Vous êtes sur la page 1sur 6

Heart Failure in Children: Etiology and Treatment

Joseph W. Rossano, MD, and Robert E. Shaddy, MD

lthough much of the care of pediatric patients with failure, and sepsis.4,7,8 Many of these morbidities are associ-
heart disease has focused on the treatment and pallia- ated with a striking increase in the risk of death (Figure 1).
tion of various forms of congenital heart disease, there It is unknown how many children have heart failure
is increasing recognition of the importance of heart failure in outside of the hospital. The annual incidence of cardiomyop-
child health.1 Many children with heart disease are at risk for athies has been reported as 1.1-1.2 per 100 000 children, with
developing heart failure, and heart failure can occur in the the peak incidence occurring in infancy (7.8-8.3 per 100 000
context of other diseases such as sepsis, cancer, and inflamma- per year).9,10 Although these patients are at risk for heart fail-
tory diseases. The diagnosis and treatment of heart failure in ure, not all will develop heart failure. Andrews et al11 reported
children has emerged during the past decade as a subspecialty that new-onset heart failure due to heart muscle disease
field within cardiology, with heart failure specialists being occurred at a rate of 0.87 per 100 000 children aged <16 years
trained at many centers throughout the world. As the field per year. Only 66% were free from death or transplantation 1
has expanded rapidly over time, this review will focus on the year later.11 This high risk of death or transplant has been
epidemiology of pediatric heart failure, the diagnosis and confirmed in multiple single-center and multicenter reports,
risk-stratification of patients with heart failure, advanced ther- with the 5-year transplant-free survival ranging from 50% to
apies for heart failure, and new paradigms for management. 65%.12-14 However, not all patients deteriorate, and a signif-
icant minority of patients will have meaningful recovery of
Epidemiology ventricular function.12,15

Heart failure is defined as a clinical and pathophysiologic Diagnosis and Risk Stratification
syndrome that results from any structural or functional
impairment of ventricular filling or ejection of blood.2 There The diagnosis of heart failure is made through a series of in-
is no single diagnostic test that establishes the diagnosis of vestigations that include history, physical examination, and
heart failure; rather, it remains a clinical diagnosis with char- diagnostic studies. It is generally possible to not only confirm
acteristic signs and symptoms resulting from a combination or refute the presence of heart failure in the pediatric patient
of circulatory, neurohormonal, and molecular abnormal- but also diagnose the structural abnormality that has caused
ities.1 Even though it is estimated that there are >5 million the heart failure. There is a long list of possible etiologies for
adults with heart failure, the prevalence of heart failure in pediatric heart failure, but this review will focus on the etiol-
children is not known.3 This is in part due to the diverse dis- ogies that relate to abnormalities of systemic ventricular sys-
eases that lead to heart failure including simple and complex tolic function. Other causes that will not be discussed are
forms of congenital heart diseases, cardiomyopathies, those that are related to left-to-right intracardiac shunts
rhythm abnormalities, and acquired conditions such as that result in pulmonary overcirculation and those related
myocarditis and Kawasaki disease.4-6 to the unique abnormalities after the Fontan operation.
In the US, there are currently >14 000 pediatric heart fail- Most causes of systemic ventricular systolic dysfunction in
urerelated hospitalizations annually, which corresponds to children that can lead to heart failure can be categorized as
14-18 hospitalizations per 100 000 children.4 The majority a form of dilated cardiomyopathy. The list of potential causes
of these children have some form of congenital heart disease, of this in children is very long, but most causes can be divided
although a significant number have a form of cardiomyopa- into several large categories: intrinsic myopathies, congenital
thy or myocarditis. This is a disease state associated with sig- heart disease, acquired conditions, arrhythmias, or ischemic
nificant morbidity and mortality.7 The overall hospital (Table).16 A thorough history (including family and social
mortality is 7%, and because the hospital mortality for chil- history) will reveal possible risk factors that could account
dren is very low, children whose hospitalization is compli- for or contribute to heart failure. This includes
cated by heart failure have a >20-fold increase in the risk of developmental and growth history, respiratory and/or
death.4 Patients hospitalized with heart failure are at risk exercise symptoms, infectious or toxic exposures, and
for multiple morbidities including respiratory failure, renal previous surgeries or interventions. Abnormal development

