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Dr. Rubenfire, the ACCP recommendations do not
offer recommendations for certain patients based on the
lack of clinical data. One such area involves patients
with clear left ventricular diastolic dysfunction who
have a very high pulmonary artery pressure. Could you
offer your thoughts on how you approach such patients?
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Melvyn Rubenfire, MD
Professor of Medicine
University of Michigan Medical Center
Ann Arbor, Michigan
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Not only are there not enough clinical data regarding
the evaluation of severe pulmonary hypertension in association
with left ventricular diastolic dysfunction (LVDD), treatment
is more a trial and error art form than evidence based.
As you are inferring, severely elevated pulmonary artery
pressures are not commonly found with isolated LVDD, but
we see at least one or two patients a month in the setting
of left ventricular hypertrophy with what I would call
disproportionate pulmonary hypertension.
Classic examples of left ventricular pathology associated
with isolated diastolic dysfunction that can result in
severe pulmonary hypertension include:
- Chronic hypertension with left ventricular concentric
hypertrophy
- Hypertensive combined with ischemic heart disease
- Hypertensive heart disease with diabetes
- Hypertrophic cardiomyopathy
- Hypertensive hypertrophic cardiomyopathy of the
elderly
- Aortic stenosis with a normal ejection fraction
In my experience severe pulmonary hypertension in hypertensive
heart disease is more common in elderly diabetes and obesity,
but there is no gender difference in aortic stenosis.
Multifactorial pulmonary hypertension is the rule more
often than the exception in pulmonary hypertension associated
with LVDD. It is important to follow the guidelines for
assessing pulmonary hypertension in patients with disproportionately
high pulmonary artery pressure and obvious LVDD associated
with left ventricular hypertrophy. The most common aggravating
conditions are obstructive sleep apnea, hypoxemia and
COPD, pulmonary embolism, and a missed atrial septal defect.
On the other hand, scleroderma-related disorders with
pulmonary arterial hypertension can have significant resting
or exercise associated increase in the pulmonary capillary
wedge pressure due to LVDD. Each of the mechanisms for
pulmonary hypertension can contribute and create a disproportionate
increase in pulmonary artery pressure. For example, chronically
elevated pulmonary capillary
wedge pressures and pulmonary congestion associated with
a hypertrophic cardiomyopathy can lead to pulmonary hemosiderosis/fibrosis,
abnormal diffusion capacity, hypoxemia, and hypertrophy
of pulmonary arterioles. Hypoxemia associated with chronic
lung disease and sleep apnea can worsen left ventricular
diastolic and systolic function.
Why does severe pulmonary hypertension occur in some
patients with LVDD? I suspect it is related to the very
long time course seen in hypertensive and hypertrophic
cardiomyopathies perhaps accompanied by a genetic susceptibility,
somewhat akin to high flow in atrial septal defects. Another
analogy would be rheumatic mitral stenosis in which long-standing
elevation of the pulmonary venous pressure leads to disproportionate
pulmonary hypertension in about 20% of patients.
There are certain features of pulmonary hypertension
associated with left ventricular hypertrophy, aortic stenosis,
and other causes of LVDD that are not well characterized
or understood. These include a disproportionate increase
in systolic pulmonary arterial pressure (sPA) [usual sPA
= 2 diastolic PA (dPA), with LVDD sPA ¡Ã3
x dPA] or wide PA pulse pressure; a relatively small gradient
between the dPA pressure and pulmonary capillary wedge
pressure; modest pulmonary vasodilator reserve to inhaled
nitric oxide; and a significant response to intravenous
or sublingual nitroglycerin.
The four major determinants of the pulmonary artery pressures
include the stroke volume, compliance or elastance of
the pulmonary artery and major branches, resistance provided
by the pulmonary arterioles and pulmonary venous pressure,
and the reflectance wave.
The right ventricular stroke volume is usually normal
in hypertensive and hypertrophic cardiomyopathies. The
resistance is predominantly from hypertrophy and increased
tone of the pulmonary arterioles (abnormal endothelial
function and increased endothelin) and pulmonary venous
pressure reflecting the high left ventricular filling
and end-diastolic pressures. The natural history of increasing
left ventricular hypertrophy over decades in hypertensive
heart disease and obstructive and nonobstructive cardiomyopathy
promotes a gradual increase in pulmonary arterial pressures
with an exaggerated rapid progression in some. In long-standing
and severe forms of left ventricular hypertrophy the resting
left ventricular filling and end diastolic pressures are
usually 15 to 18 mm Hg and 25 to 30 mm Hg, respectively,
and the pulmonary capillary wedge pressure is 18 to 25
mm Hg. The
latter rises to 25 to 40 mm Hg with modest exercise.
What are the therapeutic implications of the hemodynamic
assessment in pulmonary hypertension associated with LVDD?
Severe pulmonary hypertension in the setting of aortic
stenosis and hypertrophic cardiomyopathy is associated
with a poor prognosis and increased risk of surgery, but
should not preclude the surgical approach. We have used
intravenous nitroglycerin to demonstrate significant reversibility
of pulmonary hypertension in the setting of aortic stenosis
with and without coronary disease, which has helped in
the decision to operate. Intravenous nitroglycerin can
rapidly reduce the left ventricular filling pressure and
pulmonary capillary wedge pressure, which can be followed
by a sudden reduction of sPA, dPA, and mPA with minimal
change in CO, suggesting the pulmonary hypertension is
reversible.
In patients demonstrating pulmonary vasodilator reserve,
my approach is to keep them as dry as possible without
undo hypotension, use spironolactone to reduce myocardial
fibrosis as in CHF trials, ACE or ARB inhibitors to regress
left ventricular hypertrophy, and long-acting and sublingual
nitrates to reduce symptoms and increase exercise tolerance.
The vasodilator reserve to inhaled nitric oxide in pulmonary
hypertension associated with LVDD is useful to help in
understanding the pathogenesis and is an interesting finding.
I have too little experience to characterize the distribution
of the magnitude of response. Trials using endothelin
antagonists and prostacyclin in patients with CHF have
failed, perhaps in part because the pulmonary vasoconstriction
has protected the lungs and left ventricle. It¡¯s
important to control the heart rate, particularly in atrial
fibrillation so as to allow an adequate left ventricular
filling time. Beta blockers, verapamil, and diltiazem
are effective for rate slowing with the addition of digoxin
in atrial fibrillation. There are reports of beta blockers
and calcium-channel blockers (nifedipine) lowering left
ventricular filling pressures by enhancing the rate of
isovolumetric diastolic relaxation in LVDD and regressing
LVH, but the clinical effects are not consistent. Short
to intermediate-term trials can be used to determine their
potential value.
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