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D.Drexler H: Selectiveactivation of cardiac angiotensinogen gene
in post-infarction ventricular remodeling in the rat. J
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yamagishi H, Kim S, Nishikimi T, Takeuchi K, TakedaT: Contribution of cardiac renin-angiotensin system to ventricular remodelling in myocardial-infarctedrats. J Mol Cell Cardiol25, 1369I380( 1993)
McCluskey ER, Corr PB, Lee BI, Saffitz JE. Needleman P: The
arachinodic acid metabolic capacity of canine myocardium is increased during healing of acute myocardial infarction. Circ Rcs 51,
743-750 ( 1982)
Hirsch AT, Talsness CE, Schunkert H, Paul M. Dzau VJ: Tissuespecific activation of cardiac angiotensinconvertingenzyme in experimental heart failure. Circ Res 69,475482 ( 1991)
BrillaCG,Zhou G, Matsubara L, Weber KT: Collagen metabolism
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Clin. Cardiol. 19,455460 (1996)

Evaluation of Heart Failure Patients: Objective Parameters to Assess

Functional Capacity
ROGERM. MILLS, JR., M.D., AND W. HERBERT
HAUGHT,M.D.
University of Florida, College of Medicine, Department of Medicine, Division of Cardiovascular Medicine, Gainesville,Florida, USA

Summary: Measures of disease severity used in the evaluation of patients with heart failure include survival data, the
New York Heart Association classification,ejection fraction,
functional assessments,exercise protocols, rest and exercise
hernodynamic data, and biochemical parameters including
catecholamine levels and serum sodium. Clinicians must integrate these multiple variables into an overall assessment. An
overview of the clinical application of these techniques in the
evaluation and treatment of patients with heart failure is presented.

Key words: cardiac output, functional capacity, heart failure,

Oxygen consumption,respiratory physiology,transplantation

Address for reprints:

Roger M. Mills, Jr., M.D.

Professor, Department of Medicine
m
Io
O SW Archer Rd, Box 100277
Gaincsville, FL 32610-0277, USA
Received: April 17, 1995
Accepted: May 23. 1995

Introduction
Cliniciansoften assess severity of illness in order to evaluate a patient's response to a specific therapeutic intervention
or to compare patients for the allocation of scarce resources.
In caringfor heart failure patients,examples of these activities
include functional testing for the evaluation of therapeutic interventions14 and the assessment of potential cardiac transplant re~ipients.~.This review features a discussion of (1)
techniques currently used to evaluate heart failure patients
and (2) interpretation of data from standardized cardiopulmonary exercise testing, and rest and exercise hernodynamic
measurements. An overview of clinical applicationsof these
techniques as applied to selection of potential cardiac transplant recipients is also presented.

Techniques
Selecting appropriate objective tests and interpreting the
data acquired requires understanding both the measurement
techniques and the pathophysiologic basis of the observed
functionalimpairment.Proposed measures of disease severity in heart failure patients range from purely clinical evalua-

456

Clin. Cardiol. Vol. 19, June 1996

T,mi~iI New York Heart Association (NYHA) functional classification

Class I
Patients with cardiac disease but without resulting limitations of
physical activities. Ordinary physical activity does not cause undue fatigue, palpitations. dyspnea, or anginal pain.

Class I I
Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Physical activity results
in fatigue, palpitations. dyspnea, or anginal pain.
Class 111
Patients with cardiac disease resulting in marked limitation of
physical activity. The are comfortable at rest. Less than ordinary
physical activity results in fatigue,palpitations, dyspnea, or anginal pain.
Class IV
Patients with cardiac disease resulting in inability to cany on any
physical activity without discomfort. Symptomsof cardiac insufficiency or of the anginal syndrome may be present even at rest. If
any physical activity is undertaken, discomfort is increased.
Reproduced from Ref.7 with permission.

