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SAN FRANCISCO -- It was the tragic, sudden death of Olympic
skater Sergei Grinkov that triggered Pascal Goldschmidt' s
quest to solve the intricate genetic puzzle of heart
disease.

The Russian Grinkov and his wife, Ekaterina Gordeeva, had
won two Olympic gold medals, four world championships and three
European championships. Parents of a beautiful 4-year-old
daughter, Daria, the couple exuded health and vitality.

But on Nov. 20, 1995, at the age of 28, Grinkov died
suddenly of a massive heart attack, collapsing while in the
middle of a practice session.

For cardiologist Dr. Pascal Goldschmidt, now chief of
cardiology at Duke University Medical Center, this unexpected
death didn't seem to make sense, at least on the surface.
Grinkov's father died at the age of 52 of a heart attack, and
like his son had none of the risk factors associated with heart
disease. Yet on autopsy, he was found to have severe coronary
artery disease.

"Sergei had none of the risks we associate with heart
disease, such as smoking, diabetes, old age, being sedentary,
high blood pressure or elevated cholesterol levels,"
Goldschmidt said. "There had to be something else going
on."

While at Johns Hopkins University, Goldschmidt tested a
sample of Grinkov's blood and found that he had a variation of
the P1A2 gene -- carried by about 20 percent of the population
-- which seems to predispose people to early heart disease. The
normal gene is involved in platelet formation, and it appears
that those people with this specific variant possess platelets
that clump together too easily.

"While environmental factors are important in the
development of heart disease, they aren't the only factors,"
Goldschmidt continued. "There is a multitude of different gene
variants that might come into play in combination with
different environmental factors to produce heart disease. It is
a very complex process."

To help unravel the complicated and subtle interplay of
genes and the environment, Goldschmidt is leading a team of
Duke cardiologists, geneticists and statisticians in a unique
effort to better understand the genetic underpinnings of
atherosclerosis. They are drawing on more than 30 years of
clinical data collected by Duke cardiologists on all the heart
patients seen at Duke, giving researchers an unprecedented
trove of information about the progression of the disease and
how patients respond to different treatments.

The researchers are now adding a genetics component to this
rich data resource, performing genetic analyses on samples
taken from the patients. For example, since early this year,
they have collected more than 700 blood samples of patients
undergoing angioplasty at Duke. As the project accumulates
data, Goldschmidt and his team hope to be able to determine
which patients will do better with certain drugs.

"We currently send these patients home taking five different
drugs," Goldschmidt said. "However, for any given individual,
we don't know which drugs, or combination of drugs, are helping
the patient. Ultimately, we want to be able to conduct a
genetic test and then be able to rationally determine which
drugs that individual should be taking to prevent future heart
attacks."

To better prevent and treat atherosclerosis, Goldschmidt
believes that researchers must first better understand the
natural progression of the disease. To that end, they have
embarked on an ambitious and unique project to analyze tissues
from atherosclerotic patients.

"In collaboration with our heart surgeons, we are collecting
and analyzing aortas from heart transplant donors," he
explained. The aorta -- the main artery that carries
oxygen-rich blood from the heart to the rest of the body -- is
one of the main sites of the artherosclerotic process. "When
the surgeons retrieve the heart from transplant, they remove
the aorta as well and send it quickly to our laboratory."

Since the project began earlier this year, the researchers
have conducted detailed genetic analysis of more than 55 of
these "fresh" aortas. To date, they are tracking the
"expression, " or activity, of 83 different genes that appear
to provide resistance or susceptibility to atherosclerosis.

As the collection of analyzed aortic tissue grows,
researchers will have complete aortas that span the entire
spectrum of vessel health ? ranging from aortas that are
completely disease-free to those riddled with artery-clogging
fatty plaques, and every stage of the disease in between.

"There are many genes involved, some that seem to protect
individuals from atherosclerosis and some that seem to
predispose them to the disease," Goldschmidt said. "Once we get
a handle on the natural progression of the disease ? which
genes are turned on or off and when ? we can better know when
and where to intervene."

"Without a strong and talented team that offers a unique
richness of expertise, talent and dedication that cuts across
many specialties and disciplines at Duke, this ambitious effort
could not be successful," Goldschmidt said.

"Such genomic studies are not likely to help the individual
patients being studied, but they will certainly offer
life-giving treatments for generations to come," he said. "For
example, while a better understanding of the genetics of
atherosclerosis unfortunately can't help Sergei, hopefully
we'll be able to help people like Daria."