Special Report

Right Ventricular Function and Failure

Report of a National Heart, Lung, and Blood Institute Working Group on
Cellular and Molecular Mechanisms of Right Heart Failure
Norbert F. Voelkel, MD; Robert A. Quaife, MD; Leslie A. Leinwand, PhD; Robyn J. Barst, MD;
Michael D. McGoon, MD; Daniel R. Meldrum, MD; Jocelyn Dupuis, MD, PhD; Carlin S. Long, MD;
Lewis J. Rubin, MD; Frank W. Smart, MD; Yuichiro J. Suzuki, PhD; Mark Gladwin, MD;
Elizabeth M. Denholm, PhD; Dorothy B. Gail, PhD

K nowledge about the role of the right ventricle in health

and disease historically has lagged behind that of the left
ventricle. Less muscular, restricted in its role to pumping
blood through a single organ, and less frequently or obviously
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pulmonary vascular diseases (cor pulmonale). Other diseases
affect the right ventricle in different ways, including global,
left ventricular , or right ventricularspecific cardiomyopa-
thy; right ventricular ischemia or infarction; pulmonary or
tricuspid valvular heart disease; and left-to-right shunts.

involved than the left ventricle in diseases of epidemic

proportions such as myocardial ischemia, cardiomyopathy, or
valvulopathy, the right ventricle has generally been consid-
ered a mere bystander, a victim of pathological processes
affecting the cardiovascular system. Consequently, compara-
tively little attention has been devoted to how right ventric-
ular dysfunction may be best detected and measured, what
specific molecular and cellular mechanisms contribute to
maintenance or failure of normal right ventricular function,
how right ventricular dysfunction evolves structurally and
functionally, or what interventions might best preserve right
ventricular function. Nevertheless, even the proportionately
limited information related to right ventricular function, its
impairment in various disease states, and its impact on the
outcome of those diseases suggests that the right ventricle is
an important contributor and that further understanding of
these issues is of pivotal importance.
For this reason, the National Heart, Lung, and Blood
Institute convened a working group charged with delineating
in broad terms the current base of scientific and medical
understanding about the right ventricle and identifying ave-
nues of investigation likely to meaningfully advance knowl-
edge in a clinically useful direction. The following summary
represents the presentations and discussions of this working
group.
The right ventricle is affected by and contributes to a
number of disease processes, including perhaps most notably
pulmonary hypertension caused by a variety of lung or
The Normal Right Ventricle
The right ventricle pumps the same stroke volume as the left
ventricle but with 25% of the stroke work because of the
low resistance of the pulmonary vasculature. Therefore, by
virtue of the Laplace relationship, the right ventricle is more
thin walled and compliant (Figure 1). The geometry of the
chamber is complex, consisting of an inlet (sinus) portion and
an outlet (conus) section separated by the crista supraventric-
ularis. Longitudinal shortening is a greater contributor to right
ventricular stroke volume than short-axis (circumferential)
shortening.1 It is linked to the left ventricle in several ways:
by a shared wall (the septum), by mutually encircling epicar-
dial fibers, by attachment of the right ventricular free wall to
the anterior and posterior septum, and by sharing the pericar-
dial space. The septum and free wall contribute approxi-
mately equally to right ventricular function. The right ven-
tricular free wall blood supply is predominantly from the
right coronary artery and receives about equal flow during
systole and diastole. The left anterior descending coronary
artery supplies the anterior two thirds of the septum, and the
posterior descending artery supplies the inferoposterior one
third.
