 Raymond L. Benza, MD
Division of Cardiology
Department of Medicine
University of Alabama at Birmingham
Birmingham, Alabama
|
 José A. Tallaj, MD
Department of Medicine
Birmingham VA Medical Center
Division of Cardiology
Department of Medicine
University of Alabama at Birmingham
Birmingham, Alabama
|
|
Classically, the term pulmonary hypertension (PH) refers to
a resting mean pulmonary pressure greater than 25 mmHg.
There are many different etiologies of PH, but by and large,
the most common cause is pulmonary venous hypertension
(PVH). This particular form of PH occurs in the setting of
elevated left sided filling pressure. The main causes of PVH
are listed in Table 1. Typically, in this form of PH, the degree
of elevation in pulmonary artery pressure is concordant with
the degree of elevation in left atrial pressure. Identification
of this form of PH is important because treatment with
selective pulmonary vasodilators typically reserved for use in
pulmonary arterial hypertension (PAH) may be potentially
harmful. However, some patients have a severely elevated
PA pressure with only modestly elevated left-sided filling
pressure. This class of patient often causes much confusion
for treating physicians because of the uncertainty of whether
or not these patients would benefit or be harmed by PAHselective
therapy. It is the aim of this paper to provide an
insightful and helpful review of PH related to left heart disease,
with specific emphasis on the patient with pulmonary
hypertension “out-of-proportion” to the degree of elevation
in left-sided pressure.
The differentiation of PAH from PVH can be quite difficult.
Some conditions predisposing to this form of PH are
quite obvious, such as mitral valve disease or left ventricular
(LV) systolic dysfunction. However, other causes like diastolic
dysfunction or early restrictive cardiomyopathy are
more difficult to diagnose noninvasively. PAH requires a high
index of suspicion and the appropriate diagnostic tests.
Physical examination can be nonspecific and even normal in
some of these patients. Echocardiography can be misleading,
as only the right ventricular systolic pressure is routinely
estimated. More importantly, echocardiography can not
measure left-sided filling pressure, but only comment on
abnormal left ventricle filling patterns, which can be
markedly abnormal even in the face of normal filling pressure
in advanced PH.1 It is for these reasons, that it is
imperative for patients suspected to have pulmonary hypertension
to undergo invasive measurement of the PA and
wedge pressures.
The results obtained from right heart catheterization
alone is usually enough to confirm the diagnosis of PAH.
Occasionally, however, it is quite difficult to obtain accurate
pulmonary capillary wedge pressure (PCWP) in patients with
severe PH, due to the significant dilatation of the proximal
pulmonary arteries, rapid pruning of distal branches, tricuspid
insufficiency and dilatation of the right heart chambers.
Figure 1 shows how the PCWP was erroneously measured
twice (panel A and B) before a correct PCWP (panel C) was
obtained in a patient with PAH. If there are any doubts
regarding the accuracy of the pressure obtained, then a correct
positioning could be verify by measuring the oxygen saturation
in blood obtained in the “wedge position.” However,
even this method could be inaccurate in cases of “overwedging”,
like example A of Figure 1. If the right heart
catheterization is nondiagnostic, then a left heart catheterization
should be done to accurately measure the left ventricular
end-diastolic pressure (LVEDP). We strongly believe
that an accurate LVEDP can only be measured with a multihole
pigtail catheter placed in the body of the left ventricle,
as a single end-hole catheter only measures the pressure in
one direction and not the sum of all intraventricular pressures.
|
Significance of Pulmonary Hypertension
in Patients With Left-heart Disease
The presence of significant PH in patients with left heart disease
is associated with a poor prognosis in light of its effects on the right ventricular (RV) function. Irregardless of the etiology
of left heart disease, a reduced LVEF is a powerful predictor of
death in patients with heart failure; however, its prognostic
value loses strength when applied to patients with advanced
heart failure.1 A number of studies have provided evidence that
the RVEF, either directly measured (by radionuclide angiography
or rapid response thermodilution) or indirectly estimated
(by echocardiography), is an independent prognostic factor in
patients with moderate to severe heart failure.2-6 Pulmonary
hypertension frequently complicates heart failure and is generally
considered “per se” an indicator of poor prognosis.7, 8
The RV is a low pressure, high volume pump, allowing
blood to flow into a highly compliant pulmonary circulation.
