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PATHOLOGY Protein Predicts Heart Disease Better than CholesterolTrial Will Test Whether High Level of the Protein Is Counteracted by Statins
A test for C-reactive protein, whose ribbon structure is shown above, could be run simultaneously with a test for cholesterol. "The sample would provide complementary information that would increase our ability to capture that population that current tests are missing," said Nader Rifai. (Image adapted from original by Paul Ridker) A once obscure molecule, C-reactive protein, stands poised to become a household word, thanks to a new study by HMS researchers. The protein's claim to fame is based on its power to predict a woman's risk of developing heart attack and stroke. In fact, high levels of C-reactive protein (CRP) were found to presage a woman's chances of developing heart disease more accurately than that reigning oracle of the cardiology world, cholesterol. Paul Ridker, Nader Rifai, and their colleagues followed the medical fates of nearly 28,000 women, aged 45 and older, over an eight-year period. Women with high levels of CRP at the beginning of the study were twice as likely to have a heart attack or stroke as those with low levels. In fact, women with high CRP were more likely to develop heart disease than women with high cholesterol. Remarkably, many of the women with high CRP had normal levels of cholesterol, meaning they and their doctors probably had no idea that they were at high risk for heart disease. Their findings appear in the Nov. 14 New England Journal of Medicine. "That is a major challenge to our guidelines for heart disease screening," said Ridker, HMS professor of medicine at Brigham and Women's Hospital. "We currently rely predominantly on cholesterol level, and these individuals are outside federal guidelines for screening. Yet their risk is actually higher than people inside the guidelines." Inflammation IncriminationThough massive in scope, the study echoes what Ridker and many doctors have been observing for years in their one-on-one encounters in the emergency room. For every heart attack patient with high cholesterol and plaque-clogged blood vessels, there was one with low cholesterol and apparently whistle-clean arteries. In the mid-1980s, a small band of researchers began to suspect that the second type of patient was being felled by some other disease process, namely inflammation. Peter Libby, the Mallinckrodt professor of medicine at BWH, and others proposed that an overactive immune system was attacking the plaques that accumulate to some degree in almost every adult's heart, causing them to rupture and spew their contents in the form of heart-stopping clots.
"We have one and a half million heart attacks in the U.S. each year. About 50 percent have normal cholesterol. Clearly, current guidelines are not adequate to identify all those individuals who are at increased risk," said Nader Rifai, shown at right with Paul Ridker. (Photo by Steve Gilbert) The new study offers stunning confirmation of that scenario. C-reactive protein is a highly sensitive marker of inflammation. "So these data, all of a sudden, are a very dramatic demonstration of what the vascular biology community was saying 15 years ago," said Ridker. The findings could lead to new guidelines for predicting cardiovascular risk, and the American Heart Association will be taking them into account before issuing new recommendations, probably next year. The results could also lead to more widespread use of preventive therapies, such as lipid-lowering drugs, which are currently prescribed only to patients with high cholesterol. In earlier studies, also published in the NEJM, Ridker; Rifai, HMS associate professor of pathology at Children's Hospital; and their colleagues showed that patients with high CRP benefited from statins, a class of lipid-lowering drugs. Ridker is launching a clinical trial this week to more carefully ascertain the benefits of statins for people with high CRP. In addition to widening the scope of current approaches--and there is evidence that people with high CRP could benefit from the lifestyle changes, such as smoking cessation and weight loss, that are recommended for those with high cholesterol--the findings could someday give patients and doctors entirely new treatment options. "This whole field is exploding in terms of novel pathways for drug development, novel pathways for new targets for the detection of disease, for the treatment of disease," Ridker said. "We are going to be seeing randomized trials for all sorts of fascinating, truly anti-inflammatory molecules being applied to cardiology over the next decade. That is the major excitement here." Obscure No MoreThe molecule causing all the commotion was discovered in 1931 by a Rockefeller Institute researcher who is widely credited with first identifying the substance that turned out to be DNA. Oswald Avery found that CRP levels shot up immediately after infection with Streptococcus A, indicating the protein was part of the body's innate immune response. (The protein responded to the polysaccharide C surrounding the bacteria, hence its name C-reactive protein.) While Avery's other discovery would soar into the limelight, CRP languished. Apart from a prescient paper published in 1952 suggesting that CRP might be used to diagnose acute myocardial infarction, there would be little mention of the molecule for half a century. "That gap was because we discovered cholesterol. Everything became cholesterol-driven," said Ridker.CRP was plucked from obscurity thanks to a series of chance meetings. The first was Ridker's encounter with an immune disorder as a teenager, which sparked a fascination with immunology. That interest was fanned in 1981, his first year as a student at HMS, by one of his teaching assistants, Michael Gimbrone, now the Elsie T. Friedman professor of pathology at BWH, who, with Libby, was planting intellectual seeds that would blossom into the inflammatory hypothesis. When Ridker set out to identify markers of heart disease in the early 1990s, he was more than willing to consider inflammatory candidates. He found several inflammatory markers, but most were too unstable to measure clinically. Then he found a paper demonstrating a link between CRP and acute coronary ischemia. As it happened, Rifai had recently been approached by a German diagnostics company to find applications for a highly sensitive CRP assay it had just developed. The two men met. "We connected on this from the beginning," said Rifai, who is head of the clinical chemistry lab at Children's Hospital. An earlier study by Ridker showed that men who went on to have heart attacks had elevated CRP. Rifai and Ridker conducted a pilot study to see if they could reproduce the findings in women. The results suggested that CRP might be an even stronger predictor of risk than cholesterol, but the study was small, only 366 women. Their full-scale analysis of nearly 28,000 women participating in the Women's Health Study confirms those results. Until recently, most researchers, including Rifai and Ridker, would probably have said that CRP forecasted vascular inflammation but did not have a hand in causing it. In an intriguing twist, it now appears that CRP may be more than a predictor. CRP signals a host of inflammatory proteins, such as ICAM, VCAM, and P-selectin, and research suggests that it may play a role in vascular inflammation. "Five years ago, I would have said with almost 90 percent certainty that CRP has nothing to do with atherogenesis. It was just an innocent bystander, acting as a surrogate marker," said Rifai. "Now, all of a sudden, we know CRP may not be as innocent a bystander as we initially thought." --Misia Landau |