The Right Ventricle in Pulmonary
Hypertension
The right ventricle is exposed to pressure overload by
pulmonary valve stenosis or by chronic pulmonary hyperten-

From the Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver (N.F.V.); Department of Nuclear
Medicine and Radiology, University of Colorado Hospital, Denver (R.A.Q.); CVI Institute, Department of Cardiology, Colorado University (L.A.L.);
Columbia-Presbyterian Medical Center Babies Hospital, New York, NY (R.J.B.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn
(M.D.M.); Pulmonary Hypertension Association (M.D.M.); Department of Surgery, Indiana University School of Medicine (D.R.M.); Research Center,
Montreal Heart Institute, Montreal, Quebec, Canada (J.D.); Department of Cardiology, University of Colorado at Denver and Health Sciences Center,
Denver (C.S.L.); Pulmonary Hypertension Center, University of California at San Diego (L.J.R.); Baylor College of Medicine, St Lukes Episcopal
Hospital/Texas Heart Institute, Houston (F.W.S.); Georgetown University Medical Center, Washington, DC (Y.J.S.); and National Heart, Lung, and Blood
Institute, Bethesda, Md (M.G., E.M.D., D.B.G.).
Correspondence to Norbert F. Voelkel, MD, Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, 4200 E
Ninth Ave, MC: C272, Denver, CO 80262. E-mail norbert.voelkel@uchsc.edu
(Circulation. 2006;114:1883-1891.)
2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.106.632208

1883
 1884 Circulation October 24, 2006
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Figure 1. In idiopathic pulmonary arterial hypertension (IPAH),
the right ventricle (RV) is characterized by increased end-dia-
stolic volume, change of the normal ventricular conformation
tetrahedron to a crescentic trapezoid, and varying degrees of
right ventricular hypertrophy (B). The right ventricle in severe
idiopathic pulmonary arterial hypertension assumes a spherical
shape with a greater cross-sectional area than the left ventricle
(LV), which is normally larger (A). The more spherical-shaped
right ventricle results in abnormal septal function that also
impairs left ventricle performance. C, MR angiogram of the right
ventricle and pulmonary arteries. Note the prominence of the
right atrium and the right ventricle. There is heavy trabeculation
of the right ventricle defining marked hypertrophy in the pulmo-
nary hypertensive ventricle. The degrees of dilation, hypertro-
phy, and sphericity of the right ventricle are variable in patients
with right ventricular dysfunction, but these factors are all pres-
ent in idiopathic pulmonary arterial hypertension.
sion from any cause (Table 1). An initial adaptive response of
myocardial hypertrophy2 is followed by progressive contrac-
tile dysfunction. Chamber dilatation ensues to allow compen-
satory preload and maintain stroke volume despite reduced
fractional shortening. As contractile weakening progresses,
clinical evidence of decompensated right ventricular failure
occurs, characterized by rising filling pressures, diastolic
dysfunction,3 and diminishing cardiac output, which is com-
pounded by tricuspid regurgitation due to annular dilatation
and poor leaflet coaptation. The increased size and pressure
overload of the right ventricle also produce diastolic dysfunc-
TABLE 1. Classification of Pulmonary Hypertension76
1. Pulmonary arterial hypertension
1.1. Idiopathic (IPAH)
1.2. Familial (FPAH)
1.3. Associated with (APAH):
1.3.1. Collagen vascular disease
1.3.2. Congenital systemic-to-pulmonary shunts
1.3.3. Portal hypertension
1.3.4. HIV infection
1.3.5. Drugs and toxins
1.3.6. Other (thyroid disorders, glycogen storage disease, Gauchers
disease, hereditary hemorrhagic telangiectasia,
hemoglobinopathies, chronic myeloproliferative disorders,
splenectomy)
1.4. Associated with significant venous or capillary involvement
1.4.1. Pulmonary veno-occlusive disease (PVOD)
1.4.2. Pulmonary capillary hemangiomatosis (PCH)
1.5. Persistent pulmonary hypertension of the newborn
2. Pulmonary hypertension with left heart disease
2.1. Left-sided atrial or ventricular heart disease
2.2. Left-sided valvular heart disease
3. Pulmonary hypertension associated with lung diseases and/or hypoxemia
3.1. Chronic obstructive pulmonary disease
3.2. Interstitial lung disease
3.3. Sleep-disordered breathing
3.4. Alveolar hypoventilation disorders
3.5. Chronic exposure to high altitude
3.6. Developmental abnormalities
4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease
4.1. Thromboembolic obstruction of proximal pulmonary arteries
4.2. Thromboembolic obstruction of distal pulmonary arteries
4.3. Nonthrombotic pulmonary embolism (tumor, parasites, foreign
material)
5. Miscellaneous
Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of
pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)
tion of the left ventricle.4,5 Thus, the function and size of the
right ventricle are not only indicators of the severity and
chronicity of pulmonary hypertension but impose an addi-
tional cause of symptoms and reduced longevity. Right
ventricular function is the most important determinant of
longevity in patients with pulmonary arterial hypertension.6 9
The specific mechanisms underlying the development of
right ventricular failure secondary to pulmonary hypertension
are unclear. For example, it is uncertain whether some
patients develop right ventricular myocardial ischemia,
whether there is microvascular endothelial cell dysfunction,
and whether or not myocytes undergo apoptosis. In severe,
end-stage pulmonary hypertension, the shape of the right
ventricle is changed from the normal conformation,10,11 and
right ventricular wall stress and right ventricular free wall
thickness appear to be inversely related12 (Figure 2). The
mechanism by which a severely dilated end-stage right
ventricle repairs itself after lung transplantation is also
uncertain.13,14

Figure 2. Inverse relationship between a calculated measure of
end-systolic circumferential right ventricular wall stress (RVWS)
and right ventricular systolic function as measured by ejection
fraction (RVEF). Right ventricular wall stress summarizes the
major factors that contribute to wall stress on the right ventricle
including pressure, dilation or radius, and wall thickness. Note
that the right ventricular wall stress is low in normally function-
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ing ventricles, and the right ventricular wall stress is high in
those with severe systolic dysfunction.
Plasma levels of brain natriuretic peptide1519 and troponin
T correlate with pulmonary arterial pressure and pulmonary
20
vascular resistance in patients with pulmonary arterial hyper-
tension. Increases in brain natriuretic peptide plasma levels
during serial follow-up visits are associated with increased
mortality in idiopathic pulmonary arterial hypertension pa-
tients. Paradoxically, however, atrial natriuretic peptides may
promote cardiomyocyte survival.21
The Right Ventricle in Left-Sided
Heart Failure
The hypothesis that enlargement of the left ventricle could
affect function of the right ventricle was advanced in 1910.22
However, the role of the right ventricle in congestive heart
failure has been relatively overlooked until recently,23 in part
because of the perception that it is somewhat of a passive
conduit.24 This impression has been reinforced on the one
hand by observations of successful outcomes in Glenn and
Fontan procedures and has been refuted on the other by
recognition of the sequelae of right ventricular myocardial
infarction. It is now recognized that the most common cause
of pulmonary hypertension is that associated with left ventri-
cle failure. Reeves and Groves25 reported that 44% of patients
with coronary artery disease at the time of coronary arteriog-
raphy and right heart catheterization have pulmonary
hypertension.
Right ventricular dysfunction may develop in association
with left ventricular dysfunction via multiple mechanisms:
(1) left ventricular failure increases afterload by increasing
pulmonary venous and ultimately pulmonary arterial pres-
sure, partly as a protective mechanism against pulmonary
edema26; (2) the same cardiomyopathic process may simul-
taneously affect the right ventricle; (3) myocardial ischemia
may involve both ventricles; (4) left ventricular dysfunction
may lead to decreased systolic driving pressure of right
ventricular coronary perfusion, which may be a substantial
determinant of right ventricular function27; (5) ventricular
interdependence due to septal dysfunction may occur; and (6)
Voelkel et al Right Ventricular Failure 1885
left ventricular dilation in a limited pericardial compartment
may restrict right ventricular diastolic function. Conversely,
right ventricular pressure overload, as may occur with pul-
monary hypertensive states, may compromise left ventricular
function and lead to coincident evidence of left ventricular
failure, such as pulmonary edema or effusion. Furthermore,
when the right ventricle fails in the setting of left ventricular
failure, it may be unable to maintain the flow volume required
to maintain adequate left ventricular preload. Because of the
multiple influences affecting right ventricular function due to
left ventricular failure, right ventricular status may constitute
a common final pathway in the progression of congestive
heart failure and therefore may be a sensitive indicator of
impending decompensation or poor prognosis.
