Thursday, October 10, 2002

Genetic link found for heart failures

UC trio's findings featured in prestigious medical journal

By Tim Bonfield
The Cincinnati Enquirer

In one of the biggest scientific developments to come out of the University of Cincinnati in several years, researchers report finding two genetic links to a common form of heart failure that may help explain why the disease runs high among African-Americans.

[photo] Dr. Stephen Liggett (center) led a team including Dr. Kersten Small (left) and Dr. Lynne Wagoner.
(Craig Ruttle photos)
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The findings were considered significant enough to be published as the lead article in today's edition of the New England Journal of Medicine, one of the world's most influential and widely read medical journals.

The study reports that African-Americans who have a combination of two defective protein receptors, caused by small genetic variations called polymorphisms, face a tenfold increase in their risk of developing congestive heart failure.

Essentially, the defect combination causes the heart to beat too hard for its entire life, which in turn causes it to wear out prematurely. About 5 percent of all African-Americans may have this genetic problem.

The study involved genetic testing of 348 Greater Cincinnati residents in 1999 and 2001, 159 of whom had heart failure and 189 of whom did not. The study was conducted by Drs. Kersten Small, Lynne Wagoner and Stephen Liggett, members of UC's departments of cardiology and molecular genetics, along with statistical analysis provided by two researchers from the University of Michigan.

Their findings are important for several reasons.

Heart failure, a chronic weakening of the heart's pumping ability, is a major health problem that the medical world has struggled to treat effectively.

More than 400,000 Americans a year are diagnosed with heart failure. And about 50 percent of those who are diagnosed die within five years.

Experts have known for years that African-Americans have been more likely than Caucasians to develop heart failure. But this is the first study to pin down a possible genetic explanation, Dr. Liggett said.

In the study, the UC researchers reported that two types of genetic variations are linked to heart failure, particularly in African-Americans.

First, a defective version of the Alpha 2C receptor protein fails to control nerve cells in heart tissue from releasing too much norepinephrine, a substance that helps trigger heart contractions. Then, a defective version of a Beta 1 receptor makes heart muscle cells hypersensitive to norepinephrine.

Acting in concert, the defective proteins cause a bigger risk of disease than either could cause alone, Dr. Liggett said.

The study found that the combined problem occurred in 18 percent of black patients with heart failure, but only 6 percent of white patients with heart failure. The study lacked enough participants to report any significant findings about other racial groups, such as Hispanics or Asians.

If the findings can be duplicated in larger-scale studies, the results have far-reaching implications.

There could be an increased push for genetic testing of African-Americans and others who may be at risk for heart failure. Those affected by the genetic variations could be urged to get more aggressive diagnostic testing to spot early signs of heart failure. Some high-risk people also could start taking medications to control heart failure even before showing clear symptoms of the disease.

“It is still too early to say exactly how these findings could change treatment for heart disease,” Dr. Liggett said. “But we already know that this kind of genetic testing can be done for less than $10 per test. As people learn they have both of these polymorphisms, at a minimum, they should reduce all the other environmental risk factors for heart disease, such as smoking, obesity, high blood pressure and high cholesterol.”

Leland Ramey
Leland Ramey, a 54-year-old Glendale resident and father of five, was among the African-Americans with heart failure who volunteered to provide blood samples for the study. Because of the way the study was designed, researchers do not know if Mr. Ramey's blood was actually used in the study.

Mr. Ramey was diagnosed with heart failure at age 47, after struggling with swollen feet and chronic fatigue for months. Testing later revealed that his heart was pumping at less than 20 percent of normal capacity.

As a former chemist, disabled since 1998 by his illness, Mr. Ramey said he sees logic in the idea of genetic links to heart failure.

He has never felt fully satisfied by other explanations for why African-Americans suffer high rates of heart failure, such as higher rates of people with unhealthy eating habits, diabetes, obesity and high blood pressure. And he was never sure how much weight to give to other personal factors.

“I've always known that just being African-American I was at risk, but none of that is as sophisticated as knowing that a genetic factor could be involved,” he said.

UC experts predict that the heart failure study could accelerate the fledgling concept of customized medicine by suggesting new targets for developing better medications or better uses for older medications.

Someday, Dr. Liggett said, doctors will be able to use genetic testing for a wide range of diseases to tailor care for individuals, allowing them to pick which medications offer the best chance of working while avoiding harmful side effects.

More study needed

Before then, however, the findings may cause experts to rethink how they classify people with heart failure.

“Heart failure actually is the end result of a number of different conditions, from coronary artery disease to mitral valve defects,” said Dr. Wagoner. “Unfortunately, we treat all of the patients with heart failure in the same basic way. This kind of research eventually will allow us to say Drug A is better for this group of people and Drug B is better for this group of people, rather than starting everybody on Drug A.”

An editorial about the research, also published in the Oct. 10 edition, took a cautious view of the report.

“These provocative data raise the possibility that relatively common gene variants may identify persons who are at increased risk for congestive heart failure,” wrote Drs. Roger Hajjar and Calum MacRae of Massachusetts General Hospital in Boston. “Given the available data, the effects of the polymorphisms are biologically plausible.”

However, these doctors wrote that more work should be done to duplicate the study results before considering the report conclusive. Other studies have found multiple receptors and signals at the molecular level that appear to be involved with heart failure but may not have been fully considered by UC's study.

“Studies in much larger populations of black patients with congestive heart failure will be required,” they wrote.

A boost for biotech

“Dr. Donald Harrison, senior vice president and provost of health affairs at the UC Medical Center, said the research was important.

“This is the biggest finding in several years to come out of UC that shows the clinical application of all the gene-based work that has been going on here.”

This is exactly the kind of work that UC brass hoped to see as they continue work on the UC Millennium Plan to recruit more researchers, develop new treatments and expand biotech as an engine of economic development.

For people like Mr. Ramey, it remains far too early to predict whether the UC study will change their treatment or improve their odds of living longer with heart failure. But that's not why Mr. Ramey got involved.

“I realize these findings are preliminary and probably won't do too much in my lifetime. But I am concerned about my kids,” he said. “I think they probably should be tested someday. Maybe something can be done for them.”


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