From the The Cardiac Center, The Childrens Hospital of Philadelphia, and the
ACE Angiotensin-converting enzyme Department of Pediatrics, Perelman School of Medicine at the University of
Pennsylvania, Philadelphia, PA
BNP B-type natriuretic peptide
The authors declare no conflicts of interest.
ECMO Extracorporeal membrane oxygenation
VAD Ventricular assist device 0022-3476/$ - see front matter. Copyright 2014 Elsevier Inc. All rights reserved.

Vol. 165, No. 2  August 2014

Figure 1. Hospital mortality of children with heart failure related hospitalizations. CVD, cerebrovascular disease; HTN, hyper-
tension. *Indicates a significantly increased hospital mortality (P < .05). Reproduced with permission from Rossano et al.4

can suggest a possible genetic abnormality that can include Toxic exposures are generally easy to diagnose (eg,
cardiac abnormalities. Abnormal growth could suggest the anthracyclines). In those patients with no previous medical
same but could also point toward a more longstanding history and with evidence of systemic ventricular
cardiac problem. The duration and severity of respiratory dysfunction, a thorough family history can help determine
and/or exercise abnormalities can also provide clues as to possible genetic causes. In those with a history of
the timing of cardiac compromise. Infectious illnesses can congenital heart disease, a complete review of all medical
either be an etiologic factor in heart failure or possibly records and imaging studies is necessary.
contribute to an increase in metabolic demands in a child A complete physical examination is also necessary to deter-
and therefore unmask an underlying cardiac problem. mine the presence of heart failure and to determine its
severity. Vital signs (including 4 extremity blood pressures)
can provide important information about hemodynamic sta-
Table. Etiologies of dilated cardiomyopathy tus. Four-extremity blood pressures, pulses, and perfusion
I. Intrinsic myopathies provide information about cardiac output and any aortic
a. Metabolic arch obstruction. A thorough respiratory examination can
b. Mitochondrial
c. Neuromuscular
assess for left-sided congestion, whereas hepatomegaly,
d. Familial peripheral edema, or jugular venous distention occurs with
e. Idiopathic right-sided congestion. Precordial examination may reveal
II. Congenital heart lesions (a few examples below)
a. Aortic valve stenosis
a prominent right-sided impulse in patients with elevated
b. Coarctation of the aorta right ventricular pressure (eg, pulmonary hypertension),
c. Volume overload lesions (eg, mitral valve regurgitation) whereas a prominent and displaced left-sided ventricular
III. Acquired conditions
a. Myocarditis
impulse suggests left ventricular hypertrophy, dilatation,
b. Drug- or toxin-related (eg, oncologic therapy, iron overload) and/or dysfunction. Heart tones can be soft in the presence
c. Anemia of very poor ventricular function or pericardial effusion.
d. Thyrotoxicosis
IV. Arrhythmias
An accentuated second heart sound can indicate elevated
a. Tachyarrhythmias (eg, longstanding supraventricular tachycardia) pulmonary artery pressures, which can reflect elevation in
b. Bradyarrhythmias (eg, congenital heart block) pulmonary venous pressure secondary to systemic ventricu-
V. Ischemic
a. Early coronary artery disease
lar dysfunction. A gallop rhythm is common in heart failure
b. Coronary anomaly due to ventricular dysfunction. A murmur may or may
c. Postoperative not contribute to the diagnosis of heart failure in a child.
Data from Gleason MM, Rychik J, Shaddy RE, eds. Pediatric practice: cardiology. New York: However, it is very common to have heart failure in the
McGraw-Hill; 2012. absence of a murmur, so the absence of a murmur should
THE JOURNAL OF PEDIATRICS  www.jpeds.com Vol. 165, No. 2

