over-
looked. Little and Applegate408 have shown that lesions of
only mild to moderate severity are most frequently the source
783
of plaque rupture and progression to acute myocardial infarc-
tion. This is perhaps not surprising when one considers the
usual frequency of occurrence of mild versus severe athero-
sclerosis lesions in the coronary tree. For these reasons one
cannot predict the site of the coronary lesion that will likely
progress to subtotal occlusion from a retrospective review of
angiograms taken shortly before development of the acute
event.408 Thus it is unlikely that current coronary interven-
tional approaches will play a dominant role in preventing
acute infarction.
Angiography can also be very important in yielding clues
to aid in clarification of clinical syndromes. Unimpressive
intraluminal coronary lucencies, both de novo and after
angioplasty, may forecast impending total coronary occlu-
sion. Specific morphologic characteristics such as the rup-
tured plaque or the lucency of a spontaneous coronary
dissection may serve as important clues in the diagnosis of
the cause of chest pain in the absence of alterations in coro-
nary flow reserve. Similarly, physiologic abnormalities in
coronary blood flow regulation induced by atherosclerosis
(e.g., endothelial dysfunction as assessed by infusions of ace-
tylcholine or substance P) or other abnormalities may poten-
tiate the effects of a focal coronary lesion or lead to ischemia
in the absence of a hemodynamically significant stenosis
in the epicardial arteries.409,410 Hence, the absence of a
flow-limiting stenosis at the time of angiography should not
imply the absence of myocardial ischemia or risk of vessel
closure.
The inaccuracies inherent in even the most sophisticated
methods of anatomic assessment have led to the develop-
ment of physiologically based methods to assess coronary
stenosis severity. In 1939 Katz and Lindner described the
coronary reactive hyperemia response that has subsequently
become the gold standard for the physiologic assessment of
stenosis severity.384
Angiographic Findings in Myocardial Infarction
and Acute Coronary Syndromes
It has been commonly believed that a severe coronary lesion
was the forerunner of acute myocardial infarction, and that
coronary arteries with less than 50% obstructions were rela-
tively free of thrombotic risk.411 Recent studies have convinc-
ingly refuted this dogma and give evidence that coronary
angiography cannot be used to predict accurately the site
of a subsequent occlusion that will result in myocardial
infarction.412
Although retrospective reviews of angiograms performed
shortly before the development of acute infarction have iden-
tified high-grade coronary stenoses as a risk factor for subse-
quent total coronary occlusion, studies in patients having
angiograms both months to years before and shortly after
infarction showed that the infarction-related occlusion fre-
quently occurred in a coronary segment without a severe
stenosis on the early angiogram. In only 38% of patients was
the most severe angiographic stenosis found to be responsible
for the subsequent infarction.413 In 60% of patients, the
most severe luminal diameter stenosis present in the
infarct-related artery prior to the infarction was less than
50%. Similar studies by a number of investigators414–416 have
confirmed these results.
784 chapter 34

In patients with unstable angina, quantitative angio-

graphic studies show a strikingly different picture. In such
patients angiograms have a high predictive value in deter-
mining the culprit lesion. Lesions associated with unstable
angina usually have a percent diameter stenosis of >85%, a
lesion cross-sectional area of <0.9 mm2, and a morphology
consistent with an irregular eccentric lesion, occasionally
with thrombotic intraluminal filling defects (see below).417
Hence such obstructions are usually visually obvious.
Patients presenting with symptoms of rest angina without
coronary lesions of this severity, should be carefully evalu-
ated for the possibility of coronary spasm.

Pathologic-Angiographic Correlates
Coronary angiography performed very soon after the onset
of clinical symptoms of myocardial infarction usually dem-
onstrates total occlusion of the coronary artery perusing the
infarct zone. The incidence of total occlusion is nearly 90%
if angiography is performed as early as 1 hour after symp-
toms, but drops to about 70% if angiography is delayed to 12
to 24 hours.418 Total occlusion is found less frequently (26%)
in patients having angiography within 24 hours of symptom
onset of a non–Q-wave infarction.419 This reduction in fre-
quency of total coronary occlusion is probably the result of
spontaneously occurring thrombolysis.
To understand the angiographic findings of acute coro-
nary syndromes, it is important to consider the underlying
events occurring in the artery during acute infarction. Fis-
suring or rupture of the atherosclerotic plaque appears to be
the inciting event in both unstable angina and acute myo-
cardial infarction420,421 (Figs. 34.32 and 34.33). Rupture of the
fibrous cap also allows blood from the vessel lumen to dissect
into the intima and media, thus causing the plaque to expand.
Plaque rupture as the nidus for subsequent thrombus forma-
tion can be seen only if the entire thrombus is examined by
FIGURE 34.32. Section of a coronary arterial cast (lumen area was
filled with barium gel) from a patient with unstable angina. Note
the plaque rupture with extension of the lumen into the arterial
wall (plaque ulcer).
FIGURE 34.33. Longitudinal section of a coronary artery at site of
total thrombotic occlusion resulting from atherosclerotic plaque
rupture. Proximal obstruction (right) is stasis (red blood cell) clot.
Distal obstruction (left) is atheromatous debris and primarily plate-
let clot.
serial histologic sections, and is thus often missed on routine
autopsy examination.
Pathologic and clinical evidence suggests that coronary
thrombosis after plaque rupture is a dynamic process.420,421
The occlusive thrombus typically has a multilayered struc-
ture, suggesting that it is often formed successively over an
extended period of time (days to weeks), rather than occur-
ring as a single abrupt event.422 This finding fits with the
often stuttering course of ischemic symptoms. In addition,
clot fragmentation with distal microembolization has been
identified in 73% of cases carefully studied and can be seen
on the angiogram in a smaller fraction of patients.422 Although
aggregated platelets are the major early component of the
thrombus, within in 1 or 2 days this platelet thrombus is
infiltrated and consolidated, leading to a more distinct angio-
graphic edge.422
If the coronary lumen is totally occluded, the blood
between the occlusion site and the nearest proximal side
branch will stagnate with the production of a stasis throm-
bus. The volume of stasis clot is usually (but not always)
relatively small. A recent total coronary occlusion is charac-
terized angiographically by a small remaining vessel stump
that can accumulate contrast. Injection into this stump
usually reveals an often “feathered” hang-up of contrast with
indistinct margins and slow washout. The angiographic cut-
off of an occluded bypass graft usually occurs at the aortic
anastomosis because occlusion within the graft body or at
the coronary insertion leads to total graft thrombosis.