The RV is able to accommodate large changes in volume
with minimal pressure changes. As the pulmonary pressure
rises, the RV dilates and its hemodynamics, contraction and
pressure-volume loops are similar to that of the LV. This
depends heavily on interventricular interactions which
allows the RV to expand and accommodate the additional
preload. As the RV loses the capacity to overcome the high
vascular resistance, it becomes more dependant on afterload,
and the cardiac output declines precipitously. It is this
impaired RV function that portends a poor prognosis in
patients with PH of any etiology.
Heart Failure
Elevated PA pressure and abnormal RV function are important
determinants of both prognosis and exercise capacity in
patients with LV dysfunction. Several studies have shown
that exercise capacity, as measured by peak VO2, is more
closely associated with RV ejection fraction (EF) than with
LVEF.2, 3 Moreover, the presence of PH in patients with LV
dysfunction further impairs exercise performance in patients
with heart failure (HF), as the increased PVR results in further
reduction of the cardiac output.4 In addition, RV dysfunction
is also an independent predictor of survival, in
patients with LV failure3 especially when PH is present.5
Ghio points out in his study that patients with a combined
high PAP on right heart catheterization and a low RVEF have
the worst prognosis and survival among patients with
advanced left sided heart failure. In fact these patients have
a seven times higher risk of death than those patients with
a normal PAP and preserved RVEF, a 4.3 times higher risk
than patients with a high PAP/preserved RVEF and 3.3 times
higher risk than that of the patients in the normal PAP/low
RVEF5. Historically, heart transplantation has been contraindicated
in patients with fixed PH due to the very high
rate of perioperative mortality.6 In addition, in a small percentage
of patients undergoing placement of a LV assist
device, the RV fails acutely, due to the elevated PA pressure
and pulmonary vascular resistance (PVR), requiring the concomitant
placement of a RV assist device.9,10 As the surgical
techniques and aggressive medical management
improves, it may be possible to reverse what has been called “fixed” pulmonary hypertension, allowing these patients to
be eligible for transplantation11, 12.
Pulmonary venous hypertension can occur in the setting
of LV diastolic dysfunction, or diastolic heart failure.13,14
However, the incidence of significant of PH in the setting of
diastolic dysfunction has not been well characterized or
studied. As clinicians, we often struggle to differentiate
those patients with true PAH from those who may have some
form of diastolic dysfunction with reactive pulmonary hypertension.
It has been postulated that in some patients, the
pulmonary vasculature undergoes reactive changes due to
the chronic elevation of the left ventricular filling pressure, resulting in severe pulmonary hypertension. As the pulmonary
vascular disease progresses the cardiac output is
reduced due to RV dysfunction, decreasing the venous
return to the left heart and, eventually, normalizing the LV
filling pressure. At the time of presentation and evaluation,
these patients may have normal or only mildly elevated left
heart filling pressure with significantly elevated pulmonary
pressure, being misdiagnosed as PAH.
Mitral Valve Diseases
Mitral stenosis (MS) is an important cause of pulmonary
hypertension. In this particular condition, the elevated leftsided
filling pressure is at the atrial level, with normal
LVEDP. The elevated pulmonary pressure and PVR results in
increased RV end-diastolic volume and pressure, as well as
secondary tricuspid regurgitation, which may lead to right
heart failure and systemic venous congestion. The presence
of PH, either at rest or with exercise is an indication for percutaneous
or open commisurotomy or replacement of the
stenotic mitral valve.7
Pulmonary hypertension can also occur in patients with
mitral regurgitation (MR). It is not only related to the LV dysfunction
that complicates advanced stages of mitral regurgitation,
but it is also seen in patients with chronic, isolated
mitral regurgitation with normal LV function.8 The presence
of PH in patients with MR is associated with substantial
decreases in cardiac output and possibly a poor outcome. As
in patients with MS, the presence of PH in patients with MR,
either at rest or with exercise, is an indication for mitral
valve surgery.8
Aortic Valve Diseases
The incidence of PH in the setting of aortic valve stenosis
and/or regurgitation is not as common as with mitral valve
diseases. It has been described in up to 4-29% of patients
with significant aortic stenosis,15,16 mainly as a result of elevated
LVEDP and marked diastolic dysfunction. The perioperative
mortality rate of patients with severe aortic stenosis
and PH may be as high as 40%.12 However, without therapy,
the prognosis is even worse, with almost all patients
dying after 1.5 years.
The incidence of PH in patients with isolated aortic valve
regurgitation is rare, occurring mainly when the LVEDP is
already elevated, as a result of the chronic volume overload17
and it may portend a poor prognosis, even though the
data available is rather small and largely anecdotal.18
What Is Pulmonary Hypertension Out of Proportion to Elevated Left-sided Pressure?