Figure 2. Multidisciplinary model for the care of pediatric heart failure patients. MD, medical doctor; NP, nurse practitioner; RN,
registered nurse.

not dissuade a clinician from considering a diagnosis of heart ill due to advanced heart failure. Echocardiographically,
failure. risk factors for worse outcomes include the degree of sys-
Although not an exact science, risk stratification of chil- temic ventricular dilation, the degree of depression in sys-
dren with heart failure is possible and is based on a large temic ventricular ejection fraction, and the degree of
number of findings. From the history, patients with long- systemic atrioventricular valve regurgitation.17-19 One retro-
standing feeding difficulties, respiratory symptoms, and/or spective analysis from the Pediatric Cardiomyopathy Regis-
failure to thrive secondary to systemic ventricular dysfunc- try determined 3 risk factors for sudden cardiac death in
tion generally have advanced heart failure. On physical exam- children with dilated cardiomyopathy: age <14 years at
ination, patients with respiratory distress and/or time of diagnosis, left ventricular end-diastolic dimension
hepatomegaly, with poor pulses, and with poor perfusion z-score >4, and a ratio of the left ventricular end-diastolic
due to systemic ventricular dysfunction are generally quite diameter to left ventricular posterior wall thickness of

Figure 3. Outline of diagnostic and therapeutic strategies in pediatric heart failure. ARB, angiotensin receptor blockers; ECG,
electrocardiogram; MRI, magnetic resonance imaging. Reproduced with permission from OConnor et al.47