Plaque fissuring, a multilayered thrombus, and distal
microembolization are also seen at postmortem examination
in patients with unstable angina and in humans dying
suddenly with coronary atherosclerosis without evidence
for myocardial infarction.421 Clinically and angiographically,
despite evidence of plaque rupture, patients with unstable
angina have a much smaller burden of clot within the affected
arterial segment than do patients with Q- or non–Q-wave
infarction. Coronary angioscopy performed in vivo in patients
with unstable angina has shown complex plaques and
small intraluminal clots, which are sometimes not visible
 corona ry a ngiogr a ph y 785
angiographically.423 Although patients with unstable angina CONCENTRIC LESIONS
following thrombolytic therapy show small increases in
luminal areas assessed using quantitative angiography, such
improvements are often not visually apparent or usually
clinically sufficient.411,424 A small fraction of patients may
have a more dramatic response.

Angiographic Findings ECCENTRIC LESIONS

Angiographic features of atherosclerotic plaque disruption Type I
have been described qualitatively. Postmortem angiograms
in the setting of plaque rupture have a “complicated” appear- or
ance characterized by irregular arterial borders and intralu-
minal filling defects.425 In vivo angiographic studies of
coronary lesions in patients with unstable angina also show
eccentric lesion shapes, characterized by a narrow neck and Type II
overhanging edges or scalloped borders, a high incidence of
stenosis irregularity, and intraluminal filling defects, which
or
presumably are clot. Following thrombolytic therapy for
acute infarction, similar findings are seen with marked ste-
nosis irregularities and an increased incidence of intralumi-
nal filling defects.426 Additionally, an ulcer crater that was MULTIPLE IRREGULARITIES
obscured by overlying thrombus may become evident as well
as thrombolysis (Fig. 34.34).
Ambrose et al.427,428 developed a system for classifying
coronary stenosis morphology based on its angiographic
appearance (Fig. 34.35). Lesions associated with acute throm-
botic syndromes (unstable angina and infarction) were
usually of type II eccentric morphology, and in most throm- FIGURE 34.35. Angiographic morphology of coronary arterial
stenoses. Type A stenoses (Top) are concentric and have smooth
botic lesions the edges of the lesion were irregular and borders. Type B lesions (middle) are eccentric and are divided into
scalloped.427 two groups: Type I (B1) lesions have a smooth border without over-
Visual interpretation of stenosis morphology is fraught hang while Type II (B2) lesions have irregular borders and/or over-
with marked intraobserver and interobserver variability. For hang. Type C lesions (below) have multiple irregularities.
these reasons, quantitative indices of lesion irregularity
applicable for use with computer-assisted quantitative
is independent of stenosis severity (in terms of lumen obstruc-
angiography have been developed.417 One such quantitative
tion). In one study of patients with stable angina, unstable
measure, the ulceration index, is defined as the diameter of
angina, or recent myocardial infarction, the severity of the
the least severe narrowing within the lesion (the downward
coronary lesion measured either as percent stenosis, or in
lip of the ulcer) divided by the maximum intralesional diam-
absolute terms as minimal cross-sectional area was similar
eter. This index decreases as the irregularity increases and
in all groups, although lesions causing unstable angina
tended to be more severe (Fig. 34.36). The ulceration index
Acute MI Ten days later (Fig. 34.37), however, was significantly lower in lesions
causing unstable angina (0.62 ± 0.05) or infarction (0.61 ±
45° RAO 45° LAO 45° LAO 45° RAO
0.03) than lesions causing stable angina (0.90 ± 0.01).417 A
modified index has also been found useful, but is not inde-
pendent of the stenosis severity.429
The angiographic appearance of blood flow in the artery
distal to a thrombotic lesion also carries some significance.
A system for grading blood flow was developed for the Throm-
bolysis in Myocardial Ischemia (TIMI) trial and has been
used generally since then (Fig. 34.38).430 The TIMI flow clas-
sification is as follows:
0 No antegrade blood flow
1 Faint antegrade blood flow that does not fill the distal
Initial Discharge
vessel
FIGURE 34.34. An angiogram obtained from a patient with acute
2 Reduced antegrade blood flow that fills the distal vessel
myocardial infarction demonstrating clot lysis over time. Angiog- 3 Normal antegrade blood flow
raphy soon after presentation revealed a large clot adherent to the
arterial wall and protruding into vessel lumen (leftmost panel, black Although visual interpretation of the rapidity and com-
arrow). Ten days later, angiography showed an “ulcer” at the site of pleteness of angiographic coronary flow following myocar-
clot attachment (rightmost panel, white arrow). dial infarction has proven helpful in assessing the efficacy
786 chapter 34

100 TIMI flow grade

75
Percent area stenosis

50
TIMI 0 TIMI 1
Occlusion Penetration

25

* p <.05 vs. Unstable angina

** p <.05 vs. Stable angina
0
MI SA UA MI
noninvolved involved
vessel vessel
FIGURE 34.36. Percent area stenosis of lesions causing stable TIMI 2 TIMI 3
angina, myocardial infarction (MI), and unstable angina, and non– Slow flow Normal flow
infarct-related lesions in patients with acute infarction. Although FIGURE 34.38. The TIMI coronary blood flow index, a qualitative
lesions associated with unstable angina tended to be more severe measurement of coronary blood flow.434
than those associated with infarction or unstable angina, there was
significant overlap between groups.
Although coronary flow in the infarct subserving vessel
has been the subject of the greatest study, flow in the angio-
and subsequent clinical outcomes of various therapies, this graphically normal noninvolved vessel in acute infarction
methodology (TIMI flow assessment) has recently been may not be normal. Using Doppler catheter techniques and
shown to exhibit considerable variability. This variability acetylcholine infusions, endothelial dysfunction of the non-
can be diminished by counting the angiographic frames from involved epicardial resistance vessels was found in 75% of
initial vessel opacification until filling of the distal bed.431 patients with acute myocardial infarction.
Recently, an angiographically defined index of microvas-
cular perfusion has been developed, the “TIMI myocardial
perfusion grade.” Also called a myocardial blush score, it is
1.00 measured by observing the myocardial washout of contrast
media after coronary injection. A normal response (grade 3)
is a brisk wash-in–washout. Persistence of contrast after
coronary injection (grade 2) and contrast staining of the myo-
0.75 cardium (grade 1) suggests increased microvascular permea-
bility and obstruction. The absence of myocardial opacification
indicates extensive microcirculatory obstruction, usually
associated with dense infarction. Mortality after acute infarc-
0.50 tion is inversely related to the myocardial blush score, inde-
pendent of TIMI coronary blood flow.
