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 This
discussion was moderated by Sean Gaine, MD, Director,
Pulmonary Hypertension Unit, Mater Misericordiae Hospital,
University College, Dublin, Ireland. The physicians participating
included Stuart Rich, MD, Professor of Medicine, and Director,
Rush Heart Institute Center for Pulmonary Heart Disease,
Rush Presbyterian-St. Luke’s Medical Center, Chicago,
Illinois, Norbert Voelkel, MD, The Hart Family Professor
of Emphysema Research, University of Colorado Health Sciences
Center, Denver, Colorado, and Nicholas W. Morrell, MD,
Director, Pulmonary Vascular Diseases Unit, Papworth and
Addenbrooke's Hospitals, University of Cambridge School
of Clinical Medicine, Cambridge, UK.
Dr Gaine: Let’s
start with you, Stuart. There has been a flurry of activity
over the past few years with randomized trials and new
drug approvals. Are we going to see a pause and a regrouping
with the drugs we have? What is going to happen in the
short to medium term with new drugs for pulmonary arterial
hypertension?
Dr Rich: First of
all, we are running out of patients. So we are limited
in our ability to place them in clinical trials by the
absence of a patient base. Currently the general categories
of drugs that have been developed are the endothelin receptor
blockers, the PD5 inhibitors, and the prostacyclins. I
think from this point on we will see new drugs within
these categories. You are going to probably see similar
efficacy within the class. But we will start seeing that
some classes of drugs have superior efficacy over others.
I have my own thought about which is the most efficacious
and which is the least, and I don’t think we need
any more of these “vasodilator” types of drugs.
Hopefully a newer generation of treatments will come from
an attack on the appropriate molecular pathways. We now
understand what triggers the disease, what pathways are
involved, and it may be time for pharmacogenomic therapy
or really trying to do disease reversal as opposed to
disease palliation.
Dr Morrell: I agree
that we will see more drugs of the same class as the ET
receptor antagonists and PD5 inhibitors, and of course
the combination of these agents. However, I would continue
to encourage active clinical research with vasodilators.
We know that many of the vasodilator pathways also affect
the
structure of the vessel wall, probably by influencing
growth and apoptosis. Some of these pathways exert more
profound influences than others. Take for example the
success of ACE inhibitors in the treatment of systemic
hypertension and left ventricular hypertrophy. In the
same way it is likely that some of these pathways exert
a more profound effect than others in the pulmonary circulation.
For example, we have not yet begun to reap the clinical
benefits of the basic research into the serotonin pathway.
On the vasodilator side, agents such as vasoactive intestinal
peptide and adrenomedullin may prove even more effective
than prostacyclin. We just don’t know yet.
Dr Gaine: Stuart,
you started by saying that we are running out of patients.
Will you explain that?
Dr Rich: Well, it
is a phenomenon related to the fact that the first approved
therapy, which is intravenous prostacyclin, is lifesaving.
We are at a point where the feeling is that it is unethical
to have any patient untreated. So to do placebo-controlled
trials is going to be quite difficult unless you choose
the most minimally symptomatic patients. But remember
when you do treat diseases, the most minimally symptomatic
patients will show the least. It will take a large number
of patients and will be difficult to do. For the more
advanced cases there are existing therapies that improve
quality of life, exercise tolerance, and survival. Most
people feel it would be unethical to do a randomized trial
against placebo in those patients. So now you are talking
about either head-to-head superiority trials or noninferiority
trials, and those take large numbers of patients, which
don’t exist in the pulmonary hypertension arena.
So I think it is going to be very difficult to introduce
a whole new drug into this arena, given the limited patient
base.
Dr Voelkel: I was
initially also a little confused when Stuart said we were
running out of patients, and I think he saves himself
in the latter part of his argument. My take is that we
are looking, and I agree with him totally, at new treatment
paradigms, categorically new treatment paradigms. Enough
of the vasodilators, we have had that experience. We probably
will never get a better vasodilator than prostacyclin.
So the reality is that we are dealing with patients who
are being helped initially. They are stabilized, they
are improved, and then we run out of gas, they run out
of gas. My take on this is that we design studies for
patients currently receiving established maximal therapy
with the goal of saving them, rather than at the end of
the day still transplanting them. Stuart, do you agree?
