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."
Materials provided by Duke University Medical Center. Note: Content may be edited for style and length.
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