UI

Coronary Reocclusion and Lesion Remodeling

Following Myocardial Infarction
0.25
Coronary angiography has been helpful in identifying
patients at increased risk of recurrent ischemic events after
* p <.01 vs. SA and MI (noninvolved vessel) thrombolysis. Typical plaque rupture morphology is often
not visible immediately after thrombolysis, presumably
0
MI SA UA MI because of unlysed but inapparent thrombus laminated along
noninvolved involved the vessel wall (Fig. 34.34).432 The characteristic morphology
vessel vessel of the infarct-related lesion after thrombolysis was found in
FIGURE 34.37. Calculated ulceration index (UI) of lesions causing one study to be a marker of subsequent reocclusion,433 but
stable angina, myocardial infarction (MI), and unstable angina, and not in another.434
non–infarct-related lesions in patients with acute infarction. The
ulceration index of lesions involved in MI or unstable angina (UA)
Quantitative angiographic studies show that clot lysis
was significantly less than that of lesions uninvolved in infarction continues following thrombolytic therapy for acute infarc-
or associated with stable angina (SA). tion and restoration of vessel patency. In our initial studies,
 corona ry a ngiogr a ph y
the minimum lesion cross-sectional area increased 116% ±
34% during the 7 to 10 days following intracoronary throm-
bolysis and initial lumen patency.432 In seven of 17 patients,
minimum luminal cross-sectional area more than doubled.
Similar data have been obtained by other investigators.435,436
The residual lumen caliber immediately after reperfusion
has been used to identify patients at high risk for reclosure
within the first 2 weeks after thrombolysis. In quantitative
angiographic studies following successful intracoronary
thrombolysis with streptokinase, rethrombosis occurred
exclusively in vessels with a minimum lesion cross-sectional
area of <0.4 mm2.432,435,436 In that group, 54% of patients who
had initially successful reperfusion with intracoronary strep-
tokinase developed rethrombosis within 2 weeks.432 Similar
conclusions were reached when lesion severity was evaluated
by videodensitometry.
Data compiled from trials in which thrombolysis was
achieved using recombinant tissue plasminogen activator (rt-
PA) found that recurrent ischemic events in these patients
could not be predicted by any angiographic variable: percent
diameter stenosis, absolute lesion diameter, angiographically
defined thrombus, or stenosis morphology.437 Although the
incidence of recurrent ischemic events was similar to those
reported for streptokinase (about 20%), after rt-PA reclosure
occurred in 8% of patients with a minimum diameter steno-
sis >0.6 mm (about 0.3 mm2) and in patients in whom
the residual diameter stenosis was as low as 55%. These
disparate results may be due to fundamental differences
in the mechanisms of these agents in creating the throm-
bolytic state.438
Coronary Collaterals
A preexisting network of structural connections between
various portions of the coronary arterial supply to the heart
(coronary collaterals) has been recognized for centuries.439
However, the importance of this network in providing a
degree of structural protection against the effects of ischemia
due to atherosclerotic coronary obstructions has only recently
become clear.
Where does the human coronary circulation fit in this
species listing? Autopsy studies have shown the presence
of small coronary anastomoses (native collaterals) 50 to
250 μm in diameter in nearly all normal human hearts.440,441
In human coronary disease this preexisting collateral
network is enhanced by the development of an increased
plexus of subendocardial collateral vessels that link the
perfusion field at risk of infarction with other better-
perfused areas.442 In patients with severe coronary athero-
sclerosis, a diffuse subendocardial plexus of collateral
vessels can be seen angiographically as an outline of the
left ventricular cavity.
In the human atherosclerotic state, ante- or postmortem
angiograms also often reveal larger epicardial anastomoses
(stimulated collaterals). Such connections often connect
proximal and distal segments of the same occluded artery,
connect adjacent arteries, or may traverse the atrium to
connect two arteries with adjacent atrial branches.443 These
connections are more like what is seen in the dog following
the placement of ameroid constrictors, which cause the
gradual development of coronary obstruction.
787
Human Coronary Collateral Pathways
The preferred anatomic pathways taken by collateral chan-
nels have been described in detail elsewhere.444,445 Some of
the more common anatomic connections are as follows:
Collateral Pathways to the Left Anterior Descending
Coronary Artery
1. From the posterior descending via septal branches or
around the apex
2. From the conal branch of the right coronary artery via
Vieussens’ ring
3. From the acute marginal branch of the right coronary
artery
4. From the obtuse marginal branch of the circumflex
artery
Collateral Pathways to the Right Coronary Artery
1. From the left anterior descending artery via septal
branches or around the apex to the posterior descending
artery
2. From the distal circumflex or obtuse marginal branches
to the posterolateral branch, at times via the atrioven-
tricular nodal artery
3. From the conal or right ventricular branch to the more
distal right coronary branches
4. From the left atrial circumflex artery
Collateral Pathways to the Circumflex Coronary Artery
1. From a diagonal branch of the left anterior descending to
a marginal circumflex branch
2. From a proximal marginal or left atrial circumflex to the
more distal circumflex marginals
3. From the distal right coronary artery to the distal
circumflex
4. From the posterior-lateral branch of the right coronary to
the obtuse marginal branch
Intermittent or gradual coronary occlusion results in the
growth of coronary collaterals.446,447 This maturation process
involves not only an increase in the lumen of the vessel, but
also the development of new vascular smooth muscle.443 In
dogs, at 6 months following coronary occlusion, a well-
developed tunica media is present.448 Collateral vessels
respond to several neurohumoral substances, but the response
of mature coronary collaterals differs substantially from that
of native coronary arteries and immature collateral vessels.448
Mature collaterals are also responsive to the vasoconstrictor
effects of vasopressin448 and ergonovine.449
Visible and Recruitable Coronary Collaterals
Human coronary collaterals become demonstrable by coro-
nary angiography only when the parent vessel is subtotally
or totally occluded. Unfortunately, angiographic grading of
coronary collaterals based on collateral caliber is not accu-
rate in predicting the functional ability of the collateral to
provide coronary perfusion. There are several reasons for
this: (1) Coronary collaterals in the 100-μm range are not
angiographically visible.450 (2) Angiographic techniques in
humans for quantitating collateral function are not well vali-
dated.450 (3) In the absence of near-total vessel occlusion,
788 chapter 34

collateral vessels are not visible in the resting state (e.g., Collateral Grading
during angiography). They can, however, be rendered visible Rentrop Scale
if contrast is injected into the contralateral artery during
Score Definition
coronary spasm451 or during temporary balloon occlusion of
the recipient artery.452 These collaterals have been termed
“recruitable.”453
It is likely that the above shortcomings in evaluating
0 No collaterals
collateral flow were responsible for much of the controversy
over the past several decades regarding the functional impor-
tance of coronary collaterals in humans. Until the mid-1960s,
the myocardial protective effects of collaterals were accepted
widely.442 In the 1970s, however, these prevailing concepts
1 Faint filling of the distal branch
were called into question,454,455 with the finding of a higher arteries
incidence of wall motion disturbances in patients with versus
those without collaterals. Concepts then shifted to reflect
the view that collaterals were only a marker of severe disease,
which offered no beneficial effects.