Dr Rich: Totally,
Norbert.
Dr Morrell: Of course
it would be foolish to focus all efforts on so-called
vasodilators, but I believe there is still some mileage
left in this approach. However, I do agree that the overall
benefits will be incremental rather than revolutionary.
We need to turn our attention to taking advantage of the
major new insights into the molecular pathogenesis of
PAH that have emerged over the past few years.
Dr Voelkel: I will
work with anybody who will find an interesting target.
There are plenty of those patients around because they
are all registered and on the Actelion distributorship,
patients on prostacyclin year four. Whenever you look
at them hemodynamically, or do follow-up echocardiography,
their systolic pulmonary artery pressure is 80 mm Hg,
and we don’t know where they’re going. Are
they going to crash in two years? I don’t think
we have anything else to offer. With the best of our abilities,
we are keeping them in a stable or pseudostable form.
But I think there are lots of these patients around.
Dr Rich: No doubt.
We have been focusing until now on trying to slow disease
progression and our data show that patients aren’t
dying as fast, but they are dying. The new challenge is
to try to halt progression and induce regression. And
we’ll probably start with that group you’ve
identified, patients receiving maximal therapy who are
still very sick.
Dr Gaine: You’ve
brought up twice now the notion of disease regression
therapies and I wonder if we could elaborate on that.
Diseases of the lung like emphysema or pulmonary fibrosis
result in parenchymal destruction with no reasonable chance
of reversing that process. But the pathology in pulmonary
arterial hypertension reveals proliferation of cells rather
than destruction or loss of tissue, leaving open the hope
that we may be able to reverse the pathological changes
in the future. What thoughts do you all have on the way
that is going to evolve?
Dr Voelkel: Well,
I can tell you what my fantasies are. The comparison with
interstitial fibrosis or emphysema is, thankfully, problematic
in a good sense, because I do not believe you have the
same degree of global destruction. I say this because
most of the vascular lesions are in strategic locations
in the lung circulation. This is where the work with our
three-dimensional reconstruction comes in. A published
report (Cool CD, et al. Am J Pathol. 1999;155:411-419)
indicated that if you follow down the vascular tree, eventually
you come to a blockage, but it’s not like an embolus
that’s about 15 mm long, it’s still a microscopically
small lesion. If the focus is on these abnormal cells,
and if we are smart enough to figure out how we can remove
the abnormal cells, we can be ultimately successful. You
can calculate how many of these vessels have to be occluded
in a human lung before the mean pulmonary artery pressure
goes up to, let’s say 50 mm Hg. People will tell
you that you probably have to have 95% or more of these
strategically localized arterial lesions occluded before
the mean pressure gets so high. I think to have a goal
to make all these vessels squeaky clean again would be
unrealistic. But if we can perhaps open up 20% or 25%
of these vessels, you can make the calculations, the pulmonary
artery pressure would have to fall, and fall substantially.
It would never be entirely normal, but the patients would
be out of the danger zone and I don’t think they
would ever have to go into right heart failure and die.
That’s my fantasy in a nutshell. I think it’s
realistic to say that if we can open up 20% or so of these
vessels, it would have very big hemodynamic consequences
and lead to a large improvement.
Dr Gaine: Nevertheless,
is it not reasonable to think it is a fantasy that can
become a therapeutic reality? Do people believe there
are switches we can flick to tell the vasculature to reverse
the proliferation?
Dr Rich: Probably.
I am always amazed at the body’s ability to correct
disease processes, more than we ever thought. The late
Professor CA Wagenvoort wrote a paper in the 1980s subtitled“
The point of no return” (Minn Med. 1985;68:45-48).
The pathologist had a viewpoint that if certain lesions
were present, histologically, the disease was irreversible.
But I think that has been proved wrong many times with
other organs. So I think Norbert’s fantasy is not
really fantasy. There are some changes that are likely
never to return to normal. But it is remarkable when you
look at postmortem lungs how heterogeneously the vessels
are affected, and he is right that you may not need to
reverse 100%. You may just need to reverse 10% or 15%
or 20%. The goal need not be normal, but the goal should
be stable. If patients are going to be able to go to work
and have a reasonable quality of life, with some limitations,
I think that is total victory.
