A previously obscure and rarely performed blood test appears to be as powerful as cholesterol measurements in estimating a person's risk of having a heart attack or stroke, according to new research.
The test measures levels of C-reactive protein (CRP), produced by the body as part of the process of inflammation. Elevated concentrations of CRP appear to identify individuals at increased risk of cardiovascular disease even when their cholesterol levels are normal.
The research, published in today's New England Journal of Medicine, is the strongest evidence to date supporting the emerging theory that inflammation plays a crucial role in determining whether or when a heart attack or stroke occurs. Although the precise role CRP plays is unknown, it is a reliable marker for the presence and intensity of an inflammatory process.
"This is a huge paradigm shift in how we think about the root cause of cardiovascular disease," said Paul M. Ridker, a cardiologist at Harvard Medical School who headed the new study. "The implications are very big for detection and prevention."
In practical terms, the new findings are likely to launch a debate about whether -- or how soon -- routine CRP measurement should become a part of the complex calculation of heart attack risk that now goes on in thousands of doctors' offices every day.
In addition to varying naturally between individuals, bloodstream CRP levels are elevated in smokers, diabetics and people who are overweight. It can be reduced in a variety of ways, including with exercise and weight loss, and by taking certain drugs, including the cholesterol-lowering medicines known as statins. Some experts believe the test may provide a rough "global summary" of a person's cardiovascular risk.
"I look at it today as more important than LDL," said Eric J. Topol, head of cardiology at the Cleveland Clinic, referring to low-density lipoprotein, the "bad cholesterol." "I'm not turning my back on LDL, but if I was allowed only one test, I would use CRP," said Topol, one of the country's leading heart researchers.
Others, however, think enough questions remain unanswered -- particularly the issue of whether CRP-lowering interventions are helpful -- to keep it out of workaday medicine for the time being.
"It's a very exciting area for research, . . . but at present I don't think it should be part of clinical practice," said Daniel A. Levy, director of the Framingham Heart Study, the 54-year-old research project that has been the main wellspring of insight into risk factors for heart disease.
Biologists have known since the 1950s that virtually everyone develops thickened, cholesterol-filled patches in some of their arteries, starting in early adulthood. Heart attacks and strokes occur when one of those "plaques" breaks open, causing a blood clot to form and blocking the flow of blood and delivery of oxygen. If the obstruction is not quickly cleared, the tissue downstream -- heart muscle or brain cells -- dies.
Research over the last decade suggests that inflammation -- the complicated marshaling of immune-system cells and chemicals at the site of an injury -- tends to make plaques unstable. It appears that people with elevated CRP either have plaques that are more inflamed, or have a jumpier inflammatory response overall that makes their plaques more prone to rupture.
In the new research, Ridker and his colleagues at Brigham and Women's Hospital, in Boston, studied about 28,000 women age 45 or older participating in the Women's Health Study.
Over an eight-year period, those whose CRP levels were in the top 20 percent for the entire group had 4.5 times the risk of suffering a heart attack or stroke as those in the bottom 20 percent. For LDL cholesterol, the risk to people in the top bracket was 2.2 times that of people in the bottom.
In absolute terms, the chance of having a heart attack or stroke in the group was very small. More than 97 percent of women survived the eight years uneventfully. For those who did have a problem, however, high CRP was a stronger predictor of the chance of having a cardiovascular "event" than high LDL. (That difference equalized when other heart disease risk factors were taken into account, leaving CRP and LDL with roughly equal power to identify the women at elevated risk.)
The two tests, however, clearly measured different things and identified different individuals. Women with high CRP didn't necessarily have high LDL, or vice-versa.
Especially noteworthy was the fact that there were many people whose increased risk was only evident when CRP was measured. Specifically, women with above-average CRP and below-average LDL levels had more heart attacks and strokes than women with below-average CRP and above-average LDL. However, the first group would be less likely to be prescribed preventive treatment than the second.
That's because the average LDL level for all 28,000 women was 124 milligrams per deciliter, which is within the "near optimal" range set out in clinical guidelines from the federal government's National Cholesterol Education Program. In fact, 46 percent of all cardiac events occurred in women whose LDL levels were below 130, the upper limit of the "near optimal" range and a reading at which, in most cases, LDL-lowering drugs aren't prescribed.
Previous research by Ridker and his colleagues in somewhat smaller groups of men have produced similar findings, suggesting that elevated CRP denotes elevated risk in both sexes. Nevertheless, much remains unknown about CRP.
It's unclear, for example, whether the protein itself plays a role in plaque rupture, or if it is only a marker for other, as-yet-unrecognized triggering substances. Most important, there's no direct proof that lowering CRP decreases heart attacks. Ridker is proposing a randomized, placebo controlled trial in 15,000 high-CRP, low-LDL men and women to answer that.
"We've had a lot of singles and doubles, but I think this [new research] really represents a home run," said Antonio M. Gotto, dean of Weill Cornell Medical College who has done research on heart disease prevention. "What will really clinch the game is a clinical trial in which we treat on the basis of CRP regardless of the other risk factors."
However, such a trial may be complicated by the fact that statin drugs, the main prescription medicines for lowering LDL, are also the main way of lowering CRP.
"If you give a statin and it lowers risk, how do you know if it's because it lowers CRP or lowers LDL?" asked James Cleeman, coordinator of the National Cholesterol Education Program. "It's not a cinch to do."