At present the pendulum has returned to the conclusions 2 Complete filling of branch arteries
of the earlier era456 as a result of several important observa-
tions. For any given location of acute coronary occlusion, the
degree of deterioration of left ventricular function is inversely
related to the presence of angiographically visible coronary
collaterals.457 In addition, the incidence of late aneurysm
3 Collateral filling of the main artery, in
formation following myocardial infarction is reduced in
addition to the branches
patients with an angiographically significant collateral cir-
culation, with or without successful reperfusion.458 The risk
of hemodynamically severe consequences from acute infarc- FIGURE 34.39. The Rentrop semiquantitative scale for grading col-
tion is mitigated greatly by the presence of a preexisting lateral blood flow to a coronary artery.461
severe stenosis, and thus the protective effect of a developed
collateral circulation. Conversely, when acute coronary 4 mm Hg. Signs and symptoms during angioplasty balloon
occlusion occurs in the presence of a mild stenosis and thus occlusion of ischemia occur with a significantly greater fre-
poor collateral development, it is likely to have more severe quency in patients with a low coronary wedge pressure.
clinical consequences.459 More recently it has been shown Many studies in dogs have shown that even well-
that the presence of angiographically defined coronary col- developed mature collaterals have a minimal vascular resis-
laterals extends the “window of time” for the beneficial tance that is two to four times greater than normal minimal
effect of reperfusion therapy of myocardial infarction and resistance. Thus, coronary flow during maximum dilation
results in greater improvement in cardiac function and to areas supplied by angiographically large-caliber collaterals
reduction in infarct size.460 is usually significantly reduced when compared to regions
Collateral flow can be graded using the following scale supplied by normal coronaries.462 This may explain the fre-
devised by Rentrop et al.461 (Fig. 34.39): quent clinical observation that exertional angina is not infre-
quent when an area of the left ventricle with normal or
Grade 0: No angiographically visible filling of any collateral
minimally impaired contraction is supplied by a totally
channels
occluded coronary, even when large angiographic collaterals
Grade 1: Collateral filling of the distal branches of the
are visible.
recipient artery, but not the epicardial portion of
the artery
Grade 2: Partial collateral filling of the recipient epicardial
artery
Nonatherosclerotic Coronary Artery Disease
Grade 3: Complete collateral filling of the recipient epicar-
dial artery Coronary Vasospasm
Angiographic methods for assessing collateral blood flow The diagnosis of coronary vasospasm can be made at the time
are at best semiquantitative measures. The coronary wedge of angiography by giving drugs that provoke spasm or occa-
pressure (e.g., the distal coronary pressure during transient sionally by observing spontaneous spasm.463–470 The most
balloon occlusion at the time of angioplasty) has been used commonly administered agent is an ergot derivative, usually
to assess more accurately collateral function. Spontaneously ergonovine maleate or ergometrine, although methacholine
visible collaterals are present at angioplasty four times as was used to induce vasospasm in early pioneering studies in
often as recruitable collaterals. Meier et al.453 found the coro- the catheterization laboratory. Ergot derivatives are potent
nary wedge pressure in patients with collaterals of either constrictors of vascular smooth muscle. For over 2000 years,
type to be 44 ± 12 mm Hg (spontaneously visible collaterals ergot drugs have been known to cause gangrene when given
41 ± 12, recruitable collaterals 36 ± 12 mm Hg). The coronary in large doses, but the mechanism of action still is not clear.
wedge pressure in patients without collaterals was 18 ± They appear to have α-adrenergic and serotonin receptor
 corona ry a ngiogr a ph y
agonist activity and dopamine antagonist properties, and
may also inhibit central vasomotor centers.471 More recently,
intracoronary acetylcholine (25 to 50 μg and an intracoronary
bolus) has been used to provoke spasm.472 Prior to a provoca-
tive test for vasospasm, an electrocardiogram should be
obtained and a coronary arteriogram should show the absence
of severe coronary obstruction. When vasospasm is suspected,
acetylcholine or ergonovine generally is given in incremental
intravenous doses (starting at 50 μg and increasing doses until
a total dose of 350 to 400 μg intravenously for ergonovine) is
given. Although ergonovine appears safe in doses up to 800 μg,
the vast majority of patients with vasospastic angina develop
spasm at doses of <200 μg.465–469,473
In normal patients, ergonovine causes an increase in sys-
temic arterial pressure (10–20%) and a small increase in left
ventricular end-diastolic pressure (0 to 4 mm Hg), and does
not change heart rate or lactate extraction.468,470 Normal
patients also exhibit mild, diffuse coronary constriction in
the epicardial arteries (10–20% decrease in diameter).474 The
response is more pronounced in the distal vessels.
In patients with vasospastic angina, ergonovine or acetyl-
choline causes focal, usually severe coronary constriction,
frequently leading to transient, total coronary occlusion
(Fig. 34.40). The peak response occurs 2 to 5 minutes after
administration, although onset of spasm 15 to 20 minutes
later has been reported. In its classic description, coronary
spasm leads to chest pain, ST-segment elevation on the elec-
trocardiogram, increased left ventricular end-diastolic pres-
sure, and myocardial lactate release.470 In as many as half of
patients with vasospastic angina, the response to ergonovine
is less intense. ST-segment depression (rather than elevation)
is often observed in patients with incomplete coronary occlu-
sion with spasm, in patients with collateral arteries to the
ischemic bed, and if spasm occurs in a small vessel.475–479
Most authors would consider the test positive if the patient’s
symptoms are reproduced, focal spasm >75% is demonstrated,
and there are electrocardiographic changes (ST-segment ele-
vation or depression).465
Coronary spasm induced by ergonovine or acetylcholine
usually is reversed easily by nitroglycerin, although intra-
coronary administration can be required. Vasospasm has
been induced while a patient was receiving an intravenous
infusion of nitroglycerin and nitrate-resistant induced spasm
can occur, but it is rare.480 It is important to remember that
the blood half-life of ergonovine is 30 to 120 minutes, much
longer than that of nitroglycerin.481,482 Consequently, patients
FIGURE 34.40. An angiogram from a patient with vasospasm
induced by ergonovine. Left panel: Before ergonovine, there is a 50%
diameter stenosis in the proximal left anterior descending artery.
Center panel: After ergonovine (100 μg intravenously), the left ante-
789
with spasm induced by ergonovine should have nitroglycerin
or a calcium channel antagonist administered for at least 6
hours after the procedure. An advantage of acetylcholine is
its very short half-life and absence of late spasm.
