NEWS: Reactive Reasoning --Is an inflammation protein the next cholesterol?

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March 28, 2005

Reactive Reasoning

Is an inflammation protein the next cholesterol?

By Diane dale

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, 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 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 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 Lloyd-, a

cardiologist at Northwestern University. According to Lloyd-, 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- 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- adds. " But if we look at it closely, it's not what it's

cracked up to be. "

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