Heart defense is in the genes

The Baltimore Sun

A genetic variation common in African-Americans naturally protects heart failure patients as effectively as popular heart medications, researchers reported today.

Scientists at the University of Maryland and other institutions tracked more than 300 heart failure patients for up to eight years and found that variations of a particular gene extended the lives of many of them for several years - just as if they were on beta blockers.

Researchers found the variation in 40 percent of blacks but only 2 percent of Caucasians. The finding could help explain why beta blockers seem to provide less benefit to African-Americans than other groups: Many of them already have nature working for them.

"It's a genetic mechanism that mimics the effects of the drugs," said Dr. Stephen Liggett, a co-author of the study and a professor of medicine and physiology at the University of Maryland School of Medicine.

The study, published today in the journal Nature Medicine, could eventually lead to genetic testing for heart failure patients, with the goal of tailoring therapies based on the results, experts say.

"This is cool stuff," Dr. David Kass, an expert on beta blockers at the Johns Hopkins School of Medicine, said of the report. "I've never seen anything like that."

The study showed how beta blockers affect long-term survival rates among heart failure patients with different genetic markers - adding to a growing body of evidence focused on the role genes play in how we respond to drugs.

"We're just at a point of understanding the genetics that put us at increased risk of common diseases and the differences in how we respond to a lot of the medications we use for them," said Dr. Maren T. Scheuner, a researcher at the Rand Corp. and the UCLA Center for Health Policy Research.

Black people suffer disproportionately from heart problems, scientists say. They have higher rates of hypertension and Type 2 diabetes and nearly twice the risk of developing heart failure as Caucasians. They're also at greater risk for high blood pressure, which can damage the heart if left untreated.

An estimated 750,000 African-Americans have been diagnosed with heart failure, and the number is expected to increase to 900,000 by 2010, according to the federal Centers for Disease Control and Prevention.

The genetic underpinnings of response to heart failure medication is worth studying, Liggett said, because the illness is so insidious.

Heart failure affects more then 5 million Americans and usually develops when the heart is unable to pump enough blood to the body. As the heart tries to compensate by pumping faster, it usually grows larger and becomes less effective.

A heart attack, high blood pressure, abnormal heart valves and diabetes predispose someone to heart failure. But symptoms are often missed until the person begins to feel fatigued and has trouble breathing. By then, it is often too late, said Liggett.

One in five chronic heart failure patients is dead within a year of diagnosis. More than half of those diagnosed die within five years, and only one in four survives for 10 years.

When someone experiences heart failure, adrenalin binds to the heart cell's beta-adrenergic receptors and stimulates the heart to work harder.

Beta blockers are among the most commonly prescribed medications for heart failure. In many patients, they relieve the heart by blocking the response from the receptors. The two most commonly prescribed beta blockers are carvedilol and metoprolol, commonly sold under the trade names Coreg and Toprol, respectively.

"It's really protecting the heart from chronic overstimulation," Kass said.

But the effectiveness of beta blockers varies from one patient to the next. It can take as long as a year to determine if they're working, and side effects include dizziness, fatigue, fluid retention and erectile dysfunction, Liggett said.

"You could say that up to 50 percent of the patients on beta blockers have less than an optimal response," he said.

The study does not resolve why beta blockers work better in some people than others. But the results may lead to screening tests that narrow down which patients are right for beta blockers.

"We'll be able to say, 'Here's a group we could screen for,' and if you believe in it strongly enough, you could say you don't need to go on them," Kass said.

There are probably several other genetic variations that work this way, Liggett said, and he continues to search for them.

In their study, Liggett and a team of researchers compiled genetic profiles of 2,000 black and white volunteers in Cincinnati, Kansas City and Atlanta. Some volunteers had heart failure, while others were healthy.

The profiles showed a variation in GRK5, a gene known to curb receptor activity in heart failure patients. Most people had genes that produced a protein called glutamine in cells throughout their bodies, including heart cells. Some had another protein called leucine.

The researchers created genetically altered mice and found those with leucine seemed to have a kind of natural beta blocker that reduced the impact of the adrenaline rush that normally prompts a stressed heart to work harder.

The researchers then tracked 375 black heart failure patients, some of whom were being treated with beta blockers by their physicians.

Among those with glutamine, the beta blockers were beneficial: At the end of an observation period that ran as long as eight years, 50 percent of those taking beta blockers were still alive, while only 20 percent of those not on beta blockers had survived, Liggett said.

But volunteers with leucine had the same 50 percent survival rates whether they took a beta blocker or not.

The study, funded by the National Heart, Lung, and Blood Institute, was conducted with help from researchers at the Washington University School of Medicine, the University of Cincinnati College of Medicine and the University of Michigan.

Liggett, director of Maryland's cardiopulmonary genomics program, hopes genetic tests will soon be available to help doctors determine which patients should take beta blockers. He eventually wants to develop a kind of scorecard, made up of genetic test results, that doctors could use when deciding whether beta blockers and other medications are appropriate.

"Our goal here is not to take away the physicians' judgment, but to give them some handles to work with, to know when to use a specific drug," he said.


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