Ergonovine provocative studies are relatively safe, with
complication rates comparable to routine angiography. Ven-
tricular tachycardia or fibrillation, the most common com-
plication, occurs in 0.2% to 0.4%, myocardial infarction in
0% to 0.03%, and significant heart block or severe bradycar-
dia in about 0% to 0.2%.483,484 We do not recommend prophy-
lactic temporary pacemaker insertion unless the patient has
previously developed bradycardia during angina. Platelet
activation after induction of vasospasm is reported, but its
relationship to the induction of or propensity for spasm is
unclear.485,486
Coronary spasm may be slightly more likely in the right
coronary, followed by the left anterior descending and cir-
cumflex arteries. Vein bypass grafts also can exhibit spasm,
but rarely do.487 Patients with vasospastic angina appear to
have more constriction in nonspastic coronary segments,
suggesting a generalized coronary abnormality and also may
have enhanced resting tone, as evidenced by a greater degree
of relaxation after nitroglycerin.488–491
Coronary spasm occurs in two broad settings: spasm
associated with atherosclerosis or other arterial diseases, and
spasm that occurs in the absence of identifiable arteriopa-
thy.465,467,484,492,493 The former is common but the latter is
not.465 Bertrand et al.484 administered ergonovine to 1089
patients undergoing coronary arteriography and found that
spasm was more common in patients with recent coronary
thrombosis (Fig. 34.41). Vasospasm could be induced in 20%
of patients with a recent infarction and 38% of patients with
unstable or rest angina but in only 4.3% of patients with
stable exertional angina. Equally important, only 1.2% of
patients with chest pain atypical for angina had inducible
spasm, emphasizing that spasm is not a common cause of
atypical chest pain.
Patients with inducible vasospasm and a significant
(>75%) stenotic lesion have a higher incidence of death,
infarction, and atherosclerosis progression than patients
with isolated stenotic lesions without inducible vasospasm
or vasospasm alone.494–496 Harding et al.483 and others497 ret-
rospectively analyzed ergonovine provocative studies and
found that smoking (odds ratio 4.7–7.7:1 compared to non-
smokers) and atherosclerosis were significant risk factors for
inducible spasm.
rior descending artery develops spasm at the site of the lesion (arrow)
and there is minimal antegrade blood flow. Right panel: After nitro-
glycerin (200 μg, intracoronary), the spasm is relieved and blood flow
is restored.
790 chapter
• Atypical chest pain 1.2%
• Exertional angina 4.3%
• Angina on effort & at rest 13.8%
• Angina at rest 38%
• Recent myocardial infarct 20%
• Oid myocardial infarct 6.2%
• Valvular disease 2%
• Cardiomyopathy 0%
0 50 100 150 200 250
FIGURE 34.41. The frequency of coronary vasospasm induced by
ergonovine in 1089 patients undergoing cardiac catheterization. The
incidence of provokable spasm was high in patients with angina at
rest and recent myocardial infarction, but spasm was uncommon
in patients with chest pain atypical for myocardial ischemia.
Other agents have also been used to induce spasm at the
time of catheterization. Muscarinic receptor agonists (acetyl-
choline and methacholine) appear to cause vasospasm in a
large fraction of patients with ergonovine-induced spasm.498
The specificity and sensitivity of cholinergic agents is not
well described. Induction of vasospasm by muscarinic recep-
tor agonists suggests the possibility that endothelial dys-
function may play a role in coronary spasm.498 Other agents
have also been reported to induce spasm (cold pressor test,
histamine, hyperventilation), but not enough information
is known to assess the potency and specificity of these
agents.499,500
Catheter-Induced Vasospasm
Coronary cannulation can cause vasospasm at the catheter
tip, thought usually to result from mechanical traction on
the artery. Catheter-induced spasm is much more common
in the right compared to the left coronary, and rarely may
occur distal to the catheter tip or in vein grafts.145–148 It may
occur more frequently in patients with vasospastic disease
FIGURE 34.42. Serial angiograms obtained from a patient with a
spontaneous dissection of the left anterior descending coronary
artery. Left panel: An angiogram obtained before presentation
revealed mild diffuse narrowing of the left anterior descending
artery. Center panel: After developing signs of acute myocardial
34
in other coronary segments, but the association is with clini-
cal vasospasm is very uncommon.
Spontaneous Coronary Artery Dissection
Naturally occurring coronary artery dissection occurs most
commonly in conjunction with aortic dissection and involves
the right coronary more often than the left. Isolated spontane-
ous coronary artery dissection, however, is a rare event that
occurs in all coronary arteries with approximately overall
equal incidence, although in women it may more frequently
involve the left coronary and in men the right (Fig. 34.42).501–506
It occurs most frequently in young women, particularly in the
peripartum period, but may also be associated with blunt chest
trauma, atherosclerosis (possibly related to plaque rupture),
obstruction immediately above the aortic valve (e.g., an
obstructed prosthetic ball valve), and iatrogenic complications
of coronary artery cannulation.502,507–511 Histologic examina-
tions have shown a variety of abnormalities.502,504,505,509 The
most common observation is a hematoma within the arterial
media and luminal compression.502,505 A rent in the intima
leading to the medial hematoma is observed inconsistently, as
are changes of cystic medial necrosis.504 Atherosclerosis with
aneurysm or plaque rupture has been reported.504 Perivascular
eosinophilia has also been found late after dissection but it is
not clear whether eosinophils were related to the cause or
occur as a response to the dissection.512
At angiography, spontaneous dissection appears as a
radiolucent linear filling defect that spirals down the coro-
nary artery.501,503,506,513–515 After intracoronary contrast injec-
tion, contrast material frequently persists in the false lumen.
The dissection may be complicated by total thrombotic coro-
nary occlusion. Distal emboli with abrupt vessel cut-offs are
common.506 Unless complicated by lumen thrombosis or
death, most spontaneous dissections heal, but permanent
true and false channel lumina may persist.501,513–515 A similar
dual-lumen vessel can be seen late after angioplasty compli-
cated by a spiral dissection. In one series of patients with
spontaneous dissection, the mortality rate was 18%.501
Thrombolytic therapy has been used successfully to treat
acute coronary occlusion related to spontaneous dissec-
tion,516 as has stenting.517 Recurrent dissection in another
artery is uncommon, but may occur more frequently in
women.
infarction, the angiogram revealed subtotal occlusion of the anterior
descending and a linear intraluminal filling defect along the occlu-
sion. Right panel: Angiography months after presentation and treat-
ment with streptokinase showed healing of the dissection and
minimal stenosis.