The primary goal in the initial evaluation of patients with PH
is to differentiate PAH from other causes, especially PVH. By
definition, patients with PAH should have a low or normal
left-sided filling pressure, as measured by the PCWP or
LVEDP. A left-sided filling pressure of <15 mmHg has been
accepted as the criteria for patients with pulmonary arterial
hypertension.19 As clinicians, we struggle every day with
patients who have severely elevated pulmonary pressure with
only modest elevation of the left-sided filling pressure.
Several different measurements have been used clinically in
an attempt to differentiate those patients with some component
of pulmonary arterial hypertension in addition to their
left sided disease and PVH. Most of the studies are derived
from the heart transplant literature, especially the use of the
transpulmonary gradient (TPG).
The TPG is calculated as the difference between the mean
PA pressure and PCWP measured in mmHg. It is assumed that
a TPG of less than or equal to 15 mmHg is acceptable for transplantation, as the
elevated PA pressure is in direct proportion with the elevated
left-sided filling pressure. An elevated TPG is associated with a
very high incidence of post-operative right ventricular failure
and death.20 Many studies have shown that a high PVR is also
a risk factor for graft failure due to right heart failure early after
cardiac transplantation.9,21 However, the PVR, by using the cardiac
output in its equation may be unreliable because of inherent
inaccuracies in the measurement of cardiac output by thermodilution,
particularly at low cardiac outputs. The TPG, it is
argued, is flow-independent and thus may better reflect resistance
to flow across the pulmonary bed. In patients being considered
for heart transplantation, the acute reactivity of the pulmonary
bed is tested in the catheterization laboratory with
nitroprusside or nitroglycerin or chronically with aggressive
medical management, including the used of inotropic agents
and diuretics.22,23
Using the TPG and PVR to define a patient with PH outof-
proportion to the left-sided filling pressure works best in
patients with only moderately elevated PA pressure. Most of
the patients with PVH seen in clinical practice fall into this
group. However, there is subgroup of patients (probable 10-
20% by our observation) with enough reactive pulmonary
vasoconstriction that develop severe PH with only modest
increases in the left-sided filling pressure. Interestingly,
even in this subgroup, the PA pressure normalizes with normalization
of the elevated left-sided filling pressure. It has
been shown in multiple studies that in patients with mitral
stenosis, for example, when the PCWP is between 20-25
mmHg, the TPG is in excess of 15-20 mmHg, decompression
of the left atrium, either surgically or percutaneously,
with a concomitant rapid decrease in the LA and PCWP
results in a marked decrease in PA pressure, lower TPG and
eventually leads to normalization of the pulmonary pressure.
24,25 We have observed similar results in our practice,
especially in patients being considered for heart transplantation,
after the administration of long-acting nitrates.
Interestingly, in some patients with mitral stenosis, the
improvement in the pulmonary hemodynamics does not
occur immediately, and further therapy is required, at least
acutely.26 In our institution, we considered PH out-of-proportion
to left heart disease when the PA pressure is severely
elevated (mean PA greater than or equal to 35-40 mmHg) with only modest elevation
in the left heart disease (PCWP or LVEDP less than or equal to 22
mmHg) and a TPG greater than or equal to 18-20 mmHg. It is still unknown why
some patients develop severe and/or fixed PH with the same
degree of elevated left-sided filling pressure. Hopefully, further
studies in the future will be able to answer this question,
as it is likely that genetic predisposition may play an
important role.
Therapy of Pulmonary Hypertension Out of
Proportion to Left Heart Disease
There has been a remarkable growth in the therapy for PAH
over the last decade. There are now five approved drugs in
the United States with several other awaiting FDA approval,
for a disease with a grim prognosis, once considered universally
fatal in a short period of time. The increased awareness
for PAH has resulted in an augmented interest in PH secondary
to left-heart disease. This interest has been followed
by the use of pulmonary vasodilators for patients with secondary
PH. As patients with left heart disease and PH have
a worse prognosis than those without, it has been assumed
that improving the PA pressure should translate into an
improved prognosis and survival. As we will discuss below,
there is no correlation in the hemodynamic improvement
and overall survival.
The main concern in treating patients with elevated leftsided
pressure and PH with pulmonary vasodilators is that
by decreasing the PVR, there is an associated increased in
the cardiac output and venous return to the left ventricle. If
the LV has either significant systolic or diastolic dysfunction,
it would not be able to handle this increased venous return.
