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Gene Variations Tied to Heart Failure in Blacks

Wayward pair raises risk tenfold, study says

THURSDAY, Oct. 10, 2002 (HealthDayNews) -- Variations in two genes dramatically raise the risk of heart failure in blacks, and probably in whites as well, by making the pump beat overzealously for decades, new research shows.

Both of the genes and their corresponding proteins, called adrenergic receptors, help heart muscle respond to a key stimulatory hormone. Blacks who inherit two abnormal copies of one of the genes have more than a fivefold increased risk of developing heart failure, one of the country's leading killers. Those with two abnormal versions of the pair face 10 times the risk of the deadly condition as people with the usual copies.

About 5 percent of blacks, and perhaps a tenth as many whites, have this worst-case combination, says Dr. Stephen Liggett, a heart failure expert at the University of Cincinnati and a researcher on the study. The abnormal genes could account for up to 25 percent of heart failure cases in this country, Liggett says. "You've got a double bad thing going on. You're genetically programmed to force the heart to beat hard and vigorously for decades."

Knowing a person with heart failure has the abnormal genes could help doctors better treat their condition. While drugs exist to relieve stress on the heart -- including those such as beta-blockers, which act on the same system the two genes belong to -- many people respond poorly to therapy.

"The wide range of variability in response to heart failure medication is likely due to variation in the genes the medications target," Liggett says. "Once you have heart failure, these tests can be of value because [the genes] are modifying the disease and they can be used to tailor therapy."

The discovery may also help explain why blacks suffer more death and complications from heart failure than do whites, and why they respond worse to treatments for the malady. However, Liggett notes the genetic causes, if they exist, of 75 percent of heart failure remain undiscovered. And heart failure has a substantial environmental component, too, compounded by conditions such as diabetes, high blood pressure, vessel disease and unhealthful behaviors such as smoking.

Liggett and his colleagues report their findings in today's issue of The New England Journal of Medicine.

Almost 5 million Americans suffer from heart failure and 200,000 a year die from the illness, which involves a fluid buildup in the lungs that forces patients to strain for breath. Fluid can also pool in the legs. Heart failure can lead to liver congestion, abnormal heart rhythms and, ultimately, death.

Animals studies have shown the heart can fail when made to work hard for prolonged periods of time. So Liggett's group speculated that gene anomalies that stress the pump would lead to the same problem.

They were particularly interested in two genes. One, called alpha-2 adrenergic receptor, signals the body to stop sending norepinephrine, a hormone that spurs the heart to beat more vigorously. The other, beta-1 adrenergic receptor, feeds the hormone to heart muscle.

When the alpha-2 receptors don't perform, the heart is bathed in too much norepinephrine, forcing it to pump too hard. And when the beta-1 receptors do their job too well, the same happens.

In the new study, the researchers looked for variations in these two genes in 159 men and women with heart failure and 189 people without the condition.

Blacks who inherited two bad copies of the alpha-2 receptor had between five and six times the risk of heart failure as those with two normal versions of the gene. Those with normal alpha-2 but abnormal beta-1 genes were at no increased risk. But blacks with two variants of each gene had 10 times the odds of developing heart failure as those with four normal copies.

The study included too few whites with two abnormal copies of the alpha-2 gene to establish how much, if at all, it raised their risk of heart failure. However, Liggett says the same trends seemed to exist for both racial groups and larger studies should settle the question.

He and his colleagues are now looking at whether heart failure patients with the gene variants have a poorer prognosis than patients with the usual copies. The study did show that people with faulty alpha-2 had nearly four times the risk of developing heart failure by the time they were 40. They also were much more likely to have weakened pumping power than were those with two normal copies of the gene.

Liggett says screening people for the two genes costs about $10 but would become even cheaper as the test becomes more common.

Dr. Roger Hajjar, a cardiologist at Massachusetts General Hospital and co-author of an editorial accompanying the journal article, says the gene pair will become "an important part of diagnosis" of heart failure. However, he says it's likely many other genes will prove to play a role in the condition.

And, he adds, the effect of the gene anomalies can be minimized by controlling other risk factors for heart failure, such as high cholesterol and hypertension, and through exercise and avoiding smoking.

What To Do

For more on heart failure, try the National Heart, Lung, and Blood Institute or the Heart Failure Society of America.

SOURCES: Stephen Liggett, M.D., director, division of pulmonary and critical care, University of Cincinnati College of Medicine; Roger Hajjar, M.D., cardiologist, Massachusetts General Hospital, Harvard Medical School, Boston; Oct. 10, 2002, The New England Journal of Medicine
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