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 This
discussion was moderated by Richard Channick, MD, Associate
Professor of Medicine, Pulmonary and Critical Care Division,
University of California, San Diego Medical Center, San
Diego, California. The physicians participating included
Hap Farber, MD, Director, Pulmonary Hypertension Center,
Boston University Medical Center, Boston, Massachusetts;
Nicholas Hill, MD, Chief, Pulmonary, Critical Care and
Sleep Division, Tufts-New England Medical Center, Boston,
Massachusetts; and Robert Schilz, PhD, DO, Director of
Lung Transplantation and Advanced Lung Disease, and Assistant
Professor of Medicine, Case Western Reserve University,
Cleveland, Ohio.
Dr Channick: Good
morning gentlemen. I am pleased to be moderating today’s
discussion, which will focus on pulmonary hypertension
associated with lung diseases, category 3 in the WHO diagnostic
classification system. Let me start by asking: Do you
feel this is an important, underrecognized group of disorders
that deserves attention and study?
Dr Farber: Definitely.
Patients who have underlying and chronic lung disease
are living longer than they used to because the treatments
and the ancillary care are better, and as such, a lot
of these patients who go undernoticed tend to be hypoxic
for longer periods of time
Dr Hill: I agree.
There are enormous numbers of patients with chronic obstructive
pulmonary disease out there. They usually don’t manifest
significant pulmonary vascular involvement until fairly
late in their disease, at least clinically, but there
are pathological studies showing that the pulmonary vascular
involvement is detectable quite early in the pathogenesis
of COPD. My guess is that it is involved in the progression
of the disease, so I think we need to understand more
about that part of the connection. Therapeutically, we
have always focused on the airway obstruction, but treating
pulmonary vascular disease may be helpful in some patients.
Another large group of patients with underrecognized pulmonary
vascular disease would be those with interstitial lung
disease. There is overlap with the connective tissue disease
group where we know a lot of scleroderma patients have
significant pulmonary vascular involvement. But the patients
who have idiopathic fibrosis and other forms of interstitial
disease often have a significant component of pulmonary
vascular involvement, and once again, it’s probably
involved in the pathogenesis and progression of the disease
and might serve as a therapeutic target.
Dr Channick: Hap
mentioned that hypoxia seems to be a prominent, driving
force. Do you feel that, in terms of pathogenesis and
development of this
disease on the cellular level, it is alveolar hypoxia
that brings these disorders together? Or are there other
more specific mechanisms by which these vascular lesions
develop in patients with chronic lung disease?
Dr Farber: I think
both. There are certain effects on the vasculature that
are probably unique to each of the disease entities that
we want to talk about. In all likelihood the hypoxia is
not initially important to the pathophysiology of the
vascular disease; rather, the specific aspects of the
underlying disease on the vasculature are more important.
Dr Hill: The role
of hypoxia is important but probably has been overemphasized.
I know that with the most recent change in the classification
for pulmonary hypertension, hypoxia is considered the
etiology for group 3. However, this group includes different
parenchymal diseases that may involve the pulmonary vasculature
via nonhypoxic mechanisms. For example, Barbera’s
group in Spain has found early histologic changes suggesting
inflammatory cell involvement around the small pulmonary
vessels. These changes occur well before any hypoxia is
detectable.
Dr Farber: It’s
the same in a way as looking at idiopathic pulmonary arterial
hypertension. It’s clear, especially in IPAH, that
hypoxia is not the inducing agent, but clearly patients
with IPAH, having set in motion whatever cellular and
molecular changes occur, worsen when they become hypoxic.
Dr Channick: Nick,
how about sleep apnea in terms of pathogenesis? What do
you think about pulmonary hypertension developing in sleep
apnea, why it develops, and in whom?
Dr Hill: There has
long been a debate about whether obstructive sleep apnea
alone contributes to the development of significant pulmonary
hypertension. However, longitudinal studies by Weitzenblum
and Fletcher have shown that, over a long period, some
patients with severe sleep apnea develop mild pulmonary
hypertension, but in the absence of chronic hypoventilation
leading to alveolar hypoxia you generally don’t see
severe or even moderate pulmonary hypertension.
Dr Farber: I definitely
agree with that. You do see this discussed in the studies
that Nick mentioned and elsewhere. I do not think that
the sleep apnea that most people have is enough in and
of itself to cause clinically significant pulmonary hypertension.
I think you need to have significant hypoventilation to
develop pulmonary hypertension.
Dr Channick: When
I see a patient with sleep apnea who has severe pulmonary
hypertension, the first thing I think about is concomitant
left heart disease. I wonder if you have noted that connection
as well.
Dr Farber: Those
patients with sleep apnea who have undergone catheterization
and who do have pulmonary hypertension often have all
the other metabolic issues associated with diastolic dysfunction.
Thus, it is very common for these patients to have left
ventricular disease, most prominently, diastolic dysfunction.
Dr Channick: Turning
to clinical aspects of these diseases, I think we agree
that patients with lung disease or respiratory disease
can have pulmonary hypertension. The question we are always
asked by practitioners is, so what? What is the clinical
importance of a patient with COPD having mild-tomoderate
pulmonary hypertension? Do you feel that it is clinically
important?