This would trigger further failure by increasing an already
elevated left heart filling pressure and result in pulmonary
edema, a dread complication in these severely ill patients
with a very high mortality rate. This effect is probably worse
in patients with a noncompliant LV and significant diastolic
dysfunction than in dilated LV with normal filling pressure.
Most of the studies done to evaluate the response of pulmonary
vasodilators in patients with left heart disease and
PH are in patients with advanced HF and systolic dysfunction
with secondary PH. There are no studies with the use of
pulmonary vasodilators in patients with heart failure due to
diastolic dysfunction.
Maximize Therapy for Primary Condition
Before even considering the administration of pulmonary
vasodilators to patients with left heart disease, the therapy
for the specific condition should be maximized. Mitral valve
surgery or valvuloplasty results in a normalization of the pulmonary
HTN in some patients with mitral stenosis.
Unfortunately, despite the normalization of their left atrial
pressures, a proportion of these patients are still left with
significant pulmonary hypertension. Whether specific pulmonary
arterial vasoremodeling therapy is beneficial in these
patients at this point is unknown. The use of PAH drugs in
patients with HF has failed to show any improvement in
symptoms, or survival (Table 2). Maximizing the therapy for
HF with approved drugs or assist devices may also result in
a normalization of the PA pressure in patients with secondary
PH (Table 3). Several already approved therapies are
effective in these instances, like nitrates and chronic
inotropic use.
Prostacyclin Analogues
The acute administration of epoprostenol in patients with
HF and secondary PH results in significant reductions in
mean PA, PCWP and marked increase cardiac output with a
resultant decrement in the SVR and, more importantly, the
PVR27. These beneficial hemodynamics effects persist with
long-term infusions.28 In contrast to the improved survival
seen in patients with PAH, the chronic use of epoprostenol
in patients with HF and PH was not associated with a survival
benefit. The large-scale Flolan International
Randomized Survival Trial (FIRST)29 randomized 471
patients to epoprostenol infusion or standard care. The trial
was terminated early because of strong trend (P = .055)
toward a decreased survival in patients treated with
epoprostenol. There is still debate regarding the potential
explanation for the discouraging results seen in FIRST. It
may be due to a direct stimulation of prostacyclin on certain
neurohormones, like renin30 and the sympathetic nervous
system.31 Moreover, therapeutic doses of prostacyclins exert
a positive inotropic effect in patients with heart failure,
which may explain the increased mortality observed in
FIRST28. Finally another possible explanation is that a subgroup
of patients respond “too well” to the prostacyclin analogues,
with marked decrease in the PCWP, which may lead
to negative pathophysiologic effects, not measured by the
usual hemodynamic parameters32. Ilopost is another prostacyclin
analog that has been used in patients with HF. It is
administered by inhalation, therefore, exerting most of its
effect in the pulmonary vasculature and decreasing the
potential detrimental systemic effects. However, this effect
is probable no different than that observed with nitroglycerin,
nitroprusside or nitric oxide.33 Given these results, we
believe that there is a very limited role for the use of
epoprostenol or other prostacyclin agonists in the therapy of patients with PH secondary to left heart disease; however,
this has not been proven.
Endothelin Antagonists
Endothelin-1 levels are elevated in patients with HF and correlated
with clinical and hemodynamic measures of severity,
as well as with a poor prognosis. Several studies of selective
(ETA) or nonselective (ETA/ETB) receptor antagonists in
patients with acute and chronic HF have now been completed,
all with similar disappointing results.
The short-term administration of tezosentan, a dual
endothelin-receptor blocker results in a rapid, dose-dependant
improvements in the PA, PCW pressure and cardiac
index34 in patients with advanced HF and class III to IV
symptoms. This beneficial hemodynamic effect was again
seen in patients hospitalized for acute decompensated HF35.
Further studies have failed to demonstrate any significant
clinical benefit from the use of tezosentan in patients with
pulmonary edema36 over usual therapy, including VERITAS,
37 a large randomized trial that was stopped early due
to a lack of effect in the treatment arm.