Despite variations in study populations, severity and sub-
strates of disease, and methodologies of assessment, studies
demonstrate substantial agreement that evidence of right
ventricular dysfunction portends an inferior outcome. Patients
with ischemic cardiomyopathy and left ventricular ejection
fractions of 188% who die during the next 2 years have a
worse right ventricular ejection fraction (2410% by radio-
nuclide ventriculography) than survivors (4223%).28
Among patients with an acute myocardial infarction, the
presence of a low radionuclide right ventricular ejection
fraction (0.38) plus low left ventricular ejection fraction
(0.30) results in 3 times the 1-year mortality of patients
with poor left ventricular function alone.29
Patients with myocarditis and poor right ventricular func-
tion, defined as a low right ventricular descent (difference
between the diastolic and systolic distance from the right
ventricle apical endocardium to a perpendicular line through
the tricuspid annulus; normal20.2 cm), have a higher
likelihood of death or transplantation than those with normal
right ventricular function. Indeed, right ventricular dysfunc-
tion is the strongest predictor of a negative outcome.30
The right ventricular ejection fraction (measured by ther-
modilution techniques) of patients with idiopathic dilated
cardiomyopathy correlates linearly with echocardiographic
left ventricular ejection fraction, and, by multivariate analysis
of a large number of parameters, only right ventricular
ejection fraction and left ventricular ejection fraction are
predictors of survival.31 Survival is also predicted for patients
with idiopathic dilated cardiomyopathy by increased diastolic
right ventricular chamber area measured echocardiograph-
ically, and survival of patients with right ventricular enlarge-
ment out of proportion to left ventricular enlargement is
poorer.32 Survival, left ventricular ejection fraction, and
symptoms are worse in dilated cardiomyopathy patients with
angiographically documented biventricular dysfunction (left
ventricular ejection fraction 50%, right ventricular ejection
fraction 35%) compared with those with left ventricular
dysfunction alone.33
In patients with advanced congestive heart failure due to
cardiomyopathy or ischemia, right ventricle shortening is the
only significant independent associate of survival by multi-
variate analysis (as opposed to other parameters including left
ventricular ejection fraction, cardiac index, and pulmonary
resistance). Patients with right ventricular shortening 1.25
cm have a significantly worse actuarial survival over 2 years
 1886 Circulation October 24, 2006
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(16% versus 68% for 1.25 cm).34 Not only do patients with
satisfactory right ventricular function (right ventricular ejec-
tion fraction 35%) in the setting of severe heart failure have
improved survival (Figure 3), they also have better exercise
capacity (peak %VO2).35 Indeed, right ventricular ejection
fraction correlates better with exercise capacity than left
ventricular ejection fraction does.36 Preserved right ventricu-
lar function in patients with severe congestive heart failure
and pulmonary hypertension confers a survival advantage
comparable to that in those without pulmonary hypertension,
although in this study reduced right ventricular ejection
fraction alone, in the absence of pulmonary hypertension, did
not exhibit an additional risk.37
Even among patients with only moderate congestive heart
failure (New York Heart Association classes II and III),
radionuclide right ventricular ejection fraction is an indepen-
dent predictor of survival, as were New York Heart Associ-
ation class and %VO2.38
The Right Ventricle in
Volume-Overload Conditions
Although severity of tricuspid regurgitation correlates with
worse survival,39 the right ventricle tolerates volume overload
better than pressure overload and therefore may remain well
adapted to right-sided valvular regurgitant lesions for ex-
tended periods of time. Similarly, in pulmonary hypertension
associated with initial left-to-right shunt, the lesion may
remain minimally symptomatic during the high-volume
phase, until pulmonary vasculopathy develops and the shunt
