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 Srinivas Murali, MD, FACC
Professor of Medicine
Drexel University College of Medicine
Director, Division of Cardiovascular Medicine
Medical Director, McGinnis Cardiovascular Institute
Allegheny General Hospital
Pittsburgh, PA
Epidemiology
Left-sided heart failure is an important and common cause
of pulmonary hypertension (PH). In the United States, >5
million people are affected by heart failure, and approximately
550,000 new cases are diagnosed annually.1,2 It
affects 10% of the population over 65 years of age, and is
the leading cause of hospitalization among adults.
Approximately two-thirds of heart failure is secondary to
diminished left ventricular contractility or systolic dysfunction,
and the remaining are due to impaired left ventricular
filling / diastolic dysfunction. Coronary artery disease and
primary cardiomyopathy are the most common causes of
systolic left ventricular failure, while hypertension is the
leading cause of diastolic heart failure (Table 1).
Advanced heart failure accounts for at least 10% of all
heart failure (approximately 500,000 patients), and its
prevalence is increasing, particularly because of increased
emphasis upon evidence-based medical therapies, and
because of reduction in sudden cardiac death due to prophylactic
defibrillator implantation. Severe heart failure is
frequently associated with PH, perhaps in 25-50% of
patients, but unfortunately there is little epidemiologic information
available on its prevalence. Pulmonary hypertension
in association with left-sided heart failure may be either
mild or moderate, though it can be severe in up to a third of
patients. The speculation is that significant PH may be present
in up to 250,000 heart failure patients in the United
States, which is far greater than the reported prevalence of
PH associated with other conditions. It is therefore critical
that every heart failure patient with advanced symptoms
undergo a thorough evaluation to ascertain the presence and
severity of PH.3 The focus of this discussion will be PH that
is associated with systolic heart failure.
Hemodynamic Characterization
The human pulmonary circulation, unlike the systemic circulation,
is a low resistance vascular bed.4 According to the
hydrodynamic equation which draws an analogy from Ohm’s
law, the resistance to flow (R) varies directly with the pressure
drop (P) and inversely with the rate of flow(Q) across
the pulmonary vascular bed such that R= P/Q. The pressure
drop in the pulmonary vascular bed is also known as the
trans-pulmonary pressure gradient (TPG), which is the difference
between the measured mean pulmonary artery pressure
and pulmonary capillary wedge pressure (PCWP).
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Pulmonary vascular resistance (PVR) is calculated by dividing
TPG by flow or cardiac output. It is important to remember
that TPG is a measured variable, whereas PVR is calculated.
PH in heart failure patients is usually “post-capillary,”
characterized by an elevated PCWP (>15 mm Hg) and PVR.
Initially, in PH associated with left-sided heart failure, the
TPG is normal, though over time it increases (>10 mm Hg).
The hemodynamic progression of PH is typically characterized
by a progressive rise in TPG and PVR over time (Table
2). In the later stages, pulmonary artery pressures and cardiac
output fall as right ventricular failure sets in, with
marked elevations in right atrial pressure. Occasionally, the
pulmonary artery pressure and TPG may be very high. Many
clinicians consider this to be a form of PH “out of proportion”
to left-sided heart failure. Whether or not this is an extreme manifestation of PH in the spectrum of left-sided
heart failure or a combination of heart failure and intrinsic
pulmonary vascular disease is unknown. This topic is
addressed in the 2 separate articles elsewhere in this issue.
PH can be hemodynamically classified as mild, moderate
or severe, based upon measured
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values of mean pulmonary
artery pressures, TPG and calculated PVR (Table 3).