A small pilot study using oral bosentan, a non-selective
endothelin antagonist in patients with HF, demonstrated
similar beneficial hemodynamic effects than intravenous
agents.38 A larger pilot study, REACH-1,39 randomized 377
patients with HF and NYHA class III-IV to receive oral
bosentan to goal doses of 500 mg twice daily or placebo
(four times the recommended dose for PAH). Bosentan
exerted no apparent benefit when all patients were analyzed,
but in the subgroup of patients that were treated for at least
26 weeks, there was a significant beneficial treatment effect
in favor of bosentan. The results of the large, randomized
trial ENABLE,40 powered to detect mortality differences
between bosentan-treated patients and placebo, was similarly
disappointing with a lack of survival benefit, and an
early risk of worsening HF and hospitalization, as a consequence
of fluid retention. The overall interest in the possible
beneficial effect of endothelin antagonist in HF has
declined significantly lately, and there is the possibility that
we may not have any additional trials with these class of
agents, at least in patients with systolic HF.
Phosphodiesterase Inhibitors
Sildenafil is a selective phosphodiesterase-5 inhibitor that
has been used extensively for the treatment of male erectile
dysfunction. It has been recently approved for the use in
patients with PAH, given its beneficial hemodynamic and
clinical effects and safety profile. A single oral dose of sildenafil
in patients with HF and PH results in significant reductions
in the mean PA, PCWP, PVR and an increase in the cardiac
index, and may even potentiate the effect of nitric
oxide.41 Moreover, sildenafil has been used to test pulmonary
reactivity in patients with HF and PH being evaluated
for heart transplantation.42 Sildenafil also appears to
improve the exercise capacity in this population.43 There are
also anecdotal reports of improvement in PH in patients with
HF awaiting transplantation, including one of our patients
with severe LV dysfunction, with a LV assist device and
markedly elevated PA pressure and PVR, despite adequate
unloading of the LV by the assist device to a PCWP of <12.
After 3 months of therapy the PA pressure normalized and
the patient was successfully transplanted. Whether the normalization
of the PA pressure in this particular case was the
effect of the chronic unloading of the LV and therefore resolution
of the pulmonary venous pressure, or a direct effect of
sildenafil is unknown. However, despite these anecdotal
reports, and until further studies are available, the long-term
use of sildenafil in patients with PH associated with left
heart disease should be discouraged.
Treatment of PH and Diastolic Dysfunction
The presence of diastolic heart failure has been known for
years. Epidemiologic studies have shown a very high prevalence
of up to 50% of all patients diagnosed with heart failure,
especially in the elderly population.44 However, only one
randomized trial has been done in patients with diastolic
dysfunction, the pre-specified subgroup of the CHARM trial
with preserved LVEF.45 The additional recommendations are
based on understanding the physiologic changes that occur
in a stiff, noncompliant left ventricle, like control of the
heart rate and reduction in the LV volume and pressure with
the adequate use of diuretics and nitrates. It is in this population
where we worry the most that the inappropriate use
with pulmonary vasodilators may decrease the PVR, increasing
the cardiac output and therefore the venous return to an
already non-compliant LV, increasing even further the pulmonary
venous pressure resulting in pulmonary edema. In
order to answer this concern, a trial looking at the effect of
sitaxsentan, a specific endothelin type A receptor antagonist,
in patients with diastolic dysfunction will start later this
year. Until the results of the study are available, we should
avoid the use of pulmonary vasodilators in patients with documented
left heart disease, based on a PCWP or LVEDP
greater than or equal to 16 mmHg.
Conclusions
The most common etiology for elevated pulmonary artery pressure is pulmonary venous hypertension. This is most
commonly due to LV failure, either systolic or diastolic, but
also occurs in the setting of mitral and/or aortic valve disease.
The concomitant presence of PH and left heart disease
carries a poor prognosis. In some patients, the elevated pulmonary
pressure appears to be out-of-proportion to the elevated
left-sided filling pressure. The exact reason why some
patients have severely a elevated PA pressure in the setting
of only modestly elevated left-sided filling pressure is
unknown. Pulmonary vasodilators have been tested in
patients with elevated left-sided filling pressure, mainly
prostacyclin agonists and endothelin antagonists in chronic
systolic HF. These trials have failed due to an increase in
mortality or worsening HF and hospitalization, possibly due
to fluid retention. Despite anecdotal reports of patients
improving after the addition of pulmonary vasodilators to
their HF regimen, especially with the use of sildenafil in
patients waiting for heart transplantation due to severe LV
systolic dysfunction, the routine use of these agents should
be discouraged. Further studies, using specific endothelin
anagonists in diastolic dysfunction are planned, and may be
able to answer these concerns. Until then, we recommend
maximizing the therapy for the primary condition (HF) as a
way of decreasing the elevated PA pressure in patients with
left heart disease.
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