Dr Voelkel: I totally
agree with you. That’s why we can’t really
make the analogy with interstitial fibrosis or with emphysema.
When you talk about lung volume, I mean just lung parenchyma,
you have, pound for pound, a much greater and more ubiquitous
destruction in both of these diseases. When you look at
very bad emphysema, patients who have a diffusion capacity
of 30% of predicted, all they basically have left on the
right side of the lung are two alveoli and on the left
side maybe 3.5. That is not so in the pulmonary hypertensive
disorders because, luckily, the rest of the parenchyma
is OK. The vascular obliterations, the sites where there
is no flow—and if you look at it longitudinally,
as you walk down the vascular tree—are still very
small. If this were all cast with glue and you had many
millimeters of these vessels that were occluded, I would
not be as hopeful as I am right now, When you do a three-dimensional
reconstruction of the vasculature, you appreciate how
localized that process is.
Dr Morrell: The same
is true in some animal models of this disease. Although
the vascular lesions are not the same as in PAH, such
studies have at least demonstrated the potential for advanced
obliterative vascular lesions to regress. This was elegantly
shown by Marlene Rabinovitch’s group a couple of
years ago, when they showed that inhibition of vascular
elastase could have a dramatic effect on established vascular
remodeling.
Dr Gaine: Would you
speculate on how you might achieve that fantasy, meaning,
would we be using drugs that might induce apoptosis in
the cells in that area? Would we be using genebased therapies?
Dr Rich: You’ve
asked whether people think there are really switches.
I think the answer is yes. If we believe there are switches
that turn the disease on, there should be the ability
to turn the disease off, at least in theory. I think it
is going to take understanding the molecular biology of
what goes on. Whether it comes down to inducing apoptosis
or to blocking a transporter or to inducing a growth factor
or a growth inhibitor, I don’t think we know yet.
But I think we will find our way to saying that if we
affect a certain fundamental biological process, the disease
will shut down.
Dr Morrell: The two
components of our approach to vascular obliteration as
described by Norbert should be to prevent further obliterative
lesions and to induce regression of those already established.
It may be that some so-called vasodilator
drugs will have some effect on the former, but we will
need a whole new approach to achieve the latter. The induction
of apoptosis in the obliterating lesions is an attractive
approach. We already know a lot about the mechanisms regulating
apoptosis in vascular cells, but the problem will be in
directing this process to the offending cells without
causing the whole lung to fall apart. Closer study of
the cells that make up these lesions may reveal pathways
that are restricted to these cells and could allow targeting
of therapy. For example, they may overexpress survival
factors or receptors, which are lacking on the neighboring
normal cells. Actually therapy in PAH is perhaps one example
where a gene therapy approach would not suffer from the
same limitations as in some other conditions. If the object
of therapy were to reduce the number of obliterative lesions,
then prolonged expression of genes delivered to the pulmonary
circulation would not be essential. Repeated short-duration
exposure to proapoptotic genes may be sufficient to cause
lesion regression and allow existing therapies to prevent
further lesion formation. The problem with gene therapy
for some other lung diseases, such as cystic fibrosis,
is that prolonged expression of the therapeutic gene is
needed.
Dr Voelkel: In vascular
biology we talk about an angiogenic switch. Stuart is
correct. If we can find out what the particular switch
is in our disease, we would be very much helped. Another
thing I can say is that we have worked the last three
years with an animal model of severe pulmonary hypertension
where the mean pulmonary artery pressure is somewhere
between 50 and 65 mm Hg. That is a lethal form of pulmonary
hypertension (Taraseviciene L, et al. FASEB J. 2001;15:427-
438), and we were able to reopen some of the previously
obliterated vessels by inducing apoptosis. So Stuart is
correct again. I think there are two points of the attack:
one is to identify the angiogenic switch and the other
is to make peace with the idea that the cells are there,
that they are not normal muscle and endothelial cells,
and that we need to find out how to remove them, probably
with the induction of apoptosis.
Dr Gaine: Two important
questions arise in terms of future directions and treatment.
