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Harvard Public Health Review/Summer 2002


A Modest Proponent

Dr. Paul M. Ridker, MPH'92, keeps his press clippings tucked away in a modest, but growing, file in his assistant's office. The one article that makes it to Ridker's wall--framed no less-- doesn't mention his name or his research. And that suits the director of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital in Boston just fine.

The article, from last summer's New York Times, is a seemingly standard, once-a-year story about President George W. Bush's physical exam. The article is special only because it mentions that the fit and active president--the very picture of middle-aged health--is the first to had his C-reactive protein levels tested as part of an annual physical exam. And that's the kind of news that Ridker likes to read.

In the past, patients left their physical exams with a cholesterol number and the assumption that they had all the information they need about their cardiac health. However, since nearly half of all heart attacks and strokes occur inpatients with "normal" cholesterol levels, many people obviously did not have the complete picture. "As a clinician, I worry about a healthy middle-aged patient whose cholesterol measures 'normal'," Ridker says. "That individual has heard what they want to hear. It's very difficult to get them comply with diet and exercise. They think, 'I'm average. What does it matter?' Well, it's very clear that much more than cholesterol does matter."

The simple and inexpensive blood test advocated by Ridker--the one taken by the president--is helping physicians identify previously undetected heart attack and stroke risks in patients for whom inflammation, rather than cholesterol, may be the key factor at play. Cleared by the Food and Drug Administration two years ago, the test for measuring the levels of C-reactive proteins in the blood is now moving into widespread use.

The dangers of high cholesterol levels are well understood by physicians and patients alike. The now-familiar "plumbing" model of cardiovascular disease lays the groundwork for warnings about cholesterol. The model goes like this: over years, lipids can build up in the bloodstream, clog vessels and, when the flow becomes too constricted, result in a heart attack or stroke. Patients can easily understand the benefit of reducing their cholesterol--the lower the level of lipids in the bloodstream, the less the risk of blockage. Ridker's research is part of a sophisticated new understanding of coronary artery disease that identifies inflammation as the other culpable factor--the one that that explains why patients in their 40s and 50s suffer heart attack or stroke despite "normal" cholesterol levels. The basic science behind inflammation theory says that over time blood vessels, like other parts of the body, become inflamed as they come under attack from outside invaders. The body uses its natural defenses to destroy the bacteria or viruses and then repairs the damage. However, after fighting off invaders, immune system cells burrow into artery walls and continue gobbling up fat droplets. As a result, plaque forms on the inside of blood vessels. After years of intense inflammation, this arterial plaque can suddenly rupture, choke off the supply of blood, and cause a heart attack or stroke.

Although the scientific connection between inflammation and heart attack goes back as far as the 1800s, it is only within the past ten years that medical community has begun taking a new look at the role inflammation plays in atherosclerosis, as well as other chronic diseases including Alzheimer's, osteoporosis, asthma, and even cancer. Working from the basic science on inflammation, Ridker began asking a series of epidemiologic questions to begin identifying patients who were at risk for heart attack and stroke due to inflammation. Ridker and his colleagues monitored blood samples from more than 22,000 healthy middle-aged men and 28,000 healthy middle-aged women who had been followed for up to 15 years. In both groups, he sought to locate bio- markers for inflammation unrelated to cholesterol. After exploring 12 potential markers, Ridker and his colleagues identified elevated levels of C-reactive protein (CRP) as a strong indicator of risk. The isolation of this protein, which is found in the blood and aids in the repair of cuts and responds to trauma, proved to be a very useful find.

"As it turned out, measuring CRP levels provided a simple clinical tool for looking at a much more complex process," says Ridker. Unlike other markers he explored, C-reactive proteins proved easy to measure, leading to the simple and inexpensive test now in use. And, even more importantly, CRP levels also turned out to be the strongest single predictor of risk among these patients. In fact, patients with the highest CRP levels were found to be at two times greater risk of stroke and three times greater risk of heart attack.

But identifying the risk is only the first step. For the test to be truly useful, it must also point to prevention and treatment. "Most everything that we traditionally recommend for reducing heart attack risk also reduces CRP levels," Ridker notes. "So our first step is getting our patients to lose weight, exercise, stop smoking--all things that we know reduce vascular risks." While physicians have always advised patients to take these steps, the additional evidence about CRP levels will help them make a stronger case with many more patients. Along with behavioral changes, Ridker has also begun exploring therapies for treating patients with high CRP levels--including the use of aspirin as a preventative measure. As might be expected, aspirin, an anti-inflammatory drug, has shown promise for reducing heart attack among patients with high CRP levels. Even more interesting to Ridker was the effect of drugs known as the statins, now widely prescribed to lower cholesterol. When prescribed to patients with high CRP levels but low LDL (or "bad") cholesterol levels, the statins not only lowered the CRP levels but also lowered the risk of heart attack. This outcome suggests to Ridker that statins also have an anti-inflammatory function and that many more patients could benefit from these drugs. Ridker is hoping to launch a large-scale international clinical trial on the use of statins within the next few months. Ridker is also extending his research to explore a potential link between elevated CRP and diabetes, which, like coronary artery disease, came to prominence during the 20th century.

Ridker believes his training from a biomedical perspective (he is a 1986 graduate of Harvard Medical School), combined with his formal training in epidemiology and statistics from the Harvard School of Public Health made much of this work possible. "What we have really done is plied the classical tools of large-scale population epidemiology to some of the most interesting molecular puzzles confronting heart disease patients today," he says.

The value of CRP testing has caught the attention of both the scientific community and the general population. The American Heart Association and the American College of Cardiology are currently putting together expert panels to discuss whether CRP tests should become standard practice. And the file of press clippings kept by Dr. Ridker's assistant continues to grow. His work has been profiled by the New York Times and Wall Street Journal, among others. Ridker was recognized by the editors of Time magazine in 2001 as one of America's Best in science and medicine. He was described in Time as one of the "brilliant individuals combining passion and obsession" who are pushing the boundaries of science and medicine. But Ridker remains reticent about all the attention. He prefers to talk about the research rather than himself. "The nature of this hypothesis involved many people from the microbiology level to the clinical level. We just happened to make the contribution that is easy to understand," he observes.

Although he tends to shy away from the spotlight as a rule, Ridker seems more than willing to accept one important public role--getting information out about the importance of non-cholesterol factors in cardiac health. His goal is to make sure that stories about middle-aged patients receiving a CRP test and understanding the importance of the results become as routine as that annual article about the President's physical.

Michael Floreak

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