reverses (Eisenmengers phenomenon). Even after Eisen-
mengers physiology is well established, the outlook for these
patients is better than for patients with idiopathic pulmonary
arterial hypertension,40 perhaps because of preconditioning
by the prior volume load or retention of fetal right heart
phenotype characteristics.41,42
The Infarcted Right Ventricle
Right ventricular infarction may cause sufficient myocardial
damage to result in heart failure, shock, arrhythmias, and
death in the absence of any superimposed volume or pressure
overload and unrelated to extent of left ventricular damage.38
Figure 3. Survival rates without urgent
heart transplantation in patients with
congestive heart failure grouped accord-
ing to the coupling between mean pul-
monary artery pressure and right ventric-
ular ejection fraction. Group 1 indicates
normal pulmonary artery pressure/pre-
served right ventricular ejection fraction
(n73); group 2, normal pulmonary
artery pressure/low right ventricular ejec-
tion fraction (n68); group 3, high pul-
monary artery pressure/preserved right
ventricular ejection fraction (n21); and
group 4, high pulmonary artery pressure/
low right ventricular ejection fraction
(n215).37 Reproduced from Ghio et al37
with permission from the American Col-
lege of Cardiology Foundation. Copyright
2001.
The occurrence of hemodynamic and symptomatic right heart
failure under these circumstances suggests that although the
circulation can be maintained adequately when the right
ventricle is bypassed (as in appropriately selected patients
receiving a Fontan procedure), it is more susceptible to
deterioration when a defective right ventricle is present. Thus,
the enlarged hypocontractile right ventricle appears to play an
active role in compromising overall circulatory status.
Whether this is due to ventricular interaction, septal involve-
ment, restrictive physiology, or other mechanisms is not
established.
The Right Ventricle Is Different From the
Left Ventricle
Whereas passive back-pressure, ventricular interdependence,
or diffuse disease may account for biventricular dysfunction
in most instances of left ventricular failure, recent evidence
has emerged that suggests that the ventricles are also cate-
gorically different43,44 (Figure 1) and that these differences
may have implications in the assessment and treatment of
patients with predominantly right, left, or biventricular heart
failure. For these reasons, right ventricular failure cannot be
understood simply by extrapolating data and experience from
left ventricular failure.
The Genetic, Molecular, and Cellular Biology of
Right Ventricular Development, Function,
and Dysfunction
The genetic investigation of cardiac morphogenesis has
shown that the right ventricle and the left ventricle originate
from different progenitor cells and different sites: The pri-
mary heart field gives rise to the atrial chambers and the left
ventricle, whereas the cells of the anterior heart field develop
into the outflow tract and the right ventricle.45,46 The discov-
ery of 2 chamber-restricted basic helix-loop helix transcrip-
tion factors, HAND1 and HAND2, and studies of knockout
mice led to the recognition of chamber-specific gene expres-
sion with different transcriptional events leading to right
ventricle and left ventricle formation.47,48 The transcription
factor Bop, as a regulator of right ventricular development, is
now recognized to be a transcriptional target of myocyte

enhancer factor 2C,49 and GATA4 is required for HAND2
expression and right ventricular formation.50 GATA4 regu-
lates cardiac musclespecific expression of the -myosin
heavy chain gene51 and the gene encoding atrial natriuretic
factor.52
The degree of right ventricular hypertrophy in idiopathic
pulmonary arterial hypertension, measured as right ventricu-
lar wall thickness, is highly variable (0.6 to 1.5 cm),10 and, as
in the failing left ventricle, there is evidence for changes of
gene expression in the pressure-overloaded failing right
ventricle in patients with idiopathic pulmonary arterial hy-
pertension.53 In particular, it appears that there is a recapitu-
lation of the fetal gene pattern with a decrease in the
-myosin heavy chain gene and an increase in the expression
of the fetal -myosin heavy chain.
