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NIH Conference Charts Future
Directions in Identifying Patients at Risk for Primary
Pulmonary Hypertension
This report is based on information presented at
a conference sponsored by the National Institutes of Health
(NIH) earlier this year to identify trends in diagnosis
and management of the disease.
As diagnostic and treatment approaches to pulmonary hypertension
evolve over the next few years, clinicians may look back
at an NIH conference held earlier this year as a watershed,
a meeting where many of the new directions in care were
charted.
The meeting, Translational Research in Primary
Pulmonary Hypertension, was sponsored by
the National Heart, Lung and Blood Institute and brought
together leading experts to explore ways in which basic
research may translate into clinical trials and related
investigative work. Organized by Dorothy B. Gail, PhD,
Director of Lung Biology and Disease in the Division of
Lung Diseases at the NIH, the meeting provided a venue
for reviewing new data and concepts, including recent
findings in genetics and molecular medicine, as investigators
discussed results from studies in transgenic mice and
data about modulators for angiogenesis. One of the goals
of the meeting was to provide the NIH with information
on the kinds of research it may want to encourage, according
to John H. Newman, MD, Professor of Medicine, Pulmonary
Critical Care Division, Vanderbilt University School of
Medicine, Nashville, Tennessee. The talks ranged across
a broad spectrum of topics but generally relate to implications
for the pathogenesis and treatment of primary pulmonary
hypertension.
One of the areas covered involved potassium and calcium
channel function, as delineated by Steven L. Archer, MD.
“Information from various studies suggests that an alteration
in channel function may be involved with determining whether
potassium or calcium can enter or exit cells and whether
they will contract. This issue is especially important
for smooth muscle cells in the vascular bed, because if
they contract, they cause vasoconstriction and raise pulmonary
vascular resistance, and can exacerbate pulmonary hypertension,”
said Dr Newman.
The second group of talks was concerned with signal transduction,
which is related to the manner in which circulating molecules
activate cells. Serotonin was a chief consideration in
this discussion, because it is a mediator that enters
cells through a transporter, and once in cells, it activates
certain pathways that may lead to new growth of vascular
cells and production of collagen. This process may promote
occlusion of vessels as seen in pulmonary hypertension.
This is important because it is known that blood vessels
in the lung become occluded through a process in which
fibrosis results in blockage of the central channel.
One of the exciting areas covered at the conference included
work being done on transgenic models of pulmonary hypertension.
Mutations in the BMPR-2 gene are a hereditary cause primary
familial hypertension. William C. Nichols, PhD, and David
Rodman, MD, have used transgenic mice with this gene altered
so that we have an animal model that can mimic situations
of primary pulmonary hypertension. They presented information
on these models and what directions research will take
with these animal models. “The hope is that over the next
couple of years we will be able to further characterize
animal models of pulmonary hypertension, which will lead
to a better understanding of how to treat the disease.
Currently the transgenic model is still too early in development
to have produced any striking leads, but our expectations
are high,” said Dr Newman.
The discussion of genetic factors involved in pulmonary
hypertension continued with presentations on genetic modifiers
by Jane Morse, MD, and James A. Knowles, MD, PhD, who
focused on the concept of genetic susceptibility to primary
pulmonary hypertension. “We know from patients who are
in families where the disease is highly prevalent that
there is a mutation in a receptor, called BMPR-2,” said
Dr Newman. “Even if a person has a mutation, there is
only about a 20% risk of getting the disease in his or
her lifetime, so there must be other factors that increase
the risk—either other mutations or just other genetic
characteristics. For virtually every characteristic there
are multiple genetic modifications, sometimes called polymorphisms.
Nationally and internationally, the effort to identify
the genetic makeup that may predispose to pulmonary hypertension
is growing stronger. It will turn into a big project over
the next 5 to 10 years as we examine the genome to determine
the kinds of differences that leave some patients at greater
risk. For example, why did some people who took fenphen
develop pulmonary hypertension? What are the underlying
susceptibilities to that?”
Looking ahead to the most promising therapeutic strategies,
presenters examined the relative merits of different approaches,
particularly combinations of agents. “Everyone has been
very excited about the advent of endothelin blockers and
sildenafil,” noted Dr Newman. “Now the question is, what
kind of combinations should we use? Should we start oral
drugs first and not use prostacyclin drugs until the oral
therapy fails? Or will patients fare better if they undergo
treatment with multiple drugs, such as we discovered with
cancer therapy? In animal models, statins look very promising
and they deserve clinical study because it is clear that
they are useful in other vascular diseases. Sildenafil
is also very exciting. In terms of feasible new approaches,
the statins seem to be promising, but we are 2 to 3 years
away from having specific drugs that may target other
mechanisms such as serotonin or the mechanisms involving
TGF-beta and potassium channels. These approaches are
not quite ready but in the next 3 to 5 years we should
have other new drugs with potential benefit.”
Where does that leave prostacyclin, still considered
the cornerstone of therapy? “Prostacylin remains the gold
standard and is the agent we would all like to see another
drug supercede. The goal is to get people off of prostacyclin
as primary therapy, both for cost and for safety reasons.
That’s where we want to be headed.”
One of the ultimate goals is to initiate treatment in
patients predisposed to pulmonary hypertension as early
as possible. “Familial pulmonary hypertension affords
a unique opportunity to identify people who have a mutation
and who could be candidates for preventive therapy,” added
Dr Newman. The problem in managing the “sporadic” patients
is that preventive treatment cannot be used. This is because
disease is already advanced when the diagnosis is made.
This is why the identification of patients at risk for
familial disease is so exciting. “The cases that we may
be able to prevent are those persons who have a mutation
but don’t have any disease. They are clinically completely
normal. If the statins seem to work, we could potentially
design a study that might involve administering statins,
plus several other drugs, to patients who have the mutation
but are clinically normal to determine whether we could
prevent pulmonary hypertension from developing.”
Despite the promise of genetic testing suggested by the
NIH conference, Dr Newman said it remains a long way from
being routinely applied in clinical practice. “The problem
is that in the general population, primary pulmonary hypertension
is too rare to test the whole population. The cost is
prohibitive. It would not be cost-effective if only one
person in a million gets the disease. Genetic testing
will be done in families where we know that mutations
exist and potentially in patients who already have the
disease but are the only affected person in a family.
The current problem is that the gene is so large, with
so many mutation sites, that no laboratory has been able
to develop a feasible test. What will emerge from genetic
testing and preventive therapy is a clearer understanding
of what causes primary pulmonary hypertension and where
we can successfully direct therapy. This will be a wonderful
development."
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