The Cholesterol-Inflammation Connection

Coupled with high cholesterol, inflammation can lead to buildup in the arteries, setting the stage for a heart attack or stroke.
Cholesterol has long been seen as the key culprit in cardiovascular disease. But nearly half of all heart attacks occur in people with normal cholesterol levels, which suggests that another factor is at work.

Researchers have identified cholesterols partner in crime as inflammation—the flood of white blood cells and chemicals that our immune system unleashes to ward off damage or infection. Cholesterol wouldnt be nearly as dangerous without this process, which is thought to play an essential role in atherosclerosis, the hardening that occurs when low-density lipoprotein (LDL), also known as bad cholesterol, builds up in the arteries.

When high levels of cholesterol occur in the bloodstream, excess LDL begins to seep into the inner wall of the artery. This triggers an inflammatory response, which actually speeds up the accumulation of cholesterol in the artery wall. This in turn produces more inflammation—and on and on. Eventually the deposited cholesterol hardens into a plaque, which can rupture and lead to the blood clots that cause heart attacks and strokes—an event that inflammation also appears to help along.

Some experts now believe that inflammation is the link between the many diseases and conditions that affect the heart and brain. "Inflammation is the common denominator in nearly all of the diseases we deal with," says James OKeefe, MD, director of preventive cardiology at the Mid America Heart Institute in Kansas City, Mo. "Heart disease, diabetes, dementia—theyre all tied to inappropriate, low-grade, chronic inflammation."

Measuring inflammation
Our growing understanding of inflammation's role in atherosclerosis doesn't diminish the importance of cholesterol—you still have to keep that "bad" number down and the "good" number up—but it does present another way to anticipate cardiovascular disease.

Studies show that a substance known as C-reactive protein (CRP), one of the so-called markers released by cells during the inflammation process, may be more effective than cholesterol in gauging the risk of heart attack and other cardiovascular events.

A landmark 2002 study conducted by a team of Harvard researchers and published in the New England Journal of Medicine found that women with the highest levels of CRP were nearly 2.5 times more likely to experience a first cardiovascular event (including heart attack and stroke) than those with the lowest levels of CRP. As a predictor of risk this was 40% more effective than LDL cholesterol, which, in the corresponding groups of women, produced an increased risk only 1.5 times greater.

These results got everybody's attention. A CRP test specifically designed to measure the risk for cardiovascular disease, known as a high-sensitivity C-reactive protein assay (hsCRP), was approved by the FDA in 1999, and the test has become nearly as routine as the cholesterol test. Some doctors have even begun to administer the test, which requires a simple blood workup, as part of their annual physical exams.

The importance of CRP is still a matter of dispute, however. "One of the issues and controversies regarding CRP as a risk factor for cardiovascular disease has been whether it is simply a marker, or whether the higher levels actually cause heart attack and stroke," says Alex Reiner, MD, an epidemiologist at the University of Washington School of Public Health and Community Medicine. Theres some evidence for both explanations, and according to Dr. Reiner, "Its very difficult to tease that out. It can work both ways, and my guess is, it probably does."

Dr. Reiner is one of a group of researchers across the United States who has turned to genes to establish a link between inflammatory markers and the risk of cardiovascular events. Dr. Reiner and others have identified genetic variations that predict CRP levels, and variations that predict heart attack and other events, but they have yet to find a single gene that predicts both, which would prove the connection between CRP and cardiovascular disease. "That would be the holy grail," says Dr. Reiner.

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Lead writer: Ray Hainer
Last Updated: October 14, 2008

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