Heart Mender

After cholesterol, the most important cause of heart attacks is the killer that Paul Ridker identified

By Alice Park

(TIME) -- The first time Dr. Paul Ridker appeared in the New England Journal of Medicine (NEJM), he wasn't yet a doctor. In fact, he hadn't even graduated from high school.

That's because Ridker made his debut in one of the world's most prestigious medical journals not as an author but as a research subject. He was nine years old, just returned from living in India and suffering from symptoms that none of his doctors could explain. He became the subject of a study at the National Institutes of Health, where doctors finally diagnosed his problem — a novel immune disorder — and published their findings. The mystery was solved, and Ridker's curiosity was piqued — permanently. "My first real exposure to medicine was at such a high level of research, with these talented physicians trying to understand why this young boy was having so many problems, it made medicine exciting to me," he says.

More than 30 years later, Ridker's name appears regularly in the NEJM and many other medical publications. Today he is a cardiologist at Boston's Brigham and Women's Hospital and one of the world's leading experts on arterial inflammation, an immune-system reaction that is the most powerful contributor after cholesterol to heart attacks. A variation on the immune response that causes everything from arthritis to sinus infections, inflammation in the arteries turns out to be as dangerous for the heart as high cholesterol levels in the blood. "Inflammation has really changed our whole outlook on heart disease," says Dr. Eric Topol, a cardiologist at the Cleveland Clinic.

New ideas challenging the simple plumbing model of heart disease were beginning to percolate through the medical establishment even as Ridker began his residency in 1984. The idea that heart attacks were caused by arteries gummed up with cholesterol was clearly inadequate; half of all heart attacks occurred in people with normal cholesterol levels.

If cholesterol could not explain all heart attacks, then Ridker was determined to find out what else could. His childhood experience with his own immune disorder and his yearlong fellowship in sub-Saharan Africa in 1983, just as the AIDS epidemic was beginning its sweep around the globe, convinced him that preventing disease was as important as treating conditions once they occurred.

So he combed through the few early reports that hinted at the identity of some of cholesterol's co-conspirators. Inflammation seemed the most promising, and three years ago Ridker launched the first large-scale studies designed both to confirm inflammation's role in heart attacks and provide doctors with a useful, reliable way of measuring its effect in the arteries. Few of his colleagues, however, believed that the low levels of inflammation thought to cause trouble in the heart (far below the peaks involved in arthritis or infections) could be tracked reliably with a substance in the blood. "There were many naysayers," Ridker admits.

Indeed, choosing a reliable gauge for how inflamed the arteries had become proved daunting. After running through a few common but ineffective markers, Ridker finally settled on C-reactive protein, a substance that could be detected, even at low levels, with a special, highly sensitive assay.

The choice proved fortunate. Just this summer, Ridker's group published the results of its landmark studies. As expected, patients with high CRP levels were at significantly higher risk of developing a heart attack. Even more intriguing, Ridker's team found that those with low cholesterol but high CRP were just as likely to have a heart attack as those with high cholesterol and low CRP. Ridker even showed that statins, the most popular cholesterol-lowering drugs, reduce CRP levels by equal amounts — about 13 percent — in both groups, suggesting that the medications pack a double wallop, working as both cholesterol-lowering and anti-inflammatory agents.

These findings have given doctors a new and very different model of heart disease. Inflammation and cholesterol combine, they now believe, to create a particularly unstable type of plaque that builds within blood-vessel walls. It's the rupture of these plaques, spewing debris into heart arteries, that causes clots to form and leads to heart attacks.

Already, physicians around the U.S. have begun screening their heart patients for CRP. If Ridker has his way, that number will continue to grow, and CRP testing will become as ubiquitous as cholesterol screening — and as important in saving lives.