JANUARY 22, 2001 VOL. 157 NO. 3

The Hunt for Cures

Heart Disease
Rethinking treatments for the heart
By CHRISTINE GORMAN

ALSO
The Future of Drugs
Now that our DNA has been decoded, the search for better, faster and more effective medications begins in earnest
• Inside the Brave New Pharmacy: At a leading genomics firm, the star of the show is a robot
• DNA Microarrays: The workhorse of genomic medicine
• Bioinformatics: How to design a molecule
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For decades surgery seemed to be the best bet for the treatment of heart disease. Researchers thought of atherosclerosis, or the clogging of arteries with fatty plaques, as basically a plumbing problem. Bypass the choke points with new grafts and you would more than likely bypass any future heart attacks. Over the past five to 10 years, however, doctors have come to realize that heart disease is more complicated than that. They're not by any means ready to abandon surgery, but now they rely more heavily on different types of drugs to treat both the long-term and short-term effects of heart disease.

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Drugs will play an even greater role in the near future, says Dr. Valentin Fuster, director of the Cardiovascular Institute at Mt. Sinai School of Medicine in New York City. For one thing, the wealth of data coming out of the human-genome project will allow physicians to tailor pharmaceutical treatments to an individual's specific genetic profile in ways that have never before been possible. For another, men and women at risk of developing heart disease are being identified at earlier and earlier stages of their condition, a situation in which drug therapy presents fewer risks than surgery.

To get a better idea of what could be in store, it helps to know what physicians believe lies at the root of most heart attacks. The trouble begins decades earlier, when the inside of a coronary artery becomes damaged—usually as a result of chronic high blood pressure, high cholesterol or the deleterious effects of smoking. The body tries to repair the damage, and a kind of internal scab is formed. Years go by, and the scab develops into a fatty deposit, filled with cholesterol, proteins and bits of cellular detritus. Sometimes the plaque is quite stable, and nothing much happens. Other times, for reasons that are still unclear, it becomes inflamed and prone to rupture. If the plaque breaks open, a clot forms, choking off the supply of blood. If the interruption lasts long enough, a heart attack ensues.

Doctors have already shown that drugs called statins, which curb the body's ability to manufacture excess cholesterol, can significantly reduce the risk of suffering a heart attack. But statins don't work for everyone. So drug companies are studying the biochemical pathways by which the body pulls cholesterol that has already been manufactured out of a cell. "By turning this reverse cholesterol transport on, you'd be able to stimulate removal of cholesterol from vessel walls back to the liver for excretion," says Dr. Richard Gregg, vice president of metabolic- and cardiovascular-drug discovery at Bristol-Myers Squibb. Taken in combination with statins, such drugs could virtually sweep the arteries clean of cholesterol.

Researchers are also searching for new drugs to dampen the inflammation process. The goal of such treatments is not so much to remove a fatty plaque from inside an artery but rather to convert it from a more dangerous form to a more stable one. This may be one of the reasons a daily dose of aspirin, which is both an anti-inflammatory and a blood thinner, can help prevent heart attacks. But doctors would like to have a drug that targets coronary inflammation more specifically and aggressively than aspirin.

There's more to heart disease, of course, than heart attacks. More and more Americans are developing a condition called congestive heart failure, in which the cardiac muscle becomes weakened and can no longer pump blood efficiently. Investigators are currently studying a group of specialized hormones that are released whenever the heart muscle falters. Some of these hormones help restore the heart's vigor while others, paradoxically, make the muscle stiffer and more difficult to contract. The goal is to figure out a way to boost the levels of the beneficial hormones while lowering those that make the weakened heart's job more difficult.

Drugs are bound to play a major role in any new advances based on genetic or tissue engineering as well. For example, doctors hope one day to repair the muscle damage that occurs during heart attacks by transplanting precursor cells called stem cells into the affected areas. However, the stem-cell implants can take hold only if the levels of a number of different enzymes and molecules are boosted—a task that pharmaceuticals are particularly well suited to fill.

Of course, there would be much less need for new medications to treat heart disease if we all exercised more, watched our weight and stopped eating so much food that is high in saturated fat. Public-health experts estimate that you can reduce your risk of heart disease as much as 80% by adopting a healthy lifestyle. But as long as our culture and our genes conspire to clog our arteries and strain our hearts, it's good to know that there will be some powerful drugs to help undo the damage.

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