230 Rossano and Shaddy


<0.14.17 Biomarkers have emerged as another metric for both there is compelling evidence in adults that ACE inhibitors
diagnosing and stratifying risk for heart failure in children. and b-blockers are efficacious in delaying the onset of symp-
The most extensively studied and widely used biomarkers toms. Stage C heart failure is the stage where patients develop
are B-type natriuretic peptide (BNP) and N-terminal pro- symptoms from a structural abnormality such as reduced ejec-
BNP.20-23 In a patient with evidence of fluid retention and/ tion fraction. In this stage, there is also a strong evidence base
or respiratory symptoms where there is concern for the pos- in adults that ACE inhibitors,30,31 b-blockers,32-35 and aldoste-
sibility of heart failure, BNP can help confirm or exclude a rone antagonists36,37 improve symptoms, ventricular function,
cardiac cause of these symptoms. In patients with known sys- and survival in patients with heart failure with reduced ejec-
temic ventricular dysfunction, the level of elevation of BNP tion fraction. Other medications used for the management
has been shown to be a discriminator for predicting future of chronic heart failure with reduced ejection fraction include
cardiac events or hospitalization.22,24 If the treatment of heart angiotensin receptor blockers in those patients intolerant to
failure is effective, one should see a decrease in BNP over ACE inhibitors. In children, there are no good data to conclu-
time.25 Although troponin leak reflects myocyte damage sively support or refute the use of these medications in stage B
and/or necrosis, one may see an elevated serum troponin or stage C heart failure.38 Although a randomized controlled
level in settings such as myocarditis, acute anthracycline trial of carvedilol did not show an improvement in outcomes
toxicity, or ischemic heart disease. Many new biomarkers vs control patients, these medications are commonly used and
are being studied in heart failure, primarily in adults.26 included in pediatric heart failure guidelines.39,40 There are
some data showing that certain etiologies, such as dystrophi-
New Paradigms in Pediatric Heart Failure nopathies, respond well to these medications.29,41,42 However,
it is much less clear whether these medications are of benefit in
The concept of pediatric heart failure as a subspecialty of pedi- pediatric patients with heart failure due to systemic ventricular
atric cardiology is relatively new. Pediatric heart failure as a systolic dysfunction whose systemic ventricle is a single or
discipline emerged from the development of pediatric heart right ventricle.39,43 Stage D heart failure is heart failure that re-
transplant programs in the 1980s and 1990s. As pediatric car- quires special interventions such as inotropes or mechanical
diologists started forming pediatric heart transplant programs, circulatory support. Even though inotropes are necessary to
it became apparent that the providers in these programs would improve perfusion in patients with low cardiac output, they
need to develop focus and expertise in the management of pe- are likely detrimental to long-term myocardial function.
diatric heart failure. There were 2 main reasons for this: (1) to Several studies in adult patients with heart failure have found
keep children with heart failure stable while awaiting heart increased mortality and side effects with the use of inotropic
transplantation; and (2) to optimize the treatment of heart medications.7,8,44-46 Limited data from pediatric heart failure
failure in children to avoid the need for heart transplantation patients also support this notion.7,8 Figure 3 provides a
whenever possible. Many of these pediatric heart transplant schematic for diagnosis and treatment of pediatric heart
centers soon realized that the best model for these programs failure from no symptoms through severe symptoms.47
was a multidisciplinary pediatric heart failure program that
included physicians, nurses, nurse practitioners, dieticians, so- Mechanical Circulatory Support and Heart
cial workers, and others. These programs have now become Transplantation
linked to other disciplines where children either are at risk
for heart failure or have developed heart failure. These other Heart failure is a progressive disease, and many children with
disciplines include neuromuscular disorders, oncology, ge- heart failure will progress to end-stage disease even with
netics, and others (Figure 2). This model is now widespread advanced medical therapy. Heart transplantation offers pro-
in the larger pediatric cardiology centers and provides a longed survival for patients with end-stage disease; however,
comprehensive, multidisciplinary, integrated approach to the the supply of available organs remains small relative to the
management of these complex children. number of patients that could potentially benefit from
With the onset of pediatric heart failure as a discipline, pe- them. There are <400 pediatric heart transplants performed
diatric cardiologists initially turned to their adult heart failure annually in the US, and the mortality while waiting for a heart
colleagues to extrapolate medical therapies that had been transplant remains high, especially for certain high-risk pop-
proved effective in the adult. Heart failure and its treatments ulations including infants, patients with congenital heart dis-
can be divided into 4 stages.27 Stage A is the stage where pa- ease, and those supported with extracorporeal membrane
tients are at risk for heart failure (eg, hypertension, diabetes, oxygenation (ECMO).48,49
anthracycline exposure, genetic predisposition). In this stage, Until relatively recently ECMO, which provides total car-
most therapies are directed toward periodic observation for diopulmonary support, was the only modality available to
the development of abnormalities and/or the use of medica- support small children with end-stage heart failure. With
tions to prevent or delay onset of abnormalities (eg, the use of the Berlin Excor ventricular assist device (VAD),
angiotensin-converting enzyme (ACE) inhibitors in infants as small as 3 kg could be supported successfully to
Duchenne muscular dystrophy).28,29 Stage B is the stage where heart transplant. The Berlin Heart is a paracorporeal pulsatile
there is asymptomatic structural abnormality (eg, asymptom- VAD that can be used for left, right, or biventricular support.
atic systemic ventricular systolic dysfunction). In this stage, The landmark prospective Berlin Heart Trial, which
Heart Failure in Children: Etiology and Treatment 231
THE JOURNAL OF PEDIATRICS  www.jpeds.com Vol. 165, No. 2