Dr Hill: I don’t
think that question has ever been adequately answered
and I think it is a legitimate question. If you look at
it from a very superficial angle, a patient with severe
airway obstruction still has severe airway obstruction
no matter what you do to the pulmonary vasculature. If
that obstruction is the major cause of limited exercise
capacity, then focusing on the pulmonary vasculature may
not help.
Dr Farber: I agree
that even if patients do have vascular disease, if they
still have ongoing parenchymal disease that is not adequately
treated, then treating the vascular disease is not going
to be as helpful as otherwise. This should not take away
from treating the underlying disease. Moreover, that does
not prevent treating the two concomitantly or treating
the two effectively.
Dr Hill: We’ve
never had the opportunity to address this hypothesis because
we’ve never had the kinds of therapeutic agents we
need. Now that there are some longer acting prostacyclins
that are amenable to inhalation on the horizon, maybe
the hypothesis can be tested.
Dr Channick: Certainly
if you look at studies of pulmonary hypertension in a
large group of COPD patients, it looks very mild. We’re
talking about mean pressures in the 20s. On the other
hand, pulmonary hypertension does seem to affect mortality
in COPD.
Dr Farber: There’s
a study from a decade ago by Weitzenblum et al that showed
that patients with COPD and pulmonary hypertension had
poorer outcomes.
Dr Channick: One
aspect of this problem that has received little study
is exercise effects on pulmonary hemodynamics. Patients
have symptomatic limitation with exercise. There are smaller
studies suggesting that many of these patients have a
significantly exaggerated response to exercise.
Dr Farber: You’re
right. Some of these patients may have exercise limitations
not predominantly from their underlying lung disease but
in part or maybe predominantly from exercise-induced pulmonary
hypertension.
Dr Channick: And
that raises the question, how can we identify that subset
of patients? I was very interested in the data related
to the genetics of COPD, demonstrating polymorphisms in
ACE and nitric oxide synthase that defined a subset of
COPD patients at greater risk for pulmonary hypertension.
Dr Farber: How many
patients with COPD are out there? It’s probably physically
impossible to test all of them or determine which ones
do have exercise limitations because of pulmonary vascular
disease. So it would be good if there were markers that
would at least suggest that this person is in that subset
of patients who really should be evaluated for pulmonary
hypertension. And maybe it is these polymorphisms in ACE
or nitric oxide synthase or other as yet unidentified
genes that will be important.
Dr Hill: Polymorphisms
in the serotonin transporter have also been implicated
in pulmonary hypertension.
Dr Channick: Getting
to diagnosis, what is your approach, Hap, when you see
a patient who has COPD or pulmonary fibrosis and the echocardiogram
is suggestive of pulmonary hypertension? What is your
algorithm for proceeding from that point?
Dr Farber: First,
a lot of times you’re struck by the fact that if
the patient has pulmonary hypertension by echo and it
seems out of proportion to the pulmonary function tests,
for example…
Dr Hill: Do you routinely
get echocardiograms in these patients?
Dr Farber: I don’t,
but these patients are usually referred to me after someone
else got an echo.
Dr Hill: Also, echocardiograms
are notoriously inaccurate in patients with COPD.
Dr Farber: You do
run into this problem. The ones that make you suspicious
are the patients sent to you with an echo that shows pulmonary
hypertension and the patient has an FEV1 of 2 liters.
It gets really hard because, as Nick alluded to, I do
not routinely obtain echos in these patients. They are
usually referred to me from somewhere else. If I’m
convinced that the echo is true—if the right ventricle
is dilated or there are other signs of significant pulmonary
hypertension—I make sure that there is no other reason
for pulmonary hypertension. In a lot of these patients
we do end up cathing them to determine if the echo is
correct and to determine if there is some other entity
that can be treated, specifically left ventricular diastolic
dysfunction.
Dr Hill: There are
a lot of patients with pulmonary hypertension and COPD,
depending on how you define pulmonary hypertension. Some
studies have estimated prevalences ranging between a third
and 90% of patients, depending on what detection technique
is used and how pulmonary hypertension is defined. My
practice has been to accept that mild pulmonary hypertension
is probably secondary, and in the absence of known effective
therapies, it is not sensible to chase the diagnosis of
pulmonary hypertension. I’m generally looking for
patients who have pulmonary hypertension out of proportion
to their COPD. And we can argue about how to define that.
Dr Channick: And
this is a question that is asked of us every time we lecture
on this topic. What echo threshold do you use for cathing
the patient?
Dr Farber: What Nick
is alluding to more than the echo-cath threshold is the
fact that if you see someone with COPD and an FEV1 of
2 liters but who has an echo that is suggestive of pulmonary
hypertension, everything about that patient’s disease
seems disproportionate to the existence of pulmonary hypertension.