tion, such as the New York Heart Association (NYHA)classification, to complex invasive parameters such as stroke
work index.
The NYHA criteria are widely used (Table I). Classification in this scheme is based on subjective assessment by
both patient and physician, and thus lacks precision. Van den
Broek and associates* compared NYHA classification and
peak oxygen consumption (MV02) in 94 patients with heart
failure and ejection fractions < 40%. They found marked discrepancy between MVoz and NYHA classification and believed that MVo2 subdivided patients more clearly with regard to functional impairment and prognosis. Jennings and
Esler9reviewed techniques for the functional assessment of
patients with congestive heart failure (CHF) and stated, concerning the NYHA criteria, that assessment of new therapy
for CHF. in particular, demands more precise and reproducible measures of severity and progress.
Detemiination of left ventricular ejection fraction (LVEF)
is widely available using a variety of techniques including nuclear, echocardiographic, and angiographic measurements. In
a study of 295 patients with mild to moderate heart failure,
Gradnian and associatesIO found that LVEF was the variable
most closely identified with total mortality. However, substantial numbers of patients with impaired systolic function
do not have symptomatic heart failure. In a substudy of the
Studies of Left Ventricular Dysfunction (SOLVD) trial, 184
patients with LVEF < 36% underwent functional testing.
Twenty had overt heart failure and I64 did not. Those with no
or minimal heart failure had better exercise performance,
which could not be explained by LVEFor by NYHA classification. Although decreased LVEF can identify a population
of patients at risk, it is not sensitive enough for evaluation of
therapy or prognosis in individual heart failure patients.

Results of functional testing depend on both patients and

exercise protocols. In 1977, Bruce1*proposed exercise testing
using duration of exercise following his standard protocol
mode of evaluation for left ventricular (LV) function, hut
pointed out by Cowley and colleague^,^^ the Bruce protocol,
with its rapid increases in workload, stresses patients far dif.
ferently from gentler protocols with smaller workload incre.
ments. Furthermore, as Cowley and colleagues suggested,exercise duration itself probably is a poor measure Of Workload,
Rna and KaralisI4 compared four exercise protocols in eight
patients with stable heart failure and found that anaerobic
threshold was the most reproducible and effort-independent
exercise parameter in their population. McElroy and assmi.
ates15have recently reviewed thephysiology and application
of cardiopulmonary exercise testing in heart failure patients
and concluded that cardiopulmonary exercise testing can be
used to grade seventy of heart failure, follow response therapy,
and differentiatecardiac from pulmonary limitation using bMh
anaerobic threshold and MVo2 as primary parameters. Itoh
and associates16. reported cardiopulmonary exercise test results in 99 normal subjects and 382 cardiac patients and also
concluded that anaerobic threshold, MVo2, and the ratio of
oxygen uptake to work rate could alsobe used as objective and
reliable parameters for heart failure evaluation.
A variety of invasive parameters including rest and exercise
her no dynamic^,^^* I 8 stroke work index,19maximum cardiac
power output,20 and coronary sinus oxygen content2 have
also been proposed for evaluation of heart failure patients.
However, the requirement for invasive instrumentation makes
these measures less useful than functional testing for repeated
assessments in the heart failure population.
Functional Testing in Heart Failure

Functional assessment with cardiopulmonary exercise

testing evaluates the entire physiology of respiration. Wassermann22has highlighted both the complexity of coupling between external and cellular respiration and the central role of
cardiovascular system in exercise physiology. Oxygen transport from the atmosphere to the mitochondria involves three
closely linked processes: external or pulmonary respiration,
internal respiration or oxygen transport, and tissue respiration
or cellular uptake. Functional assessment in patients with
heart failure focuses on oxygen transport as the major limiting
factor in maximal exercise. In a study correlating hemodynamic and exercise data in 34 heart failure patients, Metra and
associates23found that MVo2 correlated well with cardiac index and stroke work index. They concluded that cardiac index was indeed the central hemodynamic determinant of exercise capacity in these patients. However, ventilatory
changes and skeletal muscle metabolic abnormalities are a h ?
important in long-term studies. In addition, clinicians should
keep in mind that functional capacity relates to prognosis only
in patients with relatively severe illne~s.~.9
Both normal individuals and heart failure patients maintain
tissue respiration by attaining a relatively fixed arterial veiims
oxygen difference with exercise, so that cardiac output in-