compared patients supported on the Berlin Heart VAD with Reprint requests: Joseph W. Rossano, MD, Division of Cardiology, The
Childrens Hospital of Philadelphia, 34th Street and Civic Center Boulevard,
a historic matched cohort of patients supported on ECMO, Room 6NE 40, Philadelphia, PA 19104. E-mail: jrossano@me.com
led to US Food and Drug Administration approval of the de-
vice in 2011. The limitation of ECMO for long-term circula-
tory support is evident in this study as there were no patients References
alive on ECMO after 30 days.50 Although it is important to
note that the Berlin Heart VAD represents a significant 1. Hsu DT, Pearson GD. Heart failure in children: part I: history, etiology,
and pathophysiology. Circ Heart Fail 2009;2:63-70.
improvement over ECMO, serious complications such as 2. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH,
stroke, hemorrhage, and infection occur in a substantial et al. 2013 ACCF/AHA guideline for the management of heart failure: ex-
number of patients. ecutive summary: a report of the American College of Cardiology Foun-
In adults who require long-term mechanical circulatory dation/American Heart Association Task Force on Practice Guidelines.
support, intracorporeal continuous-flow devices have re- Circulation 2013;128:1810-52.
3. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al.
placed the pulsatile paracorporeal VADs. These devices allow Heart disease and stroke statistics2014 update: a report from the Amer-
for longer support with fewer complications. Larger children ican Heart Association. Circulation 2013;127:e6-245.
and adolescents have been supported on these devices, and 4. Rossano JW, Kim JJ, Decker JA, Price JF, Zafar F, Graves DE, et al. Prev-
many patients can be discharged home and followed as an alence, morbidity, and mortality of heart failure-related hospitalizations
outpatient. It is important to note that these devices were de- in children in the United States: a population-based study. J Card Fail
signed for adults with structurally normal hearts. However, a 5. Sommers C, Nagel BH, Neudorf U, Schmaltz AA. Congestive heart fail-
continuous-flow device for infants and small children will be ure in childhood. An epidemiologic study. Herz 2005;30:652-62.
studied as part of the National Heart, Lung, and Blood Insti- 6. Massin MM, Astadicko I, Dessy H. Epidemiology of heart failure in a ter-
tute Pumps for Kids, Infants, and Neonates program.51 Pa- tiary pediatric center. Clin Cardiol 2008;31:388-91.
tients with complex congenital heart disease, including 7. Shamszad P, Hall M, Rossano JW, Denfield SW, Knudson JD, Penny DJ,
et al. Characteristics and outcomes of heart failurerelated intensive care
those with functional single ventricles, may not be supported unit admissions in children with cardiomyopathy. J Card Fail 2013;19:
as well with traditional VADs. The outcomes of patients with 672-7.
functional single ventricles supported with VADs are inferior 8. Price JF, Mott AR, Dickerson HA, Jefferies JL, Nelson DP, Chang AC,
to patients with cardiomyopathies.52,53 Successful use of the et al. Worsening renal function in children hospitalized with decompen-
total artificial heart in patients with complex congenital heart sated heart failure: evidence for a pediatric cardiorenal syndrome? Pe-
diatr Crit Care Med 2008;9:279-84.
disease has been reported.54 9. Lipshultz SE, Sleeper LA, Towbin JA, Lowe AM, Orav EJ, Cox GF, et al.