One is the issue of placebo-controlled trials. First,
are we finished with placebo-controlled trials, or do
we have a small window left? Second, given the evidence
recently from Olivier Sitbon and the French group that
the number of people who are going to benefit from calcium
channel blocker therapy is significantly less than 10%,
are we going to see the day soon where the vasodilator
trial is considered irrelevant and not included in the
therapeutic algorithm?
Dr Rich: No, it is
not impossible to do it, it is just going to be a matter
of trial design. If your end point is measured over a
very short interval, let’s say two weeks, you could
probably justify putting most patients in a trial for
two weeks and randomize to placebo. If your end point
is a year, you have a whole different ethical issue in
terms of risk. Sean, it also depends on what the therapies
are designed to do and what kind of end point you choose,
but clearly we’ve shown that we can make people
feel better, walk farther, and live longer. And ethics
demand that you inform patients that participating in
a trial and being randomized to placebo will jeopardize
them with respect to such benefits. The other option is
to compare treatments, but that would mean superiority
or noninferiority trials requiring many patients. I don’t
think the pharmaceutical industry has enough interest
in this disease to invest what it would take to do that.
Dr Voelkel: I think
everybody agrees that we all do our job with trying not
to miss things that are particular to this and not to
the other patient. That’s why we have to take all
patients on a very individual basis. But I am a little
concerned about a practice I’m beginning to see.
It has to do with people who are not very experienced
with pulmonary hypertension patients giving them endothelin
receptor blockers. We used to have relatively few patients
come to us who were supposedly getting “good treatment.”
Now we are seeing patients coming to us after two months
or so of treatment with an endothelin receptor blocker,
and they are not doing well. I don’t know whether
this is going to spread around the country, with more
practitioners saying, because of effective advertisement,
well, there’s a drug that’s an oral agent,
it’s easy to use, we only have to check liver function
tests, and we can do that. Stuart, what do you think?
Dr Rich: Well, you
know, Norbert, this was expected to happen. The practice
of medicine in this country does not require you to have
certification to prescribe a certain medication. It is
so interesting how this disease therapy has evolved,
because the best therapy that we have is the first one
that we’ve ever tested, and that’s epoprostenol.
Our mission is to try to avoid using it. Now that we have
bosentan, physicians ask, “Do I need to refer this
patient? What’s the downside if we treat first?
Why can’t I treat first and diagnose later?”
There is nothing we can do to prevent that, so all I can
say is that it is almost a predicted consequence of the
approval of the oral agent that physicians with less expertise
are going to use it. It was kind of a honeymoon period,
if you will, when the therapy was so complex that it almost
mandated that only a specialist could use it. But the
honeymoon is over.
Dr Morrell: It’s
the same in the UK, with increasing use of oral drugs
outside the specialist centers, though this is being resisted.
We all know that patients with PAH are a complex and heterogeneous
group. This is often not appreciated outside the centers
and the problem is that patients may be deprived of timely
intervention with prostanoids, atrial septostomy, or transplantation
Dr Voelkel: I think
a consequence of what you developed is that we have a
bit of a responsibility to tell practicing physicians
that unfortunately it’s not going to be so easy,
that you can’t just pop the bosentan and hope for
the best.
Dr Rich: I lived
through the same thing with calcium blockers. We published
a paper showing there is a subset of patients who have
a really remarkable response. And what happened is that
calcium blockers became an automatic treatment for any
person with an elevated pulmonary pressure for any reason.
How many of those patients never made it to see us because
their referral was inappropriately delayed because of
the calcium blocker? How many were worsened and put into
right heart failure because of calcium blockers? This
has become a two-edged sword. I think you are going to
see the same thing with the endothelin receptor blockers,
and potentially with any oral agent, that is, physicians
who use it and don’t know how to monitor.
Dr Voelkel: All I
am saying, Stuart, is that what you have already started,
this detective work, is something we need to continue
to do. It is our responsibility to get that information
out. I wish you had published that calcium experience
paper.
Dr Gaine: Now is a
good time to consider publication of those data because
they teach us how starting with a particular therapy for
defined indications can quickly get lost when translated
to the wider physician pool.
Dr Voelkel: The categorical
problem remains, Sean, that from our point of view, if
you want the dissenter’s view, we continue to face
the problem of what we would call delay of maximal treatment.