Initially, PH in heart failure is “reactive” and readily
reversed acutely with vasodilator challenge. Over time, PH
becomes “non-vasoreactive” or “fixed,” with reduced or no
responsiveness to pharmacologic treatments.5 Histologically,
PH associated with left-sided heart failure is characterized
by intimal thickening and fibrosis, medial hypertrophy and
adventitial fibrosis of the pulmonary vasculature. Hemodynamic
progression from “reactive” to “fixed” disease is
accompanied by progressive structural pulmonary vascular
remodeling. Plexiform lesions, which are the histologic signature
of idiopathic PH, are not typically seen in heart failure
patients with PH.6,7
Pathogenesis
 Figure 1—Proposed mechanism of pathogenesis of PH in left heart
failure. LVEDP=left ventricular end-diastolic pressure, EC=endothelial
cell, MR=mitral regurgitation, ET=endothelin-1, NO=nitric oxide.
Adapted from Moraes et al. Circulation.2000; 102:1718-23.
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Left ventricular injury leading to structural remodeling and
dysfunction is the seminal event in the progression of heart
failure (Figure 1). The translation of injury to remodeling is
dependent on the up-regulation and down-regulation of several
neuro-hormone and cytokine pathways that results in
neurohormonal imbalance. The renin-angiotensin-aldosterone
system, the sympathetic nervous system and
endothelin are the vasoconstrictor systems that are activated
whereas endogenous vasodilator systems, such as nitric
oxide and kinins are deactivated. All of these systems extensively
interact with each other resulting in pulmonary vascular
endothelial cell dysfunction. This triggers pulmonary
vasoconstriction and vascular remodeling through multiple
mechanisms, leading to the development of pulmonary
hypertension. The translation from endothelial cell dysfunction
to intimal thickening and medial hypertrophy is not well
understood, but involves endothelin-1 and nitric oxide, both
of which play a critical role in the maintenance of vascular
tone in health.8 Left ventricular remodeling also results in
mitral regurgitation which causes left atrial hypertension
and further triggers pulmonary vascular endothelial dysfunction.
9
Plasma endothelin-1 levels vary directly with pulmonary
artery pressure and PVR, and vary inversely with stroke volume
in heart failure patients with PH.10 Plasma endothelin-
1 level is a direct correlate of mortality in heart failure
patients.11-13 The increased pulmonary artery pressure and
vascular resistance increases the afterload of the right ventricle
leading to right ventricular dysfunction, remodeling
and failure. Thus, left ventricular dysfunction always results
in right ventricular failure by way of pulmonary hypertension.
However, when the initial insult affects both ventricles
simultaneously, such as in acute myocarditis or myocardial
infarction involving the right and left ventricles, pulmonary
hypertension rarely develops as the failing right ventricle is
unable to generate high pulmonary pressures to overcome
the downstream resistance to flow.
Diagnosis
 Figure 2 —Proposed diagnostic work-up if PH is detected in a patient
with left heart failure. Once the diagnosis is suspected by echocardiography
and confirmed by catheterization, other contributing
factors such as pulmonary emboli, parenchymal lung disease and
sleep apnea has to be ruled out. RHC=right heart catheterization,
V/Q scan=ventilation-perfusion scan, CT=computed tomography,
CTEPH=chronic thrombo-embolic PH, PFT=pulmonary function test,
ABG=arterial blood gases, COPD=chronic obstructive
pulmonary disease.
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Every patient with PH associated with left-sided heart failure
must have a detailed diagnostic work-up to help characterize
the etiology of the heart failure and to identify if the
heart failure is from systolic or diastolic left ventricular dysfunction14 (Figure 2). A transthoracic echocardiogram can
frequently recognize the presence of PH and right ventricular
dysfunction, in addition to providing evaluation of the left
ventricle and the valves. Pulmonary artery pressure can be
estimated from the Doppler measurement of the regurgitation
velocity across the tricuspid valve. Right heart catheterization
must however be performed to accurately measure
pulmonary artery pressures, PCWP, TPG and cardiac output.
Other potential causes or contributors to PH should be considered
and appropriate testing done as indicated. In particular,
thromboembolic pulmonary disease, coexistent pulmonary
parenchymal disease such as chronic obstructive
pulmonary disease, and sleep apnea should be ruled out.
