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Gene Mutation and Stress Linked to Heart Failure

By Cheryl Simon Silver


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Heart Disease

When most people think about heart disease, they assume that something is wrong with the heart’s pumping or electrical systems. But in some patients, neither explanation is satisfactory. Now researchers have identified a third factor that may increase susceptibility to heart failure. Some heart disease patients have defects in a gene that helps the heart recognize stress signals.

Researchers at the Mayo Clinic in Rochester, Minnesota, have identified genetic mutations that may prevent the heart from perceiving stress normally. When stress signals are ignored, the heart is vulnerable to damage.

Lead researcher Andre Terzic explains that when the body is able to decode stress signals, it can adjust the overall function of the cardiac cell. “It’s like an alarm system that not only let’s you know there’s a fire, but allows the fire to be contained,” he says.

When the signal malfunctions, however, the heart can fail.

This is a totally new approach to understanding the progression of heart failure.
Terzic and his colleagues report in Nature Genetics that some people have defects in cell structures known as ATP-sensitive potassium channels, and the defects were caused by genetic mutations.

A properly working potassium channel helps regulate levels of potassium and calcium in the heart. The heart needs calcium in order to contract, but too much damages the cell structure, leading to heart failure.

In the study, the researchers focused on patients with severe heart disease known as idiopathic dilated cardiomyopathy, a form of heart failure that can occur as early as middle age and whose causes are unknown.

Terzic’s team collaborated with Timothy Olson, of the Mayo Clinic Cardiovascular Genetics Laboratory. Olson conducted genetic scans on DNA obtained from samples of their blood.

“The exciting thing for the field is that this is a totally new approach to understanding the progression of heart failure,” says David Lathrop, of the National Heart, Blood, and Lung Institute in Rockville, Maryland. 

“We hadn’t thought before that ATP-sensitive potassium channels could be involved in the progression of heart failure,” Lathrop says. “Simply understanding that may provide a whole new realm of targets for treatment.”

Of the 323 heart disease patients studied, two were found to possess mutations in a gene called ABCC9. One consequence of the defects is an abnormal potassium channel. None of the 500 healthy individuals screened had the mutations.

While the percentage of the patients found to have the defective gene is small, the defect could still be present in perhaps 2,000 of the 225,000 Americans with this form of heart failure, Lathrop says. 

Standard screening for heart disease currently overlooks potential defects in the heart’s stress management system because no one knew they might be a factor. Lathrop says a genetic test could be developed if more people who develop heart failure are found to have the defective gene.

For patients who have the channel defect, effective treatment already exists. Several known medications directly open the potassium channels, Lathrop says.

In the next phase of their research, Terzic and his colleagues will further screen healthy individuals and heart failure patients to learn how prevalent the genetic defect is in different populations.

“We are not presenting this as a cause for heart failure, but as a susceptibility factor,” Terzic says. “This may be the drop that swings the pendulum that precipitates heart failure, or a poor outcome from a heart attack.”

Terzic, Andre, et al. ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating. Nature Genetics 36, 382-387 (April 2004).

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