 corona ry a ngiogr a ph y
Myocardial Infarction in Patients with
Angiographically Normal Coronary Arteries
One to 16 percent of patients with documented acute myo-
cardial infarction are found at angiography to have normal
or nearly normal coronary arteries.518–521 Coronary embo-
lism, in-situ coronary thrombosis with spontaneous lysis,
and vasospasm have been proposed as possible mecha-
nisms.522–525 Compared to patients with infarction associated
with coronary atherosclerosis, those with a normal coronary
angiogram after infarction tend to be younger (16–22% of
patients are less than 35 years of age), and have fewer
antecedent symptoms of angina and fewer risk factors for
atherosclerosis.526,527 In contrast to the male predominance
of atherosclerosis-associated infarction, men and women
are approximately equally affected.524,527 Associations with
tobacco smoking, a prior history of migraine headaches,
Raynaud’s syndrome, mitral valve prolapse, cocaine abuse,
and birth control pill use have been reported.527–529 Cocaine,
sumatriptan, nifedipine, or excessive alcohol use also may
precipitate infarction, presumably by causing vasospasm or
transient thrombosis.530 Coronary spasm induced by ergono-
vine can be demonstrated in a minority of patients, but no
definitive underlying mechanism can be found in most.524
Sudden sympathetic discharge (e.g., with emotional
stress, shock, or postoperative pain) has also been associated
with transient anterior wall dysfunction, chest pain and deep
T-wave inversion across the precordial leads on the ECG, in
the presence of normal coronary angiography.531 Although
blood markers of infarction are elevated, nearly all patients
have recovery of ventricular function.
Infarctions associated with a normal coronary angiogram
tend to be smaller than those associated with atherosclerosis,
and the mortality rate may be lower.527 The long-term prog-
nosis is generally good in terms of mortality, but recurrent
infarction and stroke may be more common than in patients
with atherosclerosis.520,527
Microcirculatory Coronary Disease
Studies in highly selected patient populations suggest that
microvascular coronary dysfunction may be a frequent
cause of symptoms in the 10% to 25% of patients undergo-
ing coronary angiography for chest pain in whom no signifi-
cant obstruction to blood flow is found in the epicardial
vessels.532–536 Of patients with angiographically normal coro-
nary arteries, Cannon et al.537 reported that 71% had abnor-
mal microvascular function, and Geltman et al.538 found
reduced coronary flow reserve in 50%. It is now accepted
that microvascular dysfunction can cause clinically impor-
tant myocardial ischemia, including anginal syndromes,
exertional dyspnea, and left ventricular dysfunction, but the
mechanism(s) and incidence are unclear.534,535,539–541 One
investigator has become skeptical of the diagnosis and its
clinical importance.542
A number of diseases are associated with or cause micro-
vascular dysfunction. These include prolonged hypertension,
hypertrophy, cardiomyopathies, collagen vascular diseases,
and atherosclerosis,543–547 diseases associated with endothe-
lial dysfunction. Although common entities, these specific
disease entities are present in less than half of patients found
7 91
at catheterization to have microvascular disease. Hence, it is
likely that other, still uncharacterized, syndromes alter
microvascular function in these patients.
The function of the microcirculation can be tested in
several ways at the time of angiography, although the clinical
significance of abnormalities in function in the absence of
symptoms is not yet certain. Maximal coronary conduc-
tance can be assessed by measurements of coronary flow
reserve (the ratio of peak hyperemic blood flow to resting
flow).209,388,406,548 In patients with a severe epicardial coronary
stenosis (e.g., atherosclerotic stenosis), treadmill exercise
performance is reduced proportionately to coronary reserve.549
Patients with fixed microvascular disease may have simi-
larly reduced coronary reserve, suggesting a fixed reduction
in maximal coronary conductance.
Cannon et al.534,535,539,540 identified a subgroup of patients
with chest pain and angiographically normal arteries who,
after ergonovine administration, failed to normally increase
coronary blood flow conductance during atrial pacing. The
majority of these patients also had abnormally low maximal
coronary conductance after dipyridamole, reduced left ven-
tricular compliance, failure to increase the ventricular ejec-
tion fraction with exercise, and abnormally low myocardial
lactate uptake (even lactate release) during pacing at a rapid
heart rate. Furthermore, many of these patients also may
have reduced forearm flow reserve, suggesting a systemic
microvascular abnormality.550 The mechanism of this abnor-
mality is not known.
It has been postulated that endothelial dysfunction may
play an important etiologic role in microvascular disease
syndromes.551 The functional integrity of the endothelium
can be tested at the time of angiography by measuring the
amount of large vessel dilation and the change in blood flow
(i.e., microvascular dilation) during intracoronary infusion
of pharmacologic agents that normally elicit the release of
endothelial dilating factor(s). The responses to two agents
have been characterized in humans: acetylcholine and sub-
stance P. When normal endothelium is present, acetylcholine
causes a dose-dependent epicardial coronary and microvas-
cular dilation.410 In the absence of endothelium, acetylcho-
line causes short-acting constriction. Hence, the response to
intracoronary acetylcholine infusion (dilation or no change/
constriction) is one marker of endothelial function that can
be tested in humans. The acetylcholine response is abnormal
in several diseases with known endothelial dysfunction (ath-
erosclerosis, transplantation).410,552 The endothelial response
to acetylcholine also was abnormal in both the large conduit
coronary arteries and the coronary microcirculation (i.e.,
constriction, or subnormal dilation) in a series of nine
patients with anginal symptoms and normal coronary angi-
ography even though the response to nonendothelial depen-
dent pharmacologic vasodilators was preserved.553 These
findings suggest that functional as well as fixed abnormali-
ties in the coronary microcirculation may be causes of isch-
emia in the absence of epicardial atherosclerosis.
Radiation-Induced Coronary Artery Disease
Chest irradiation can lead to narrowing or occlusion of the
epicardial and intramural coronary arteries, typically pre-
senting several months to 12 years after the exposure.554–564
792 chapter
Radiation-induced injury usually leads to adventitial fibro-
sis, smooth muscle cell loss in the media, and intimal
proliferation.554,557 Atherosclerotic changes have also been
observed, although lipid deposition is less marked than in
patients with typical atherosclerosis. The angiographic
findings are similar to those of atherosclerosis.559 The coro-
nary lumen can be diffusely narrowed or occluded entirely
from radiation-induced fibrosis. Acute myocardial infarction
is reported.562 The proximal vessels are affected more
commonly.