R. M. Mills, Jr.. and W. H. Haught: Evaluation of HF patients

457

produces increased tissue lactate, which is subsequently

buffered by extracellularbicarbonate, producing a break in the
slope of the carbon dioxide production curve which defines
the anaerobic threshold (Fig.
Functional assessment with cardiopulmonary exercise
testing, in context, provides an overall assessment of the patient's degree of impairment. The primary limiting factor for
most patients with advanced heart disease clearly can be identified as forward cardiac output, but the effects of cardiovascular disease on pulmonary function and skeletal muscle
metabolism also contribute to reduced physical capacity in
many individuals.

2
%02

Rest and Exercise Hernodynamics

1.0

R
0.5

././-

-.-.A'

Anaerobic threshold

12

Stages of exercise
FIG.I Response in oxygen uptake (VO~),
carbon dioxide production (VCo2).and respiratory gas exchange ratio (R) to incremental
treadmill exercise in a normal subject. Reproduced from Ref. 24
with permission.

cmses by approximately 600 ml/minlm2 for every 100 mV

midin? increase in oxygen consumption. Thus, by the Fick
equation, MVo2 is proportional to maximal cardiac output."
When tissue perfusion is inadequate, glycolytic metabolism

0 15 30 45 60 75 90105120
Workload (W)

Recently reported rest and exercise hemodynamic data

have given new insights into exercise intolerance, and these
data may also help to assess long-term prognosis in heart failure. In contrast to the focus of maximal exercise testing on the
integrated physiologic response of the intact patient, rest and
exercise hemodynamics in heart failure address primarily the
adequacy of LV systolic and diastolic function, the functional
integrity of the rnival valve apparatus, and the response of the
pulmonary circulation to chronic pressure loading. Roubin
and associateslg evaluated hemodynamic changes in 23 patients with heart failure and 6 control subjects (Fig. 2). The
subjects exercised semiupright on 7 bicycle ergometer. As expected, patients with heart failure had significant elevations of
pulmonary wedge pressure and systemic vascular resistance.
Pulmonary vascular resistance remained markedly elevated in
the heart failure patients compared with control subjects.
However, despite high pulmonary pressures, the heart failure
patients were limited in exercise capacity by fatigue secondary

0 15 30 45 60 75 90 105120
Workload (w)
p<o.o01

r"r(

Workload (W)

Workload 0

7- Hemodynaniic changes in 23 patients with heart failure and 6 control subjects after exercise on bicycle eRometer.RAP = right atrial
PeSsure. HR = heart rate. PAWP = pulmonary artery wedge pressure, MAP = mean arterial pressure.43 = Control,
= CHE Adapted froin
18 with pennission.