Clinical experience suggests that some patients with car-
diomyopathy or pulmonary arterial hypertension develop
right ventricular failure earlier than others as assessed by
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right heart filling pressures and cardiac output at the time of
diagnosis.54 This has suggested that there may be a genotypic
difference between patients; some patients develop greater
hypertrophy (thicker free wall) of the right ventricle for the
same degree of afterload than do others.10 A small cohort
study of patients with idiopathic pulmonary arterial hyperten-
sion suggested that patients with the angiotensin-converting
enzyme DD polymorphism had a normal right atrial pressure
and cardiac output, whereas the non-DD patient group dem-
onstrated increased right atrial pressure and decreased cardiac
output.55 Whereas it is unlikely that this polymorphism alone
can explain differences in degree of right ventricular hyper-
trophy between patients, this observation has suggested the
concept of genetically controlled right ventricular
hypertrophy.
Mechanics of Right Ventricular Function
Despite the aforementioned observations, the mechanisms by
which left ventricular failure leads to right ventricular dys-
function are incompletely understood. Congestive heart fail-
ure adversely affects lung mechanics and gas exchange.56
Pulmonary function abnormalities include a reduction in lung
volumes with decreased lung compliance.57,58 Although this
restrictive lung physiology is improved somewhat by fluid
removal or after heart transplantation, the reduced alveolar-
capillary membrane diffusing capacity is not reversible,
demonstrating the clinical importance of lung structural
remodeling in heart failure.59 61 The lungs from animal
models of heart failure as well as from humans with pulmo-
nary venous hypertension demonstrate septal thickening with
myofibroblast proliferation and interstitial matrix deposi-
tion.62,63 The physical and biological determinants of these
changes and their eventual impact on the development of
right ventricular failure are currently unknown.
Measurement of Right Ventricular Function
Implicit in the discussion of right ventricular function and
dysfunction is the notion that there are reliable means by
which to assess these parameters and that there is agreement
about what meaningfully defines function or dysfunction.
The measurement of right ventricular function is difficult for
Voelkel et al Right Ventricular Failure 1887
TABLE 2. Markers of Right Ventricular Dysfunction Associated
With Clinical Status and Prognosis
Right ventricular ejection fraction (echocardiography, radionuclide
angiography or thermodilution) 28,29,31,33,35-38,77
Right ventricular ejection fraction response to pulmonary vasodilation65
Right ventricular dilation78
Degree of right ventricular dilation compared with left ventricular dilation32
Tricuspid annular velocity (systolic and/or diastolic) or excursion, or echo
right ventricular descent (shortening)30,34,79-81
Right ventricular index of myocardial performance80,82,83
Doppler-estimated dP/dt84
Tricuspid regurgitation85-87
Doppler echo-derived right ventricular tissue displacement and strain88
Right atrial size85,89
Radionuclide angiographic, invasive angiographic, or echo/catheterization
pressure-volume or pressure-area loops90-92
Brain natriuretic peptide level15-19
Heart rate variability93
many reasons, in part because of the interplay between
intrinsic myocardial performance and right ventricular load-
ing conditions. The development of load-independent mark-
ers of right ventricular function is a worthwhile goal. Markers
of right ventricular dysfunction that have reported implica-
tions for clinical deterioration and mortality in heart failure or
pulmonary hypertension are shown in Table 2.7793 The extent
to which any of these parameters are useful as outcome
measures in clinical research or practice remains unclear.