Generally, a dose of over 3000 R is associated with
increased risk of radiation-induced coronary disease. In one
series of 16 young patients (<33 years of age) who had received
>3500 R to the heart, six had severe focal epicardial coronary
stenoses.559,560 In another series, patients treated for Hodg-
kin’s disease with mantle radiation had a 2.7-fold increase in
risk for coronary disease.556
Transplant-Related Arteriopathy
The most persistent problem in patients surviving more than
1 year after transplantation has been the development of
coronary arteriopathy characterized by diffuse intimal thick-
ening of the transplanted arterial wall.565–569 The process
extends from the large conduit arteries into smaller branch
vessels >400μm in diameter. Serial angiographic studies
demonstrate the development of luminal irregularities or
frank stenosis within 3 years of transplantation in 25% to
45% of patients.570–578 Serial angiographic measurements of
coronary luminal cross-sectional area using quantitative
angiography show that the large conduit arteries decrease in
diameter by 6% to 10% in the first year after transplantation,
but thereafter the lumen diameter remains fairly stable until
more advanced vasculopathy occurs.574
The angiographic studies probably underestimate the fre-
quency of arteriopathy because they detect only luminal
encroachment but do not reflect wall thickening, which may
occur in an abluminal manner.569 Intravascular ultrasound
imaging of transplanted coronary arteries generally demon-
strates a substantially greater degree of intimal thickening
than is observed using angiography.579,580 The presence of
angiographically undetected intimal thickening may predict
progression to more severe arteriopathy over time.581,582 At
the present time, many angiographers routinely image the
coronary arteries at the time of angiography. Nonetheless,
development of angiographically detectable vasculopathy is
associated with shortened survival.578
In its classic angiographic description, transplant vascu-
lopathy is characterized by diffuse luminal obliteration,
which is most marked in the smaller branch vessels seen on
angiography (Fig. 34.43). In reality, the process affects the
entire conduit artery, and focal stenoses in the large epicar-
dial arteries—similar in angiographic morphology to athero-
sclerotic lesions—are not infrequent (Fig. 34.42). The typical
patterns of transplant vasculopathy observed in 81 transplant
recipients were described by Gao et al.572 Angiographic hall-
marks of vasculitis are absent (FIg. 34.44).
Several physiologic abnormalities of coronary vasomo-
tion also have been detected. Endothelial function is
frequently abnormal.552 In many patients, intracoronary ace-
tylcholine administration fails to elicit the expected coro-
34
FIGURE 34.43. An angiogram of the left coronary artery of a patient
with transplant-related vasculopathy. The left anterior descending
artery is occluded (open arrow) and fills distally by faint collaterals
(solid arrow). The remainder of the coronary tree has diffuse irregu-
larities and pruning of the distal branches.
nary dilation and increase in blood flow, suggesting a failure
of the endothelium to normally release endothelium-derived
relaxing factor (nitric oxide, NO). Some transplant recipients
have frank vasoconstriction in response to acetylcholine.
Whether an abnormal endothelial function presages more
severe vasculopathy is unclear, but preliminary studies
suggest a link. Endothelial function testing during angiogra-
phy may have a role in research institutions.583
Epicardial coronary tone is also reduced in the first
several months after transplantation.584 Tone returns to
normal by 1 year after transplantation, but the reemergence
of normal tone is not related to reinnervation. Spontaneous
focal coronary spasm also has been observed during angiog-
raphy in transplanted hearts.585 Tone can be misinterpreted
as diffuse narrowing. Nitroglycerin should be administered
immediately prior to angiography to allow a true assessment
of the lumen caliber.
Coronary Abnormalities Associated with Vasculitis
Coronary vasculitis can result from vascular infection or
collagen vascular diseases and causes four angiographically
detectable coronary abnormalcies: focal stenotic lesions,
diffuse narrowing, thrombosis, and late aneurysmal dila-
tion.586,587 Lesions may be located from the aortic origin of
the coronary arteries to the microcirculation. Aortitis asso-
ciated with syphilis, Takayasu’s arteritis, and, more rarely,
tuberculosis can cause stenosis of the coronary ostia.588
Involvement of the larger epicardial coronary arteries is
reported, but is rare.586,589
Of the collagen vascular disease, systemic lupus erythe-
matosus most commonly involves the angiographically
visible epicardial coronary vessels, although large coronary
involvement can be seen in polyarteritis nodosa, progressive
systemic sclerosis, and, more rarely, giant cell arteritis and
rheumatoid arthritis.590–594 The epicardial lesions associated
with vasculitis typically resemble atherosclerotic lesions.587
Diffuse luminal narrowing is less common and the typical
 corona ry a ngiogr a ph y
Type A lesion
Type B1 lesion
Type B2 lesion
Type C lesion
FIGURE 34.44. Angiographic morphologies of coronary lesions
associated with transplant vasculopathy. Lesion type A: Discrete
tubular or multiple stenoses. Lesion type B1: Distal concentric nar-
rowing and obliterated vessels with sparing of proximal vessel.
Lesion type B2: Diffuse concentric narrowing. Lesion type C: Narrow
irregular distal branches with abrupt terminations.
beaded appearance of vasculitis seen in other vascular beds
is notably absent, although one case of a huge coronary aneu-
rysm associated with systemic lupus erythematosus is
reported.590,592,595 Thrombosis of vasculitic segments can
occur, leading to total arterial occlusion or the typical angio-
graphic appearance of a thrombotic lesion.
The incidence of coronary vasculitis is probably underes-
timated by angiography because the findings are so similar
to atherosclerosis.590 In young patients with systemic lupus
erythematosus and no important risk factors for atheroscle-
rosis, coronary lesions and myocardial infarction should be
assumed to be due to vasculitic involvement of the coronary
arteries until shown otherwise, although accelerated athero-
sclerosis due to corticosteroid therapy may also account for
angiographically detected lesions. Late aneurysmal dilation
of the large coronary arteries, especially in periarteritis
nodosa, has been reported to occur in nearly all of the vas-
culitic syndromes, and rupture of the aneurysm has been
reported as a rare consequence.590,592,596
Microcirculatory vasculitis occurs frequently in patients
with systemic lupus erythematosus, scleroderma, and rheu-
matoid arthritis. In these patients, maximal coronary con-
ductance (e.g., coronary flow reserve) is usually reduced and
ischemia due to microvascular obstruction or dysfunction
has been proposed.597,598
The most common infectious agent to involve the angio-
graphically visible coronary vessels is Kawasaki disease
(mucocutaneous lymph node syndrome). It is characterized
by coronary aneurysmal dilation, stenosis, and thrombosis
occurring primarily in the proximal coronary arteries.599,600
The aneurysms can be huge. Late after the acute illness about
one half of the aneurysms present during the febrile episode
resolve.601,602 In angiographic studies of 1100 patients at an
average of 25 months after disease onset, Suzuki et al.603
found that 36% had frank aneurysms, 28% had coronary
dilation, 24% had localized coronary stenosis, and 8% had
an occluded coronary. Aneurysmal calcification can occur.604
Most of the Kawasaki disease–associated aneurysms were in
the proximal coronary arteries but about one in five was in
the more distal vessels. Large aneurysms (>9 mm in diame-
793
ter) were particularly prone to occlude or develop stenotic
lesions.605 Rarely, aneurysms can rupture.606 Basal coronary
blood flow is usually normal, but coronary flow reserve is
usually reduced in the microvascular bed of arteries affected
by Kawasaki disease.607 Kawasaki disease should be consid-
ered in the differential diagnosis of young adults presenting
with aneurysmal coronary artery disease or myocardial
infarction.