Pediatric VAD use has increased dramatically in the past The incidence of pediatric cardiomyopathy in two regions of the United
decade. Even though some patients, especially with myocar- States. N Engl J Med 2003;348:1647-55.
ditis, will have recovery of function and have the VAD 10. Nugent AW, Daubeney PE, Chondros P, Carlin JB, Cheung M,
removed, the vast majority of pediatric patients will be placed Wilkinson LC, et al. The epidemiology of childhood cardiomyopathy
in Australia. N Engl J Med 2003;348:1639-46.
on a VAD with intention of bridging the patient to heart 11. Andrews RE, Fenton MJ, Ridout DA, Burch M, British Congenital Car-
transplant.55 This is not necessarily the case with adult pa- diac Association. New-onset heart failure due to heart muscle disease in
tients. The use of VADs as destination therapy, that is place- childhood: a prospective study in the United Kingdom and Ireland. Cir-
ment of the device with no intention of listing for heart culation 2008;117:79-84.
transplantation now accounts for >40% of VADs in adults.56 12. Daubeney PE, Nugent AW, Chondros P, Carlin JB, Colan SD,
Cheung M, et al. Clinical features and outcomes of childhood dilated
As the durability and safety of VADs increase, it is conceiv- cardiomyopathy: results from a national population-based study. Circu-
able that more children will be placed on VADs without lation 2006;114:2671-8.
the expectation of heart transplantation. For example, pa- 13. Towbin JA, Lowe AM, Colan SD, Sleeper LA, Orav EJ, Clunie S, et al.
tients with Duchenne muscular dystrophy have been placed Incidence, causes, and outcomes of dilated cardiomyopathy in children.
on VADs for destination therapy.57 JAMA 2006;296:1867-76.
14. Kantor PF, Abraham JR, Dipchand AI, Benson LN, Redington AN. The
impact of changing medical therapy on transplantation-free survival in
Discussion pediatric dilated cardiomyopathy. J Am Coll Cardiol 2010;55:1377-84.
15. OSullivan JJ, Roche SL, Crossland DS, Chaudhari MP, Kirk RC, Asif H.
Heart failure in children is a serious disease with a high Recovery of heart function in children with acute severe heart failure.
morbidity and mortality, and there is increasing recognition Transplantation 2008;85:975-9.
16. Hsu DT, Mital S, Ravishankar C, Margossian R, Li JS, Sleeper LA, et al.
of its importance in child health. The field has evolved over Rationale and design of a trial of angiotensin-converting enzyme inhibi-
the past decade to meet the growing demand and challenges tion in infants with single ventricle. Am Heart J 2009;157:37-45.
in the care of these patients, and there has been an explosion 17. Pahl E, Sleeper LA, Canter CE, Hsu DT, Lu M, Webber SA, et al. Inci-
in research and utilization of advanced technologies. dence of and risk factors for sudden cardiac death in children with
Ongoing research and a collaborative multidisciplinary dilated cardiomyopathy: a report from the Pediatric Cardiomyopathy
Registry. J Am Coll Cardiol 2012;59:607-15.
approach will likely continue to improve the outcomes of 18. Ross RD. The Ross classification for heart failure in children after 25 years:
this complex patient population. n a review and an age-stratified revision. Pediatr Cardiol 2012;33:1295-300.
19. Patange A, Thomas R, Ross RD. Severity of mitral regurgitation predicts
Submitted for publication Feb 3, 2014; last revision received Mar 18, 2014; risk of death or cardiac transplantation in children with idiopathic
accepted Apr 30, 2014. dilated cardiomyopathy. Pediatr Cardiol 2014;35:232-8.