Dr Schilz: We certainly
recognize it when we see it. Everyone would probably agree
that anyone with a mean pulmonary pressure of greater
than 50 mm Hg we are probably thinking about in a careful
fashion. There have been a handful of reports of people
who walk in with an FEV1 of 65% and pulmonary pressures
of 100 mm Hg on catheterization, and a cardiac index of
1.7. Anecdotally we all have these people and we usually
treat them as if they have pulmonary arterial hypertension,
and if prostacyclin therapy is started, they’re a
little more hypoxic, but their cardiac index is better
and they have better exercise performance.
Dr Channick: The
devil is in the middle ground. Patients who have moderate
COPD and moderate pulmonary hypertension.
Dr Hill: Where is
the threshold? That is the question.
Dr Farber: The problem
we are all dancing around is the fact that at least in
this group of patients, and probably in any group of patients,
the echo is just not a sensitive enough tool. It overestimates
pulmonary hypertension, in some studies by up to 33% of
people. It’s a real problem.
Dr Schilz: There
is an interesting comment that has been made before. The
use of cardiopulmonary exercise testing actually might
be able to tease through the middle. In some respects
almost everyone with COPD is ventilatory limited and so
these patients hit their maximal exercise capacity at
pretty much peak ventilation. It may be interesting whether
someone without cardiac disease starts reaching a circulatory
limitation without a ventilatory limitation. It’s
an interesting concept because functionally you’re
not going to get patients better if they reach ventilatory
threshold.
Dr Hill: It’s
an interesting thought. The specificity of cardiopulmonary
exercise tests in differentiating between specific causes
of cardiovascular limitation is limited.
Differentiating among deconditioning versus cardiomyopathic
changes versus pulmonary vascular disease is challenging.
Sometimes you pick up gas exchange problems that might
lead you down the pulmonary vascular disease path.
Dr Farber: The problem
also would be that if in fact cardiopulmonary exercise
testing were adopted as a screen, you would be exercising
an inordinate number of patients to find a very small
number. It would be nice if we had a biomarker that would
predict which patient is potentially at risk.
Dr Channick: So it
sounds like we’re still wrestling with how far we
would go with these patients and it’s clearly a clinical
judgment.
Dr Schilz: So you
would go up the list. And the other thing that is the
hallmark of this is that the progression or increase in
pressures is very low. So there are not tremendous increases
in pulmonary pressures on a yearly basis.
Dr Hill: In the range
of a fraction of a millimeter a year.
Dr Farber: How frequently
do you see someone with underlying lung disease who has
a pulmonary artery systolic pressure of 100 mm Hg or over?
You almost never see it. If you see a pressure that is
really high—probably above 80 mm Hg—you think
that something else is going on.
Dr Hill: You said
it earlier, Bob. A mean over 50 mm Hg, I think the red
flags go up if you see that.
Dr Schilz: And the
closer you get to that the more you do. A lot of us wouldn’t
wince at 35 mm Hg or under. I think that is the range.
Most of the literature spots you up to about 35 mm Hg
as being very routine.
Dr Channick: That
is an extremely important point. For the physicians receiving
this publication, that is the group of patients they are
struggling with. They only rarely see patients with idiopathic
pulmonary arterial hypertension. They see overweight patients
who have some lung disease and sleep apnea, and should
they be working these patients up? I hope we can provide
them some guidance.
Dr Farber: I think
the guidance is, as Nick pointed out, are we willing to
accept minimal or mild pulmonary hypertension without
an extensive workup unless the patient has something obvious
that directs you to another cause? But certainly if a
patient has an echo, is very limited, and falls into this
“we don’t know how big a group,” but presumably
a small group of patients who have a much higher mean
or systolic pulmonary artery pressure than expected, an
individual such as this one definitely should be evaluated.
Dr Hill: We’ve
talked about the limitations of screening in these patients.
Hap said earlier that if the FEV1 is not all that severely
reduced and dyspnea seems disproportionate, an echo should
be done as a screening test. And as far as a threshold
on the echo that would get my attention, I would suggest
that an estimated pulmonary artery systolic pressure of
60 mm Hg or higher would start raising the flags.
Dr Schilz: Those
are realistic. We have to remember too that even among
the National Emphysema Treatment Trial patients the mean
pulmonary artery systolic pressure was 26 mm Hg and an
FEV1 of 27%. That’s pretty bad. On the other
hand, is there an exercise circulatory limitation in some
patients that we can improve on?
Dr Farber: There
are actually very limited data to tell us what happens
to hemodynamics in patients with lung disease during exercise.
Before we recommend cardiopulmonary exercise tests with
catheterization for all these patients, we need a lot
more data on what happens to these patients in general.
Dr Channick: Let’s
finish by talking about treatment. Before we talk about
experimental approaches, what about the tried and true
treatments for lung disease and pulmonary hypertension?
Does oxygen help these patients when you see mild
to moderate pulmonary hypertension?
Dr Schilz: We all
know that the only place it’s been proven is in the
National Emphysema Treatment Trial.
Dr Farber: If they
are not hypoxic, you are making yourself feel better but
you are not doing anything substantial for them.
Dr Channick: I found
it interesting in that trial that oxygen did not reduce
pulmonary artery pressure. But it improved survival.
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