458

Clin. Cardiol. Vol. 19, June 1996

to acidosis in exercising muscle. Gibbs and associates reported continuous long-terni pulmonary artery pressure measurements with a micromanometer-tipped catheter in nine
men with medically treated chronic heart failure. With ambulatory pulmonary arterial pressure monitoring, they found the
highest pulmonary arterial pressures during treadmill exercise
and the lowest pressures with level walking. The subjective
sensation of breathlessness did not correlate with pulmonary
artery pressures, except during level walking. The investigators concluded that the symptom of breathlessness did not
correlate with the changes in pulmonary artery pressure and
the latter was unrelated to heart rate during exercise.
Several investigators have studied the ventilatory response
to exercise in patients with chronic heart f a i l ~ r e .Abnor~~.~~
mal ventilatory mechanisms are clearly involved in exercise
intolerance in heart failure, with higher physiologic dead
space, ventilation perfusion mismatching, and abnormal
breathing pattern. Sullivan2recently reviewed exertional dyspnea in chronic heart failure and suggested that the subjective
sensationof dyspnea is partly due to interaction of respiratory
niuscle dysfunction,restrictive pulmonary function abnormalities, and excessive ventilation.
Hemcdynamic data, however, are powerful predictors of
prognosis in heart failure.Griffin and associatesi9studied multiple parameters in 49 patients with chronic CHF at rest and
during symptom-limited exercise. Using multiple logistic regression,they identifiedpulmonary wedge pressure at rest and
peak exercise stroke work index as the only independent predictors of mortality. [Stroke work index = (aortic pressure left ventricular end diastolic pressure) X stroke volume X
0.0144 + body surface area; stroke volume = cardiac output
(ml/nun) +- heart rate (beatdmin); 0.0144 is the conversion
factor for mmHg to cmHzO]. Survivorshad a mean pulmonary
wedge pressure of 15 5 10 mmHg compared with 22 10 in
nonsurvivors. Peak stroke work index in survivors was 32 5
14 g/m2compared with 20 +- 7 g/m2in nonsurvivors.
In a series of studies, Stevenson and Milles have shown
that the response of pulmonary capillary wedge pressure at
rest to afterload reduction therapy is an important predictor of
prognosis in patients with heart failure. Those patients who
achieved a resting pulmonary capillary wedge pressure < 16
mmHg without hypotensionon afterload reduction had an excellent first-year prognosis; patients who could not respond
with improved hemodynamics did very poorly (Fig. 3).
In contrast to cardiopulmonary exercise testing, with its
global functional assessment. rest and exercise hemodynamics provide insight into the precise degree of cardiac impairment. The physician can often make significantimprovements
in medical therapy on the basis of these data, especially when
physical examination or chest films do not reflect the true extent of hemodynamiccompronuse.

100

F
.-

80

I\

CM high PCW
(p=0.05)

x?

20

01
0

CAD high PCW

7
I
J

6
9
Months on tailored therapy

12

FIG.3 Response of pulmonary capillary wedge pressure (PCW) at

rest to afterload reduction as a predictor of prognosis in patients with
heat failure. CM = cardiomyopathy, CAD = coronary artery disease. Adapted from Ref. 5 with permission.

failure.28,29 However, the response of these parameters to intervention and their usefulness in studying therapeutic response have not been widely studied.
Functional mitral regurgitation may serve as a marker for
severe derangementof the structural geometry of the heart and
poor long-term prognosis.mHamilton and associates3have
documented sustained reduction in functional mitral regurgitation with vasodilatortherapy. Evangelista-Masipand associa t e recently
~ ~ ~ studied 30 patients with severe systolic dysfunction, 14 with significant mitral regurgitation,and 16 with
trivial or no mitral regurgitation. Only the patients with severe
mitral regurgitation showed significant improvement in exercise tolerance with oral captopril therapy. The hemodynamic,
echocardiographic, and functional data all suggest that patients who respond to vasodilator therapy, with substantialreduction in regurgitant volume as manifest by lower pulmonary
capillary wedge pressure, reduced echocardiographic evidence of miual regurgitation, and improved functional capacity, are those who tend to do well with medical management.
In contrast, our datamand the studies of Stevensonand Mille+
indicate that patients with persistent elevation of pulmonary
capillary wedge pressure and Doppler echocardiograptucevidence of significant mitral regurgitation on vasodilator therapy do very poorly. If appropriate, these patients should be
transplantedpromptly. Parenthetically,our clinical experience
with vasodilator therapy in patients who have advanced degrees of heart failure and normally functioningnonregurgitant
prosthetic mitral valves has been dismal. This is yet another
piece of circumstantialevidence favoring the critical role of redistributionof regurgitant LV stroke volume as a critical factor
in successful medical therapy.

Other Parameters

Clinical Applications
Catecholamine levels. serum sodium, and evidence of electrical instability are other parametersthat also may be useful in
identifying patients at risk for death due to congestive heart

From this mass of data, the clinical cardiologist must identify and integrate multiple variables into an overall assess-

R. M. Mills, Jr., and W. H. Haught: Evaluation of HF patients

Clinical heart failure
Careful and complete history and physical examination
Basic laboratory studies including complete blood count,
renal function, and thyroid studies
Chest x-ray, electrocardiogram, echocardiogram

Diagnosis firm and

nonsurgical
and
NYHA Class I or II on therapy

sc

Diagnosis in question

or
ootential for suraerv
I

Of

NYHA class 111 or IV on

initial treatment

3.