232 Rossano and Shaddy


20. Johns MC, Stephenson C. Amino-terminal pro-B-type natriuretic pep- guidelines for management of heart failure in children. J Heart Lung
tide testing in neonatal and pediatric patients. Am J Cardiol 2008;101: Transplant 2004;23:1313-33.
76-81. 39. Shaddy RE, Boucek MM, Hsu DT, Boucek RJ, Canter CE, Mahony L,
21. Law YM, Hoyer AW, Reller MD, Silberbach M. Accuracy of plasma B- et al. Carvedilol for children and adolescents with heart failure: a ran-
type natriuretic peptide to diagnose significant cardiovascular disease domized controlled trial. JAMA 2007;298:1171-9.
in children: the Better Not Pout Children! Study. J Am Coll Cardiol 40. Kantor PF, Lougheed J, Dancea A, McGillion M, Barbosa N, Chan C,
2009;54:1467-75. et al. Presentation, diagnosis, and medical management of heart failure
22. Auerbach SR, Richmond ME, Lamour JM, Blume ED, Addonizio LJ, in children: Canadian Cardiovascular Society guidelines. Can J Cardiol
Shaddy RE, et al. BNP levels predict outcome in pediatric heart failure 2013;29:1535-52.
patients: post hoc analysis of the Pediatric Carvedilol Trial. Circ Heart 41. Jefferies JL, Eidem BW, Belmont JW, Craigen WJ, Ware SM,
Fail 2010;3:606-11. Fernbach SD, et al. Genetic predictors and remodeling of dilated cardio-
23. Das BB. Plasma B-type natriuretic peptides in children with cardiovascu- myopathy in muscular dystrophy. Circulation 2005;112:2799-804.
lar diseases. Pediatr Cardiol 2010;31:1135-45. 42. Viollet L, Thrush PT, Flanigan KM, Mendell JR, Allen HD. Effects of
24. Price JF, Thomas AK, Grenier M, Eidem BW, OBrian Smith E, angiotensin-converting enzyme inhibitors and/or beta blockers on the
Denfield SW, et al. B-type natriuretic peptide predicts adverse cardiovas- cardiomyopathy in Duchenne muscular dystrophy. Am J Cardiol
cular events in pediatric outpatients with chronic left ventricular systolic 2012;110:98-102.
dysfunction. Circulation 2006;114:1063-9. 43. van der Bom T, Winter MM, Bouma BJ, Groenink M, Vliegen HW,
25. Wong DT, George K, Wilson J, Manlhiot C, McCrindle BW, Adeli K, Pieper PG, et al. Effect of valsartan on systemic right ventricular func-
et al. Effectiveness of serial increases in amino-terminal pro-B-type tion: a double-blind, randomized, placebo-controlled pilot trial. Circu-
natriuretic peptide levels to indicate the need for mechanical circulatory lation 2013;127:322-30.
support in children with acute decompensated heart failure. Am J Car- 44. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM,
diol 2011;107:573-8. et al., for The PROMISE Study Research Group. Effect of oral milrinone
26. Ahmad T, OConnor CM. Therapeutic implications of biomarkers in on mortality in severe chronic heart failure. N Engl J Med 1991;325:
chronic heart failure. Clin Pharmacol Ther 2013;94:468-79. 1468-75.
27. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, 45. Abraham WT, Adams KF, Fonarow GC, Costanzo MR, Berkowitz RL,
Ganiats TG, et al. ACC/AHA 2005 guideline update for the diagnosis LeJemtel TH, et al. In-hospital mortality in patients with acute decom-
and management of chronic heart failure in the adultsummary article: pensated heart failure requiring intravenous vasoactive medications:
a report of the American College of Cardiology/American Heart Associ- an analysis from the Acute Decompensated Heart Failure National Reg-
ation Task Force on Practice Guidelines (Writing Committee to Update istry (ADHERE). J Am Coll Cardiol 2005;46:57-64.
the 2001 Guidelines for the Evaluation and Management of Heart Fail- 46. Cuffe MS, Califf RM, Adams KF Jr, Benza R, Bourge R, Colucci WS, et al.
ure). J Am Coll Cardiol 2005;46:1116-43. Short-term intravenous milrinone for acute exacerbation of chronic
28. Duboc D, Meune C, Lerebours G, Devaux JY, Vaksmann G, Becane HM. heart failure: a randomized controlled trial. JAMA 2002;287:1541-7.
Effect of perindopril on the onset and progression of left ventricular 47. OConnor MJ, Rosenthal DN, Shaddy RE. Outpatient management of
dysfunction in Duchenne muscular dystrophy. J Am Coll Cardiol pediatric heart failure. Heart Fail Clin 2010;6:515-29. ix.
