New therapy raises good cholesterol results in regression of heart disease in mice

October 24, 1999

DALLAS, Oct. 26 -- A new type of therapy that raises the good form of cholesterol -- and caused a "shrinkage" of atherosclerosis in mice experiments -- may lead to novel treatment approaches for heart disease and stroke, according to a study in today's Circulation: Journal of the American Heart Association.

By injecting mice with apoA-1 -- a gene that makes a key protein involved in forming high-density lipoprotein or HDL, the "good" cholesterol -- researchers were able to shrink artery-blocking deposits that characterize atherosclerosis.

Atherosclerosis occurs when deposits, called plaque, collect on the inside walls of arteries. A blood clot can develop on the plaque, blocking the blood vessel and triggering a heart attack or stroke.

"There has been a tremendous interest in raising HDL cholesterol levels, not only as a way to prevent heart disease, but also to help shrink the existing blockages in blood vessels," says the study's lead author Daniel J. Rader, M.D., director of preventive cardiology at the University of Pennsylvania Health System at Philadelphia.

There are medications called "statins" that lower levels of low-density lipoprotein, LDL, the "bad" cholesterol. However, those drugs raise HDL cholesterol levels only slightly, if at all. There are very few effective treatments to raise HDL cholesterol levels.

The mice used in the study were fed a diet high in cholesterol and saturated fat to induce atherosclerosis. Some of the mice were injected with an inactive virus, while the others were injected with a virus containing the apoA-1 gene.

After four weeks, the mice treated with the apoA-1 gene had significant regression of the pre-existing atherosclerotic lesions as well as a moderate increase in their levels of HDL cholesterol. By comparison, the control animals' atherosclerosis progressed during the four weeks.

Previous studies in animals have shown that apoA-1 can slow progression of atherosclerosis. However, this latest study is the first to show an actual regression of atherosclerosis induced by apoA-1, says Rader.

High levels of LDL cholesterol are known to increase an individual's risk of coronary heart disease. High levels of HDL cholesterol, on the other hand, protect the heart and reduce the risk of heart disease. Researchers estimate that at least 25 percent of those who develop coronary heart disease have low levels of HDL cholesterol, and could benefit from treatments designed to raise those levels.

This could lead to the development of important new treatments aimed at inducing regression of coronary heart disease, especially in persons with low levels of HDL cholesterol.

"Once we have safe and effective ways to substantially raise the levels of the good HDL cholesterol, we could use them in conjunction with medications designed to lower levels of bad LDL cholesterol, which could offer patients an even greater benefit in preventing future heart attacks and strokes," says Rader.

In an accompanying editorial, Hayes M. Dansky, M.D., and Edward A. Fisher, M.D., Ph.D., praise the research stating it is remarkable that significant "lesion" regression occurred in just four weeks because the increased levels of apoA-1 and HDL-cholesterol levels lasted only a short time following the injection. Lesions are another term to describe the fatty deposits that block blood vessels.

Fisher, professor of medicine and director of lipoprotein research at Mount Sinai Medical Center in New York City, calls the research a significant achievement, and adds that the latest research supports the goal to develop new medications that induce long-lasting, large increases in apoA-1 and HDL cholesterol levels in humans.

Co-authors are Rajendra K. Tangirala, Ph.D.; Kasuhisa Tsukamoto, M.D.; Sam H. Chun, B.A.; David Usher, Ph.D.; and Ellen Puré, Ph.D.

American Heart Association

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