The diagnosis is delayed at the start because of asthma
as the principal first misdiagnosis. Then the diagnosis
is made because somebody finally orders an echocardiogram.
We now will have an additional phase where some of the
patients will become severely ill because of treatment
that, perhaps, is not optimal.
Dr Gaine: In the
time remaining we will explore basic science and I will
start with you, Norbert. You and your colleagues had a
fascinating paper recently concerning risk factors for
pulmonary hypertension (Cool CD, et al. N Engl J Med.
2003 Sep 18;349:1107-1109). Are there going to be more
viruses?
Dr Voelkel: Retrospectively
it is always easier to make statements, and hindsight
is always 20/20. From where we stand now we could have
learned a little more about some of these things in primary
pulmonary hypertension if we had thought through the human
immunodeficiency virus story. What it means for me now
is that what HIV infection and herpes virus infection
have in common is some degree of immune insufficiency.
This is something to hold on to. If you have, let’s
say a 60% rate (and this has to be confirmed by other
groups) of infection with herpes virus in patients with
primary pulmonary hypertension, then many, many questions
follow. One that you raised concerns the other ones, where
we have not identified the HHV-8 strain, those caused
by other virus infections. Indeed, we take the position
that we have to search further for other viral agents
and we have ideas about that. The second one is, what
is it about the immune system? Stuart is one of the early
people who published that 30% of patients with PPH, that
we honestly call PPH, have a positive LANA. So, that spectrum
of the immune response, one moving toward an autoimmune
process, and perhaps as importantly, showing us a face
of immune insufficiency, is getting very important. Take
the data from the French group, from Marc Humbert, who
published data about elevated plasma cytokine levels.
Well, that goes with a viral infection pattern. Work has
to go on in this direction for it to have consequences
for diagnosis because we may have blood tests of some
kind that will help us identify the virally infected patients.
Dr Morrell: The viral
hypothesis is an attractive one, though to be a devil’s
advocate, it’s one that’s raised its head
in many other chronic inflammatory and autoimmune diseases
over the years. However, the lungs are uniquely exposed
to airborne viruses and the exclusive susceptibility of
the lung circulation to the obliterative process in PAH
makes viral exposure a compelling hypothesis in this setting.
The observations on HHV-8 are an intriguing breakthrough
that urgently need confirmation by other groups and studies
of potential mechanisms. Of course, the other major recent
breakthrough is the identification of mutations in the
bone morphogenetic protein type II receptor (BMPR2), which
underlie at least 55% of cases of familial primary pulmonary
hypertension. Having a mutation in BMPR2 is the biggest
risk factor for PAH yet identified, by orders of magnitude.
This vital piece of genetic evidence provides a solid
basis from which to begin to unpick the molecular pathogenesis
of PAH. Clearly other factors are also involved, which
may include viral infection. Several groups are working
on precisely how these mutations contribute to the development
of obliterative lesions in PAH. Personally, I believe
this approach will yield novel therapeutic options within
a relatively short period.
Dr Gaine: Stuart,
what are your thoughts on risk factors and future directions?
Dr Rich: Well, Norbert
is really the molecular biologist and I am more the epidemiologist,
so let me wear that hat for a second. PPH has so many
variations. Probably a number of different molecular pathways
can be involved, and you may need a certain critical number
to come down with it clinically. That may be why some
patients are vasoreactive and some are not, and some have
a good response to this drug and some do not. The work
Norbert has done, and the work that supports this, is
absolutely on the money. There probably are some patients
who through some abnormal immune modulation have further
disease expression, but there are probably others who
don’t, who have different things, such as patients
in the fen-phen group, who may have had the drug turn
on a certain switch. So I think a generation from now
they’ll look back and see that we were at an embryonic
stage here, that PPH is really the final consequence of
abnormalities in several pathways that lead to it. Looking
at this from a broader perspective leads me to believe
all of this work is going to be important, but there is
not going to be a single answer to this disease, there
are going to be a lot of answers.
