Gene Error Linked to Heart Failure

Scientists identify flaw in protein that normally helps heart contract

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By
HealthDay Reporter

MONDAY, Jan. 28, 2002 (HealthDayNews) -- An errant protein that normally helps the heart contract may help explain some cases of heart failure.

So says a new study by American and German scientists who've identified a genetic flaw in certain patients with dilated cardiomyopathy, or DCM. This condition, which slowly erodes the heart's pumping power, claims approximately 10,000 lives a year in the United States.

The discovery marks the ninth gene mutation so far associated with heart failure. This gene controls the production of a protein, called metavinculin, that acts as a sort of protein transmission system in the contraction of heart muscle.

Lead author Dr. Timothy M. Olson, a pediatric cardiologist at the Mayo Clinic, says the effect of flawed metavinculin on the heart is akin to metal fatigue in a car's drive shaft. Although the vehicle's engine may be working fine, the part that converts energy into motion wears down.

"With each heartbeat, individual cells are subject to a considerable amount of mechanical stress," says Olson, whose work appears in tomorrow's Circulation. Specialized proteins such as metavinculin help muscle tissue withstand normal stress. But in patients with defective genes for these proteins, muscle cells are more vulnerable to damage.

Most cases of heart failure are caused by narrowing of the coronary arteries, which keep the organ supplied with blood. As a result of the blockages, blood backs up in the heart and lungs, making breathing difficult and eventually leading to death.

However, in some cases, the source of the heart failure isn't clear, and is called DCM. Because the disease often runs in families, doctors have suspected a genetic link.

In earlier work, Olson and his colleagues had proposed that, for at least some of these patients, weakening of the force-transmitting proteins might be to blame for their condition. And indeed, scientists have found a handful of gene defects that support that hypothesis.

In the latest study, the researchers looked for defects in metavinculin, which they already knew to be involved in heart muscle contraction, in a group of 350 men and women with unexplained DCM.

Three, or roughly 3 percent, had one of three mutations in the protein. Tests by scientists in Germany showed two of the flaws weakened the overlapping discs that connect heart muscle cells and facilitate coordinated contraction. The role of the third gene was less apparent, the researchers say, but it may boost the risk of cardiomyopathy rather than directly damage the organ.

Olson's group also tested another 500 people without heart problems for the metavinculin errors. This time, only one person, a woman, had a mutation in the protein, which didn't seem to be causing heart muscle problems but may have explained her slightly abnormal heart function.

Taken together, the nine gene flaws probably make up only between 10 percent and 20 percent of DCM cases, Olson says. The rest may be caused by undiscovered errors or other mechanisms.

Still, he says, the findings suggest the seeds for the condition are present at birth in a sizable group of people who can be identified through genetic screening.

If a defect is found, doctors could treat these patients with existing drugs, including beta-blockers and angiotensin-converting enzyme (ACE) inhibitors, that are now prescribed to reduce muscle stress in those with full-blown heart failure.

Since heart failure develops gradually over years or decades, "if you gave medications that reduced the mechanical stress in these patients early on, it might, in fact, lessen the muscle damage that occurred," Olson says.

Dr. Mark Keating, a Harvard University cell biologist and a co-author of the study, adds that ACE inhibitors cut back on the heart's workload by dilating arteries, "and that mean's it's easier for the heart to pump blood." Beta-blockers help by reducing the force and rate of the pump's contractions.

What To Do

To find out more about dilated heart failure, try the Texas Heart Institute or the Familial Dilated Cardiomyopathy Project Group at Oregon Health & Science University.

This site has general information about cardiomyopathy.

SOURCES: Interview with Timothy M. Olson, M.D., assistant professor, medicine and pediatrics, Mayo Clinic, Rochester, Minn.; Mark Keating, M.D., investigator, Howard Hughes Medical Institute, and professor of cell biology, Harvard Medical School, Boston; Jan. 29, 2002, Circulation: Journal of the American Heart Association

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