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Reactive Reasoning

Is an inflammation protein the next cholesterol?
FATTY DEPOSITS



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Calming inflammation in the body might be just as important for fighting heart disease as lowering cholesterol, according to two studies released in January. Some experts see the findings as evidence to more aggressively monitor and perhaps even treat inflammation in patients. But others are not yet convinced that doing so would extend more lives.

A key mediator in atherosclerosis, inflammation damages the lining of the artery walls and contributes to the formation and rupture of fatty plaques. Starting in 1997, Paul M. Ridker, a cardiologist at Brigham and Women's Hospital, began finding a relation between an inflammation compound called C-reactive protein (CRP) and heart disease. For instance, CRP levels of more than about two milligrams per liter of blood almost tripled the risk for heart attack and doubled the risk for stroke.

In two separate studies published in the January 6 New England Journal of Medicine, Ridker and Steven E. Nissen of the Cleveland Clinic looked at nearly 4,300 patients with severe heart disease who were taking moderate or high doses of statin drugs to lower their cholesterol. They wondered why some patients seemed to be doing better than others despite having reached the same low levels of LDL, the bad cholesterol.

Ridker confirmed his earlier findings, and Nissen found a link between lower CRP levels and a regression of atherosclerosis (the plaques got smaller). More important, the reductions in CRP had a beneficial effect independent of lowering LDL, suggesting that statins lessen both cholesterol and CRP.

The reports indicate that cutting CRP is at least as critical as lowering cholesterol, Ridker says, and "support the concept that CRP is not only a useful clinical marker of inflammation but also a player in heart disease." Nissen agrees: "In the future, we will attack CRP with the same vigor that we attack cholesterol." Ridker suspects that healthy individuals who have normal cholesterol (130 milligrams per deciliter of blood) but high CRP levels might also benefit from taking statins and has started a new trial of 15,000 people to explore the possibility.

Despite the strong evidence, other experts warn that more work is needed to prove that CRP directly causes atherosclerosis or that people should take statins to control CRP. "These studies tell me that drugs that lower both LDL and CRP may have a greater effect than therapies that lower just LDL," says David S. Siscovick, co-director of the cardiovascular health research unit at the University of Washington School of Medicine. "But this is not going to change the way I treat my patients." That's because statins may not reduce CRP directly. Instead the drugs may interfere with the inflammatory pathway in the body, and less inflammation may reduce cardiovascular risk. If so, then CRP is at most a marker, not a cause, of heart disease.

In fact, the mechanisms that raise CRP levels are not entirely clear. Infections and chronic diseases such as rheumatoid arthritis as well as obesity, smoking, high blood pressure and diabetes all boost CRP levels. And when a person loses weight, quits smoking, and controls diabetes and blood pressure, their CRP levels fall, indicating that CRP is a marker of these other problems associated with inflammation.

What is more, some experts doubt the usefulness of CRP for patient screening in the clinic. "It doesn't help me determine who is at risk--who I should and shouldn't treat," remarks Donald Lloyd-Jones, a cardiologist at Northwestern University. According to Lloyd-Jones, who is also an epidemiologist and has explored risk factors in heart disease, there has been too much emphasis on the fact that CRP can give a statistically significant relative risk but not enough focus on whether it actually adds to our ability to discriminate risk. For instance, using established risk factors such as cholesterol level and obesity, physicians can tell who will get heart disease from those who will not 80 percent of the time. When CRP is added to the mix, Lloyd-Jones notes, that number goes up to 81 percent. "It turns out that this is statistically significant, but it doesn't help me as a doctor," he says.

Such a viewpoint is certain to disappoint the statin drugmakers, which sponsored the latest studies. "This train of CRP has so much momentum," Lloyd-Jones adds. "But if we look at it closely, it's not what it's cracked up to be."

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