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Researchers Find Potential Key to Preventing Heart Attack Damage

In mice, the drug cyclosporin shields cardiac cells from destruction

WEDNESDAY, March 30, 2005 (HealthDay News) -- A new discovery may lead to interventions that prevent the death of cardiac and brain tissue linked to heart attack and stroke, researchers report.

Investigators say they've discovered a critical mechanism key to heart attack-linked cell death, and they say a drug already exists to block this mechanism. That drug, cyclosporin, is an immunosuppressant often used in patients undergoing organ transplants.

"We found a protein that explains a way in which cells die," said Jeff Molkentin, senior author of the report and associate professor of pediatrics at Cincinnati Children's Hospital Medical Center.

The protein, called cyclophilin D, "is the target for cyclosporin," he said. "It could mean another way to treat people after a heart attack."

"In heart attack and stroke, the treatment objective is to minimize a person's disability by saving as much heart muscle or brain tissue as possible," added Dr. David A. Meyerson, a cardiologist with Johns Hopkins University in Baltimore and a national spokesman for the American Heart Association.

"This preliminary study suggests that treatment with new medication may be able to lessen the damage to brain cells and heart muscle while we are trying to restore blood flow in someone who is having a stroke or heart attack, " Myerson added. "It is preliminary and it will have to be tried in humans, but it is intriguing."

The findings are published in the March 31 issue of the journal Nature.

A person undergoing a heart attack experiences damage to the heart both during and after the actual attack. Blood flow is cut off during the initial attack, causing tissue to die. But once doctors restore blood flow -- either with drugs or artery-opening techniques such as angioplasty or a stent -- the heart receives a sudden burst of oxygen that also causes damage, Molkentin explained.

The first cellular victims in this scenario are vulnerable mitochondria -- microscopic energy centers located within every cell in the body. Mitochondria generate energy for whatever activities the cell needs to perform.

"These organelles are what underlie specific types of cell death," Molkentin said. "When they go, the cell goes."

During a heart attack, the mitochondria sense the depletion of oxygen (brought on by the disruption in blood flow) and start shutting down. As part of this shutdown phase, the mitochondria swell and rupture, and the sudden reestablishment of blood flow causes them to explode, leading to cell death, he said.

Using cyclosporin to block the mitochondrial "sensor" -- cyclophilin D -- appears to interrupt that process and spare vulnerable cardiac tissue, however. In studies with mice, Molkentin's team cut off the mitochondria's ability to sense changes in oxygen status by blocking cyclophilin D. The result: mitochondria survived, as did cells.

"When we knock that protein out, the mitochondria are protected," Molkentin said. "The mitochondria don't pop."

"We think that if we infuse a drug it could block about one half of the damage during the reperfusion [blood-restoring] process," he added.

Although this study only involved mice, drugs such as cyclosporin have proven safe in humans.

"The drug is an immunosuppressant so we wouldn't want to use it long term," Molkntin cautioned. "But for an acute problem, there shouldn't be any immunosuppression."

A pharmaceutical company would need to do the appropriate clinical trials to show that immunosuppressant drugs actually work in human heart attack victims, he said. Several animal studies have also indicated these types of medications protect against heart attack and stroke-related tissue damage, he added.

"If someone did the right clinical trials, this very well could be a way to treat post-heart attack and post-stroke," Molkentin said.

More information

Visit the American Heart Association for more on heart attack treatments.

SOURCES: Jeff Molkentin, Ph.D., associate professor of pediatrics, Cincinnati Children's Hospital Medical Center; David A. Meyerson, M.D., cardiologist, Johns Hopkins University, Baltimore, and national spokesman, American Heart Association; March 31, 2005, Nature
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