2005;45:855-7. 48. Mah D, Singh TP, Thiagarajan RR, Gauvreau K, Piercey GE, Blume ED,
29. Duboc D, Meune C, Pierre B, Wahbi K, Eymard B, Toutain A, et al. Peri- et al. Incidence and risk factors for mortality in infants awaiting heart
ndopril preventive treatment on mortality in Duchenne muscular dys- transplantation in the USA. J Heart Lung Transplant 2009;28:1292-8.
trophy: 10 years follow-up. Am Heart J 2007;154:596-602. 49. Almond CS, Thiagarajan RR, Piercey GE, Gauvreau K, Blume ED,
30. Effects of enalapril on mortality in severe congestive heart failure. Results Bastardi HJ, et al. Waiting list mortality among children listed for heart
of the Cooperative North Scandinavian Enalapril Survival Study transplantation in the United States. Circulation 2009;119:717-27.
(CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med 50. Fraser CD Jr, Jaquiss RD, Rosenthal DN, Humpl T, Canter CE,
1987;316:1429-35. Blackstone EH, et al. Prospective trial of a pediatric ventricular assist de-
31. Effect of enalapril on survival in patients with reduced left ventricular vice. N Engl J Med 2012;367:532-41.
ejection fractions and congestive heart failure. The SOLVD Investigators. 51. Baldwin JT, Borovetz HS, Duncan BW, Gartner MJ, Jarvik RK,
N Engl J Med 1991;325:293-302. Weiss WJ. The National Heart, Lung, and Blood Institute Pediatric Cir-
32. Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, culatory Support Program: a summary of the 5-year experience. Circu-
Hershberger RE, et al. Carvedilol produces dose-related improvements lation 2011;123:1233-40.
in left ventricular function and survival in subjects with chronic heart 52. VanderPluym CJ, Rebeyka IM, Ross DB, Buchholz H. The use of ventric-
failure. MOCHA Investigators. Circulation 1996;94:2807-16. ular assist devices in pediatric patients with univentricular hearts. J
33. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Thorac Cardiovasc Surg 2011;141:588-90.
Randomised Intervention Trial in Congestive Heart Failure (MERIT- 53. Weinstein S, Bello R, Pizarro C, Fynn-Thompson F, Kirklin J,
HF). Lancet 1999;353:2001-7. Guleserian K, et al. The use of the Berlin Heart EXCOR in patients
34. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised with functional single ventricle. J Thorac Cardiovasc Surg 2014;147:
trial. Lancet 1999;353:9-13. 697-705.
35. Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Krum H, et al. 54. Rossano JW, Goldberg DJ, Fuller S, Ravishankar C, Montenegro LM,
Effect of carvedilol on the morbidity of patients with severe chronic heart Gaynor JW. Successful use of the total artificial heart in the failing Fon-
failure: results of the carvedilol prospective randomized cumulative sur- tan circulation. Ann Thorac Surg 2014;97:1438-40.
vival (COPERNICUS) study. Circulation 2002;106:2194-9. 55. Wilmot I, Morales DL, Price JF, Rossano JW, Kim JJ, Decker JA, et al.
36. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The Effectiveness of mechanical circulatory support in children with acute
effect of spironolactone on morbidity and mortality in patients with se- fulminant and persistent myocarditis. J Card Fail 2011;17:487-94.
vere heart failure. Randomized Aldactone Evaluation Study Investiga- 56. Kirklin JK, Naftel DC, Kormos RL, Stevenson LW, Pagani FD,
tors. N Engl J Med 1999;341:709-17. Miller MA, et al. Fifth INTERMACS annual report: risk factor analysis
37. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Epler- from more than 6,000 mechanical circulatory support patients. J Heart
enone, a selective aldosterone blocker, in patients with left ventricular Lung Transplant 2013;32:141-56.
dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-21. 57. Amodeo A, Adorisio R. Left ventricular assist device in Duchenne car-
38. Rosenthal D, Chrisant MR, Edens E, Mahony L, Canter C, Colan S, et al. diomyopathy: can we change the natural history of cardiac disease? Int
International Society for Heart and Lung Transplantation: Practice J Cardiol 2012;161:e43.

Heart Failure in Children: Etiology and Treatment 233