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If the TPG and PVR are elevated, acute vasoreactivity
testing should be done at the time of right heart catheterization,
particularly if the patient is to be considered for cardiac
transplantation.15-19 Intravenous sodium nitroprusside,
milrinone, prostacyclin or inhaled nitric oxide are generally
used to assess acute vasoreactivity in PH associated with
left-sided heart failure (Table 4). Though there is no standard
definition to identify a responder, the goal is to see if
the TPG and PVR can be decreased appreciably, without raising PCWP or lowering cardiac output or causing systemic
hypotension. Patients who are acutely vasoreactive and listed
for transplantation will require serial testing every 6-8
weeks to ensure that they remain vasoresponsive.
Clinical Course and Prognosis
When PH complicates heart failure, both morbidity and mortality
are increased.20 Patients complain of worsening
fatigue and dyspnea, and declining exercise tolerance. The
peak exercise oxygen consumption (peak VO2) inversely correlates
with mean pulmonary pressure and PVR, and correlates
directly with resting right ventricular ejection fraction.
21,22 Atrial arrhythmias are more frequent, which further
compromises cardiac output. As right ventricular failure sets
in, cardio-renal syndrome with progressive renal insufficiency,
hyponatremia, and diuretic resistance develop. In the
advanced stages, patients have anasarca, severe tricuspid
regurgitation secondary to annular dilatation, and chronic
hepatic congestion that can lead to cardiac cirrhosis. Rarely,
patients develop hypoxemia either at rest or with activity
because of a right to left shunt through a patent foramen
ovale. Heart failure patients with PH have increased frequency
of hospitalizations, increased risk of cardiovascular
events, and a higher mortality, compared to patients without
PH. The risk of death is directly proportional to the pulmonary
vascular resistance.23 PH in Transplant Candidates
In heart failure patients, the presence of significant PH is a
contraindication to orthotopic cardiac transplantation.24,25The donor right ventricle will fail acutely, resulting in allograft
failure and death if it is required to pump into a high
resistance pulmonary circulation. A normal right ventricle
cannot acutely generate a pressure in excess of 50 mm Hg.
The risk posed by PH in transplant candidates is a continuous
risk that is directly proportional to both PVR and TPG;
in other words, the greater the TPG and PVR, the higher the
risk of acute right ventricular failure following transplantation.
26-28 Nonetheless, for clinical reasons, thresholds have been
defined for PVR and TPG beyond which the risk is considered
excessive, and orthotopic transplantation contraindicated.
29 These thresholds vary among transplant programs, and are higher in experienced, high volume transplant centers.
Heart failure patients with a TPG 12mm Hg or PVR
3 Wood Units are considered suitable with an acceptable
risk in most transplant centers, whereas patients with a TPG
15 mm Hg or PVR 5 Wood Units, despite acute vasoreactive
testing, are clearly not appropriate candidates. The
early post-transplant mortality is 3-fold higher in the latter
high risk group, and even higher if the gender is female.30-
34 In these patients, heterotopic transplantation, where a
donor heart is implanted without explantation of the recipient
heart or heart-lung transplantation may be considered.
Long-term outcomes with heterotopic heart transplantation
are inferior to orthotopic transplantation, and therefore not
performed in most transplant centers.35 Heart-lung transplantation
is limited by the lack of availability of donors. A
Domino procedure where the cardiac allograft from a donor
with idiopathic pulmonary hypertension who is to receive a
heart-lung transplantation is used has been advocated for
severe PH patients. The remodeled, hypertrophied right ventricle
in these allografts can adequately sustain function in
the early post-operative period.36 Data from the International
Society for Heart and Lung Transplantation (ISHLT) registry
demonstrate that pre-transplantation PH is an independent
risk factor for poor outcome following transplantation.37 This
risk exists even with oversizing the donor allograft.
