NEW YORK (May 5, 2009) –The danger of clogged arteries seems so simple: fat and cholesterol slowly build up inside a vessel, until one day, the growing plaque – like a clog of hair in a sink - completely jams the artery and shuts off blood flow. That’s how most lay people understand atherosclerosis. And it’s completely wrong.

“If plaque just slowly accumulated inside our arteries, it would not cause acute heart disease,” says Columbia University Medical Center’s Ira Tabas, M.D., Ph.D. “Before the deposits of fat and cholesterol could obstruct an artery, the body would sense the reduction in oxygen supply and build new vessels to bypass the blockage.”

View of an artery with plaque rupturing from a necrotic core, or "graveyard" of dead cells. Credit: Paris Constantinides

The real danger from the fatty deposits lies not with their size, but with what lies underneath the surface of the deposit. Like magma underneath a volcano, rumblings in the core can break open the plaques. Once the plaque ruptures, the body quickly tries to cover and repair the opening by forming a blood clot. “It is this sudden clotting that restricts blood flow and can cause a heart attack, stroke, or sudden cardiac death,” Dr. Tabas says.

While a vast majority of atherosclerotic lesions are relatively harmless, the rest – some two percent of all plaques – eventually lead to an acute blood clot and to heart attack, sudden death or stroke. What separates the average blood vessel plaque from those that are at high risk for triggering the development of dangerous – even fatal – blood clots, is the “billion dollar question,” says Dr. Tabas, whose most recent findings on arterial plaque are presented in the cover story of the May issue of Cell Metabolism.

Cover of the May 2009 issue of Cell Metabolism

Cholesterol-lowering drugs can reduce the amount of plaque stuck to our arteries, but it’s a tall order. Fatty streaks start appearing in our arteries by the time we’re in our teens, and atherosclerotic plaques continue to develop from then onward.

The good news, Dr. Tabas says, is that “about 97 percent of plaques will never become a problem.  If we can make that 100 percent, we would eliminate the number one cause of death in the industrialized world.”

For that, doctors will need a plaque whisperer. “The wave of the future in atherosclerosis treatment will be in preventing harmless lesions from becoming dangerous ones, or soothing dangerous plaques so they don’t rupture.”

The best way to do that is unclear at the moment. Volatile plaques are complicated, and there are likely many things that lead to instability and rupture.

But a graveyard of dead cells inside the plaque undoubtedly contributes, Tabas says, in part because substances released by the dead cells tend to weaken the cap covering the lesion and thereby trigger clot formation (see image above).

Ira Tabas, M.D., Ph.D., the Richard J. Stock Professor & Vice Chairman of Research in the Department of Medicine, and professor of medicine, anatomy and cell biology.

A therapy that prevents the deaths of these cells may be able to reduce the number of vulnerable plaques and prevent heart attacks and strokes in the 70 percent of people who aren’t protected from cholesterol-lowering drugs.

Recently, using mouse models of atherosclerosis, Dr. Tabas pinpointed a major cause of the cells' death, opening the way to the possible development of cell-saving therapies. The killer – a slow but deadly increase in stress in one of the cell’s compartments – has also been seen in vulnerable plaques found in people. 

“Our results show that the stress inside the cell is really killing the cells,” Dr. Tabas says, “and that its presence in unstable human plaques is not just a coincidence."

Though relieving this stress, or preventing cell death, could soothe volatile plaques and be an effective way to reduce heart attacks and strokes, it may take years before such a therapy is available. On the other hand, it may be possible to bypass the problem of cell death by coaxing other cells in plaques to rapidly capture and clean up the dead cells before they do damage.

In the meantime, the best way to quiet volatile plaques is probably one that you’ve already heard of. “Our understanding of atherosclerosis may be changing, but the old standbys, diet, exercise, and keeping your risk factors like cholesterol and blood pressure in check still remain the best option,” Dr. Tabas says.

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