An alcohol-busting enzyme may help prevent heart attack damage, according to a new study in Science. Researchers report that aldehyde dehydrogenase 2 (ALDH2), an enzyme important for processing alcohol in the human body, clears harmful toxins produced in cells when blood flow is blocked in the heart—and a new drug can switch it on.

Red wine has long been toted as a preventive measure against cardiac disease. In fact, heart cells exposed to ethanol in the laboratory actually recover better when researchers temporarily stop the flow of oxygenated blood to them. The study published today suggests that ALDH2 may contribute to wine's beneficial effects. The enzyme, activated as cells work to clear alcohol, also eliminates toxic by-products from the breakdown of fats in cells during a heart attack—thereby reducing damage to this vital organ.

During a cardiac event, blood flow to the heart ceases. Free radicals (highly reactive molecules released during energy production) accumulate in cells struggling through oxygen deprivation, damaging critical fats and proteins and increasing the chance of premature cell death. ALDH2 may help heart cells survive this onslaught by repairing some of the damaged fats, according to the study. Although not all cardiac damage is avoided, "any time you can save cells, you have a better chance of recovery," says study co-author Thomas Hurley, a biochemist at Indiana University School of Medicine in Indianapolis.

Researchers, aware that alcohol triggers the protective effects of ALDH2 during a heart attack, searched for drug alternatives that could switch on the enzyme. The synthetic compound aldA1 was found to directly bind ALDH2, enhancing its activity and reducing cardiac damage by 60 percent when injected directly into the hearts of live healthy rats five minutes before blood flow blockage was induced. Although these results are promising, adapting this therapy for intravenous or oral use in humans will be a challenge, cautions Michael Sack, a cardiologist at the National Heart, Lung and Blood Institute in Bethesda, Md., who did not participate in the study.

The researchers remain optimistic about the newly identified drug, however, arguing that it could help patients in east Asia where 40 percent of the population has nonfunctional ALDH2 due to a gene mutation. Aside from enhancing ALDH2 activity two-fold in normal rat hearts, aldA1 can actually restore full function to the mutant form of the enzyme, Hurley notes.

For populations from east Asian countries, including China, Japan and South Korea, this could mean a reduction in cardiac damage following heart attacks and augmentation of current therapies for angina, or chest pain. Currently, nitroglycerin (which dilates blood vessels) is used to treat heart patients who have chest pain, but functional ALDH2 is required to break down the drug into its active form. If aldA1 is co-administered, it could make patients more responsive to therapy.

But aldA1 may even have beneficial effects for those angina patients carrying the normal version of the enzyme but who have become immune to nitroglycerin's effects. Prolonged use of nitro can lead to drug tolerance and a return of chest pain, but researchers found that aldA1 reversed tolerance in rats when the animals were administered nitro before an induced cardiac event. The question remains, however, whether these laboratory results can be replicated in humans.

Study leader Daria Mochly-Rosen, a pharmacologist at Stanford University School of Medicine, believes that aldA1 could have far-reaching applications beyond cardiac patients. "By looking at people with the ALDH2 mutation, we can identify other chronic diseases associated with not having the enzyme function," she says.

She notes that because ALDH2 is active in all cells of the body, its function may be critical for eliminating toxic by-products in other organs throughout life. Toxin accumulation could be offset by aldA1, helping to prevent diseases of old age. The risk for Alzheimer's disease, for example, may be reduced if aldA1 can help clear these harmful molecules, which have been implicated in promoting plaque formation in the brain. Mochly-Rosen also believes that liver damage resulting from the stress of continually processing pharmaceuticals may also be diminished by aldA1.

Critics note that these potential benefits remain untested and will require a long period of drug development. For now, reaping the benefits of aldA1 in its current state is limited by the necessity that physicians administer the drug immediately before a cardiac event. Because doctors cannot look into a crystal ball and predict heart attacks, "the clinical implications of this work are probably minimal," notes cardiologist Michael Cohen from the University of South Alabama in Mobile, who was not involved in the study.

Even in the case of open-heart surgery, where aldA1 could presumably help the heart recover from a temporary cessation of blood flow, the amount of heart damage is so minimal with current technologies that aldA1 may not make a significant biological contribution, he adds.

Organ transplantation, however, may be an area in which the current form of aldA1 could make a significant contribution, Mochly-Rosen contends. Treating organs with the compound may potentially reduce damage to these tissues resulting from toxic by-products induced in oxygen-starved cells. Perhaps this will allow the organs to remain viable longer, or simply preserve a larger fraction of healthy tissue during surgery.

"AldA1 remains a promising start, but it is just the first step in a long process if it will be used clinically," says John Baker, a biochemist at the Medical College of Wisconsin in Milwaukee, who did not participate in the research. With continued study, scientists may be able to design drug modifications that will enhance the beneficial effects of aldA1 and make it more "human friendly," as well.

In the future, Hurley says, "we want to get aldA1 to work in a more acute setting, such as during a heart attack." And that would be great news, considering that heart disease remains the number one killer worldwide.