Left-sided heart failure patients with PH who undergo
transplantation will have gradual, complete resolution of
their PH during the first 6-12 months.38-40 However, even
those with only a mild to moderate degree of PH pre-transplantation
have residual PH during the first few months.41The greater the severity of PH prior to surgery, the longer the
time to resolution. In some patients with severe PH, there is
incomplete resolution, with residual elevations in pulmonary
pressures and PVR. Even those patients who undergo heterotopic
heart transplantation have some resolution of PH
over time.35 Remodeling of the allograft right ventricle and
development of tricuspid insufficiency accompany the resolution
of PH after transplantation.
Management
 Figure 3—Proposed algorithm for management of PH in left heart
failure. In patients who are acutely vasoreactive, the testing should
be repeated every 6-8 weeks as they await transplantation.
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The managment paradigm for PH associated with left-sided
heart failure is outlined in Figure 3. All left-sided heart failure
patients whether they have associated PH or not, should
be treated with evidence-based therapies which include
digoxin, diuretics, angiotensin converting inhibitors, -adrenergic
blockers and aldosterone antagonists.42 Any contributing
condition should also be treated appropriately. If
PH is present and acutely vasoreactive, the patient may be
considered for transplantation, provided there are no other
contraindications. Every effort must be made to prevent the
progression of PH until transplantation and frequent monitoring
(every 6-8 weeks) with right heart catheterization may
be necessary. If PH is not acutely vasoreactive, then chronic
infusions of intravenous Neseritide (48-72 hrs) or intravenous
milrinone (up to 2 weeks) or aerosolized inhalation of
milrinone should be considered in order to decrease pulmonary
pressures, TPG and PVR.43-46 Chronic left ventricular
unloading with a left ventricular assist device (either continuous
flow or pulsatile) may also be considered in select
patients to reverse PH.47,48 If there is significant improvement
in pulmonary hemodynamics with any of these strategies,
cardiac transplantation may be feasible.
Figure 4 —The list of treatments available for pulmonary arterial
hypertension (PAH) and PH associated with left heart failure (LHF).
*FDA approved, PDE=phosphodiesterase, ACE=angiotensin converting
enzyme, VAD=ventricular assist device
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None of the therapies that are approved for the treatment
of pulmonary arterial hypertension have shown benefit in
chronic heart failure patients49 (Figure 4). Except for
amlodipine, calcium channel blockers worsen outcomes in
patients with left heart failure due to systolic dysfunction.
Though acute administration of endothelin antagonists
induces pulmonary vasodilation in left-sided heart failure
patients, chronic therapy has no proven survival benefit in
randomized, controlled trials.50,51 Likewise, intravenous epoprostenol infusions failed to show survival benefit in
patients with chronic heart failure.52 Incidently, several
patients in this study experienced reductions in pulmonary
pressures, PCWP and PVR.53 Unfortunately, none of the
aforementioned clinical trials carefully evaluated the longterm
clinical and survival benefits in patients with PH associated
with chronic left heart failure. Oral sildenafil, a phosphodiesrterase-
5 inhibitor, which is approved for the treatment
of pulmonary arterial hypertension, has been shown to
decrease pulmonary pressures and PVR in PH associated
with heart failure.54 This hemodynamic effect is augmented
when the drug is co-administered with inhaled nitric
oxide.55, 56 Whether chronic treatment with sildenafil can
cause sustained benefit in PH associated with heart failure
is unknown at this time.
Summary
Left heart failure is an important, and perhaps common
cause of PH. The morbidity and mortality in left heart failure
is independently determined by the presence of associated
PH which also directly contributes to the progressive
decline in symptoms and functional status in these patients.
Though, advances in medical and surgical therapy have significantly
improved the outlook of chronic left heart failure
patients, to date, there is no FDA approved therapy for PH
associated with left heart failure. Cardiac transplantation is
risky in general, but can be offered for vasoreactive patients,
who have no other contraindications. Parenteral continuous
therapy with neseritide or milrinone and chronic left ventricular
unloading with a left ventricular assist device may
improve pulmonary hemodynamics and allow successful
transplantation in certain select patients, who are not
responsive to acute vasoreactivity challenge. Clearly, further
research to identify targeted therapy for PH associated with
left heart failure is sorely needed.
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