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 As
early as his residency, colleagues of Alfred P. Fishman,
MD, recognized the first flashes of brilliance pointing
toward a career that has taken him to the pinnacle of
research in pulmonary hypertension. Soon after his residency,
he introduced the artificial kidney in the United States
and began investiga-tive work in laboratories headed by
physicians who won the Nobel Prize for their groundbreaking
research. In a long and distinguished career, Dr Fishman
is still recognized as one of the preeminent scholars
in his field, the pioneer who organized the National Registry
on Pulmonary Hypertension and the recent recipient of
the Trudeau Award, the highest accolade given by the American
Thoracic Society. Dr Fishman received the award from Claude
Lenfant, MD, Director of the National Heart, Lung, and
Blood Institute.
After publishing a paper on the artificial kidney and
seeing his research lead to the widespread use of dialysis,
Dr Fishman was supported by the Ameri-can Heart Association,
which helped him in his studies at Harvard University,
New York University, the University of Chicago, and Oxford
University. He currently serves as William Maul Measey
Professor of Medicine Emeritus at the University of Pennsylvania,
Philadelphia. Throughout his career, his work has focused
on the heart and kidneys and the interplay of these organs
with the lungs. He found that the most intriguing aspect
of this interplay—and one that raised implications
for therapy in humans—could be found in the African
lungfish and its ability to achieve a state of suspended
animation for several years without the need of food or
water. “
We wanted to know whether you could take patients who
were on a downhill course —as in pulmonary hypertension—
and slow their metabolism down and bring them to a state
of suspended animation, like the lungfish, until you could
bring therapies to bear on them,” said Dr Fishman.
“We wanted to study the control, and the pulmonary
circulation in very primi-tive animals because we might
get some clues regarding their nerve supply, their hormones
or other factors at work. All the way through, my research
has been oriented to how we might learn lessons from comparative
physiology and pathology. “
Based on the animal models, the most important issue
was whether there was a way to drop the metabolism so
that we would not be in as much of a hurry or as desperate
when we got a patient with pulmonary hypertension. When
we began working with patients with pulmonary hypertension,
the patients had a lifespan of a year. But we could see
only one or two patients a year.”
The big break came when the National Registry was established
and Dr Fishman gained access to more pulmonary hypertension
patients. By the time the registry was closed, 300 patients
had been enrolled. “We were able to see which drugs
work, and suddenly we had 18 centers working together;
but most importantly, we created a pathology center at
the University of Pennsylvania, so that all the data from
autopsy or biopsy are analyzed by one pathologist. Right
now every-body
is concerned about remodeling—but you couldn’t
think about that without the pathology. “
We need to explore the mechanisms by which one develops
occlusion of the vessel,” added Dr Fishman. “They
close because the linings proliferate. There are certain
stages when the vessel is so scarred that you can’t
reverse it. But there are many proliferative lesions that
might be stopped or reversed. One thing seems to be true—if
you can drop the pressure and keep it down, the vessels
start to reverse their proliferative changes. A key question
is whether the antiproliferation is working because you
are relieving vasoconstriction or are you starting another
process which undoes the proliferation? So remodeling
in the pulmonary circulation must be examined. It is not
easy to do and we will have to go primarily to animal
models, although there are a few human cases that have
been studied, who came to autopsy. Apparently you can
reverse many of these changes, but the secret of how you
do it, other than by dropping the pressure, is not known.”
Dr Fishman urged physicians to suspect pulmonary hypertension
at an earlier stage. One of the problems is that the disease
does not manifest itself clearly except by fatigue, shortness
of breath, and a sense of deconditioning that may appear
in someone 20, 30, or 40 years of age. If he were to suggest
how training programs for physicians might be improved,
he suggested that programs include molecular biol-ogy,
genetics, and developmental biology “because until
we understand growth and development we can’t understand
why blood vessels close. You need to go back to the fundamental
process that you see during developmental biology. Why
does a lung become a lung? Why does the lining stay flat?
There must be susceptibility genes. That’s why the
studies on famil ial pulmonary hypertension are so important.
The period of training could be a very rewarding one because
timing is absolutely right for developmental biology,
molecular cell biology, and genetics. Without that, you
cannot approach pulmonary hypertension in the future.”
PH
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