Dr Voelkel: The basic
epidemiology, Stuart, will remain, that for any identified
or identifiable risk factor, the denominator is always
very, very large. So if 17 million Americans took fen-phen
and you end up with a few thousand (even if we don’t
know all of the patients who will still develop the disease),
the denominator of those who were potentially at risk
is huge. The same of course has been true for the AIDS
association, and I assume it will be exactly the same
for the KS virus association. If you look at the blood
donor pool in America, I think the numbers are about 3%
or so of US blood donors, you can show there is evidence
for herpes virus 8 infection. If you go closer to the
Mediterranean, it goes up to about 20%. But that doesn’t
mean the incidence of primary pulmonary hypertension necessarily
goes up with it. I don’t think we have the understanding
that just because you move closer to the Mediterranean
Sea the numbers of patients with primary pulmonary hypertension
are much higher. I don’t think they are.
Dr Rich: No. I think
we agree there, Norbert. What I am getting at is that
all of these new risk factors and the roles they may play
are starting to be uncovered and described, that we shouldn’t
think there is going to be a single answer here, and that
it is going to require several defects within the whole
vascular control milieu, if you will, in order to contract
this disease.
Dr Voelkel: I agree.
You have to have some kind of a basic genetic disposition,
which we don’t understand at this moment. And there
are multiple trigger factors that, alone or in combination,
in a susceptible person trigger the disease. But my take
is that the common denominator at the end is the angioproliferative
process, and that there are many ways you can get there.
Dr Rich: It is fascinating
to go back to old news of the histology, from all of those
papers published decades ago. A lot of people who died
with PPH had just medial hypertrophy, but others had advanced
concentric laminar intimal fibrosis and plexiform lesions
everywhere. I can’t believe the molecular process
is the same in both instances.
Dr Voelkel: But Stuart,
I think a lot of the old literature is contaminated by
not shining the correct searchlight on the tissue. People
did not stain for angioproliferative processes. Most of
the old pathologists looked to find a plexiform lesion,
and if you don’t look in multiple sections, in particular
in the subpleural regions, you sometimes miss them. So
I would not be too confident in some of the old literature.
I think we are getting better, and we are looking harder,
and we are finding more.
Dr Gaine: Are there
things maybe we haven’t touched on that you think
we should?
Dr Rich: Yes. This
is a disease of right heart failure. One thing that’s
intrigued me and that I don’t think we have focused
enough on, is the fact that there are patients, congenital
heart disease patients, who have severe pulmonary hypertension
and
minimal limitation with respect to their physical activities
because of the tremendous ability of their right ventricles
to hypertrophy and adapt to the pressure load. I attribute
that to the expression of fetal genes and it is apparent
if the insult occurs when you are a baby as opposed to
when you are an adult. A lot could also be achieved by
looking not just at the pulmonary vasculature, but at
the ventricle itself and asking how we can program these
hearts to better adapt to the pressure load. We may never
be able to relieve the pressure load, but if we can get
the ventricle to adapt to the pressure load, the patients
might live almost normally. So an area of potential gain
that hasn’t really been touched on is genetic control
over myocardial performance and trying to get the ventricle
to better adapt.
Dr Gaine: If only
we could teach right heart myocytes to believe they are
actually left heart myocytes, or switch on the left heart
differentiating genes, then the heart would last a lot
longer despite the pressures.
Dr Rich: In utero
they are the same. Some genes are turned off when the
baby is born. We need to switch those genes back on.
Dr Voelkel: No question
about that. People die of right heart failure. That’s
very important, and perhaps a future conference should
have a very sharp focus on that particular issue of the
right ventricle.
Dr Gaine: Cardiologists,
when looking at coronary artery heart disease and left
heart failure, are years ahead in terms of drugs and procedures
compared with their colleagues in the field of right heart
failure and pulmonary vascular disease. In this
regard, are there any drugs or tools that are beneficial
in left heart disease that might translate into future
directions in the treatment of the right heart? I’m
thinking in terms of surgical procedures that might help
the right heart, mechanical assist devices, or electrical
pacing, etc.
Dr Voelkel: I wouldn’t
think of electrical mechanical devices. I think the strategies
will, at the end of the day, have to be molecular strategies,
where you do what Stuart suggested. You have to basically
generate an Eisenmenger right ventricle and that would
be the concept to follow. If we could do that with molecular
tools and get good quality, strong, robust right ventricular
muscle, we would be saving a lot of people.
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