J.
Complete diagnostic
cardiac catheterization

Continue medical management

459

peak MVo2 > 14 ml/kg/min had cumulative I - and 2-year survival rates of 94 and 84%, respectively, essentially equal to
survival rates after transplantation.Patients with MVo2 < 14
ml/kg/min were at risk for death with only pulmonary capillary wedge pressure providing additional information.The addition of resting hemodynamics, particularlyrefractory elevation of the pulmonary wedge pressure > 16 mmHg despite
afterload reduction, helps to define patients at high risk for
death within 1 to 3 years5 On the basis of these findings, we
have set threshold values for evaluation of patients with relatively severe disease. In general, transplantcandidates fall into
NYHA class LII or IV and demonstrate both impaired MVo2
(<I4 ml/kg/min) and persistent elevation of the resting pulmonary capillary wedge pressure to > 16d
g on maximal
therapy.

Tailored therapy

Conclusion
Measure MV
,,
on
tailored therapy
MVo2 < 14
PCWP > 16

Consider heart transplantation

%
MVo2 > 14
PCWP < 16

Continue medical
management

FIG.4 Decision tree for assessment and therapy of patients with

heart failure. PCWP = pulmonary capillary wedge pressure, NYHA
=New York Heart Association, MVo2 =peakoxygen consumption.

ment of an individual patient (Fig. 4). To be useful, this process must be relatively simple. As Zelis and co-authors2emphasize, many variables, including MVo2, are dichotomous
rather than continuous. Establishing threshold values for intervention provides one useful strategy for dealing with these
parameters. This approach changes the clinical question from
how sick is this patient? to is this patient sick enough to
cross the threshold for a complex intervention? Maximal
cardiopulmonary exercise studies and determination of right
heart hernodynamics provide useful answers for these questions. When using these parameters, however, the clinician
must keep in mind that altered skeletal muscle metabolism
contributesto exercise tolerance, and that immediate hemodynamic improvement with intensified therapy may require
weeks to produce significantfunctional
As an example, we employ the threshold values approach
In evaluation of patients as potential candidates for orthotopic
Cardiac transplantation, limiting detailed studies to NYHA
class 111or class IV patients. With the exception of a few individuals with severe diastolic dysfunction, these patients have
LVEFS < 30%.In this group of patients, both hemodynamic
and functionalassessment help in selecting the patients at risk
for early death. Mancini and associates6reviewed 122 ambulatory patients referred for cardiac transplantation and found
that patients with preserved exercise capacity, defined as a

Given the,relentless increase in numbers of paGents with

congestive heart failure, clinical cardiologists must be prepared to evaluate patients carefully for treatment with new
drugs having significant potential toxicities and for costly,
complex procedures such as assist devices, dynamic myoplasty, and transplantation. The NYHA classification and
determination of LVEF provide some stratification. NYHA
class I and II patients with LVEF > 30% generally should not
require complex intervention. For individuals with more advanced heart failure, determination of anaerobic threshold
and MVo2 by cardiopulmonaryexercise testing, and evaluation of hemodynamicstatus by right heart catheterizationprovide useful data both for prognostic evaluation and for modification of therapy. Cliniciansmust understand that anaerobic
threshold and MVo2 depend primarily on maximal cardiac
output, but improvement in these parameters may lag behind
improvement in hemodynamics because of delayed improvement in skeletal muscle function and the ventilatory response
to exercise. Hernodynamic parameters, in contrast, give insight into both LV muscle function and the integrity of the mitral valve apparatus.Redistribution of LV stroke volume with
afterload reduction can produce striking hemodynamic improvement without altering intrinsic cardiac muscle function.
These hemodynamic benefits clearly translate into improved
survival for patients who respond. Both the data from functional assessment and hemodynamics may be approached as
dichotomousvariables, and setting threshold values for intervention represents a more clinically useful approach to data
interpretation than more complex systems of risk assessment
using continuousvariables.

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