Treatment of Right Ventricular Dysfunction
Current therapies directed toward pulmonary vasoconstric-
tion, cellular proliferation, and thrombotic factors have im-
proved the quality of life and survival in many patients with
severe pulmonary arterial hypertension.61 Likewise, therapies
with afterload-reducing agents, -receptor antagonists, ino-
tropes, and diuretics have improved the functional status and
prognosis of patients with left ventricular failure. Moreover,
acute responsiveness to pulmonary vasodilators is associated
with a better prognosis and survival in patients with advanced
heart failure.64,65 Afterload reduction, however, cannot be
achieved in many cases, but the increased right ventricular
wall thickness and reversal of a fetal gene expression pro-
gram have not yet been investigated as potential targeted
treatments. Chronic intravenous epoprostenol infusion ther-
apy in patients with pulmonary arterial hypertension appears
to improve right ventricular function66,67 (although dilation
and hypertrophy may not reverse over a 1-year period of
observation68), and the effects of the endothelin receptor
antagonist bosentan on echocardiographic right ventricular
parameters have also suggested a similar improvement in
right ventricular function.69 However, the specific myocardial
effects of these or other therapies for pulmonary arterial
hypertension remain incompletely understood. In addition,
right ventricular function, right ventricularleft ventricular
interaction, and right ventricularpulmonary arterial coupling
have largely been overlooked as potential targets for investi-
gation or therapy.
 1888 Circulation October 24, 2006
Continuous intravenous prostacyclin (epoprostenol) infu-
sion therapy improves survival in idiopathic pulmonary
arterial hypertension patients more than in patients with the
limited variant of scleroderma-associated pulmonary arterial
hypertension. Although the reasons for this discrepancy in
treatment outcome are not clear, one possible explanation is
the presence of a myocardial global microangiopathy in
scleroderma patients.70
Future Directions
Given the pivotal involvement of the right ventricle in both
common and rare cardiovascular diseases and the paucity of
basic knowledge at all levels about its normal and patholog-
ical functions, support for further research should be a high
priority for investigators and National Institutes of Health
funding. Areas of deficient understanding worthy of further
exploration include the following issues.
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Measurement
Although a fair amount of study has been devoted to
assessment of right ventricular function, there remains a need
to understand how to better define normal parameters of right
ventricular function. Critical information is required to deter-
mine the most sensitive and specific variables to describe
abnormal right ventricular function. It is likely that the
definition of function will include parameters of geometry,
ejection volume, hypertrophy, dilation, contraction, and ox-
ygen supply to the ventricular wall. A clear picture of these
parameters would help in determining which measurements
are the best predictors of early right ventricular failure (such
as right ventricular wall thickness, muscle perfusion, or
metabolic activity). Ideally, a combination of approaches
would be used to evaluate right heart function, including
imaging techniques (Doppler echocardiography, computed
tomography, magnetic resonance imaging, positron emission
tomography), implanted continuous monitoring devices, and
electrophysiology. Collaboration with the National Institute
of Biomedical Imaging and Bioengineering to promote the
development of imaging methods to study right ventricular
function and dysfunction should be encouraged.
Distinguishing Characteristics of Right Heart
Compared With Left Heart
Preliminary inquiry suggests that there are distinctions be-
tween the ventricles that need to be further evaluated and
clarified to understand the differences, similarities, and inter-
play between the left and right heart. This issue can be
addressed with chamber-specific studies in animal models
that examine changes in gene expression, protein synthesis,
histology, and geometry during development, injury, and
stress (exercise and disease).
Investigation of Mechanism and Role of
Hypertrophy
Although initial right ventricular hypertrophy in response to
pressure overload may be adaptive, it is also the seemingly
initial step in a remodeling process that is ultimately damag-
ing, perhaps irreversibly so. Attention should be devoted to
determining whether right ventricular hypertrophy is good or
Figure 4. Postulated pathobiology of right ventricle failure in
pulmonary hypertension.
bad. Research is needed to compare hypertrophy seen in
athletes with that seen in patients with diseases such as
pulmonary arterial hypertension. Mechanisms of right ven-
tricular hypertrophy and remodeling need to be determined.