Coronary Artery Aneurysms
True aneurysms of the coronary arteries are associated with
thinning of the tunica media and are very uncommon, but
when present can reach over 2 cm in diameter (Fig. 34.45).608–610
The angiographic morphology of coronary aneurysms can
be saccular or fusiform. They frequently contain thrombotic
material laminated against the borders of the aneurysm that
may not be identifiable on the angiogram. Occasionally, the
majority of the aneurysmal cavity can be filled with throm-
bus, leaving the angiographic appearance of a normal artery.
After angioplasty or thrombolytic drug treatment, a portion
of the aneurysm cavity can be revealed and at first may
resemble a coronary perforation.
Aneurysms can be congenital in origin, or occur as a
result of atherosclerosis, inherited diseases of connective
tissue (e.g., periarteritis nodosa, systemic lupus erythemato-
sus), inflammatory arteritis (e.g., Kawasaki disease), mycotic-
embolic events,611 or coronary trauma (usually iatrogenic).
True atherosclerotic coronary aneurysms are very uncom-
mon, occurring in only 0.2% of coronary arteriographic
studies,608,612 but the overall incidence from all causes ranges
from 0.5% to 1.1% of coronary angiographic studies.613 When
associated with atherosclerosis, usually there are coexistent
stenotic lesions in multiple vessels. Atherosclerotic aneu-
rysms almost never rupture, but they may contain throm-
botic material and can cause myocardial infarction by in-situ
thrombosis or embolization. Dissection of atherosclerotic
aneurysms has been reported, but also is uncommon.505
Congenital disorders of connective tissue are associated
with multiple aneurysms, particularly of the proximal arter-
ies. Ehlers-Danlos syndrome type IV is characterized by dila-
tion of the proximal and mid-coronary artery.614 One case of
FIGURE 34.45. A large fusiform aneurysm of the left anterior
descending coronary artery (arrow).
794 chapter
FIGURE 34.46. An angiogram of the left coronary artery of a patient
who underwent angioplasty 6 months previously and developed an
irregular, saccular pseudoaneurysm at the site of dilation (arrow).
rupture and another of thrombosis have been reported. Both
angiography-related dissection of the coronary ostium and
peripheral vascular pseudoaneurysm have been linked to the
syndrome.
Interventional coronary artery procedures also can result
in true coronary aneurysms, including laser angioplasty,
atherectomy, stent placement, and balloon dilation.615–617 One
report suggests that the use of corticosteroids around the
time of the stent placement may promote aneurysm forma-
tion.617 Aneurysms have also developed at the site of coro-
nary anastomosis of vein bypass grafts.618 Pseudoaneurysms
can occur after coronary rupture from balloon dilation
(Fig. 34.46).619 Recently, paclitaxel-coated stents have rarely
caused aneurysms.620
Coronary Embolism
Angiography soon after embolization of the coronary circula-
tion can reveal abrupt occlusion of a coronary artery with
persistence of contrast media proximal to the occlusion
(usually to the nearest proximal branch) or a filling defect
with the coronary lumen. Embolism from an infected mitral
or aortic valve can lead to mycotic aneurysm formation and
rupture. Embolism should be suspected in patients with an
acute ischemic syndrome, otherwise normal coronary arter-
ies with a smooth luminal surface, and a source of emboli
(e.g., abnormal native or prosthetic valves with thrombus or
infectious vegetation, and left atrial or ventricular thrombus,
or atrial fibrillation).621–623
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 3 Echocardiographic
5 Evaluation of Coronary
Artery Disease
Stephanie A. Coulter
Measurement of Regional Myocardial Function . . . . . .
Assessment of Coronary Ischemia/Acute Myocardial
Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Location of Acute Myocardial Infarction . . . . . . . . . . . .
Extent of Acute Myocardial Infarction . . . . . . . . . . . . . .
Acute Complications of Acute Myocardial
Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
C
oronary artery disease (CAD) is the most prevalent of
cardiac diseases. Routine evaluation of patients with
suspected or known CAD nearly always includes
echocardiography. Echocardiography is a versatile, low-cost,
and portable technique that is available clinically in nearly
all medical centers and subsequently is the most widely uti-
lized cardiac testing modality. The diagnosis of CAD by
echocardiography is based on the concept that acute myocar-
dial ischemia or infarction produces a detectable impairment
in regional left ventricular (LV) mechanical function. Identi-
fication of patients with suspected CAD and acute coronary
syndrome is one of the primary indications for echocardiog-
raphy. Assessment of global LV systolic function and detec-
tion of the presence and extent of regional myocardial
dysfunction are routine clinical indications for echocardiog-
raphy. This method also has an important prognostic value
in patients with acute and chronic CAD. When combined
with exercise or pharmacologic stress testing, echocardiog-
raphy can identify patients with myocardial ischemia and
viability. Because echocardiography can provide a compre-
hensive assessment of cardiac structure, functio
811 Chronic Complications After a Myocardial
Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 819
813 Prognosis in Acute Myocardial Infarction and
814 Chronic Coronary Artery Disease . . . . . . . . . . . . . . . 821
815 Stress Echocardiography: Assessment of Ischemic
and Viable Myocardium . . . . . . . . . . . . . . . . . . . . . . . 823
815
cardial motion.1 With echocardiography, a regional wall-
motion abnormality (RWMA) is characterized as a localized
decrease in the rate and amplitude of endomyocardial motion.
These abnormalities are accompanied by a reduction
in myocardial thickening during systolic contraction and
by thinning of the myocardial segment after a transmural
myocardial infarction (MI). The loss of systolic wall
thickening is more specific for myocardial ischemia than
is the detection of a resting RWMA 2–5 because cardiac
rotation, translational motion during contraction of border-
ing segments, and loading conditions affect the latter finding.
An RWMA is not specific for coronary ischemia and also
occurs with a previous MI, a previous sternotomy, myocar-
ditis, cardiomyopathies, left bundle branch block, and
preexcitation.
The American Association of Echocardiography rec-
ommends a 16-segment standardized format for describing
RWMAs.5 To update and unify reporting of wall-motion
analysis among disparate cardiac-imaging modalities, in
2002 the American Heart Association (AHA) issued a state-