Effect of Pulmonary Disease on Right Ventricular
Function
Few studies address the interaction of right ventricular and
pulmonary function. Research is needed to study the complex
interaction of the heart and lungs and how changes in one
affect the other. Examples of changes include inflammation,
stress due to hypoxia or exercise, autoimmune reactions,
infarction, and hypertension.
Models of Right Ventricular Failure
Researchers must develop reliable, reproducible, and relevant
animal models of right ventricular failure. Animal models
would be particularly useful in determining factors that
initiate right ventricular dysfunction. Models would also help
to identify biomarkers and changes in gene expression and
protein synthesis associated with right ventricular failure.
Valuable information could be obtained from animal models
through side-by-side comparisons of changes in the left and
right ventricles. Parameters on which to focus would include
tissue analysis; gene and protein expression; and markers of
oxidative stress, apoptosis, and cell growth. When possible,
such analyses should compare tissue from patients with
animal models of right heart failure and pulmonary hyperten-
sion to address the question of whether data obtained from
manipulated animal right ventricles can be extrapolated to
right ventricular or interventricular septal biopsy material
from the hearts of patients with severe pulmonary hyperten-
sion. Animal models will be a necessary component to
determine whether right ventricle failure is associated with
myocyte apoptosis7173 or cytokine expression74 (Figure 4).
In addition, data from animal studies suggest that signifi-
cant differences exist between sexes in the development of
right heart failure.75 Studies that further examine gender
differences will be important for developing potential new
therapeutics and determining whether treatment should be
determined by sex.

Translational Research
An emphasis on translational research, particularly studies of
human myocardial tissue, is required to determine the impor-
tant markers of right ventricular function and dysfunction.
Studies to identify markers in plasma as well as those in tissue
might facilitate prediction of early diagnosis of ventricular
dysfunction and may prevent failure. Robust parameters that
predict outcome for patients with right heart failure are
needed.
Right Ventricular Morphogenesis
The developmental aspects of right heart formation need to be
studied to identify mechanisms involved in congenital heart
disease and related pulmonary vascular disease.
Targeted Therapy
The development of new therapeutic strategies for right heart
failure should be promoted. These new strategies might
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include cell-based or gene therapy, new drugs, or new
combinations of existing drugs.
Awareness
Awareness should be promoted in the pulmonary and cardi-
ology research communities about the lack of knowledge of
the right ventricle with well-publicized requests for research
proposals. New and established investigators should be en-
couraged to enter this fruitful area of research.
The consensus of the working group is that the role of the
right ventricle in a spectrum of cardiovascular diseases has
been relatively neglected proportionate to its central impor-
tance. Advancing knowledge through research about the
unique genetic, molecular, cellular, and functional character-
istics of the right ventricle and their vulnerability to disease
will lead to progress in the treatment of cardiomyopathy,
pulmonary arterial hypertension, right ventricular ischemic
syndromes, and valvular heart disease. The success in such
effort requires collaborations between and among clinical and
basic investigators from various disciplines, including those
in respiratory/pulmonary and cardiovascular fields as well
from neuroscientists, immunologists, endocrinologists, and
biomedical engineers. Joint meetings of the American Heart
Association and the American Thoracic Society would be
appropriate venues to promote the importance of understand-
ing the right ventricle and would help to accelerate the
gathering of information leading to better treatment and
preventative means to reduce morbidity and mortality asso-
ciated with right heart failure and left heart failure.
Sources of Funding
This workshop was sponsored by the National Institutes of Health,
National Heart, Lung, and Blood Institute.
Disclosures
None.
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 Right Ventricular Function and Failure: Report of a National Heart, Lung, and Blood
Institute Working Group on Cellular and Molecular Mechanisms of Right Heart Failure
Norbert F. Voelkel, Robert A. Quaife, Leslie A. Leinwand, Robyn J. Barst, Michael D.
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