Two Studies Suggest a Protein Has a Big Role in Heart Disease

By GINA KOLATA

Published: January 6, 2005

Reducing the levels of a certain protein secreted by the body may be as powerful a tool in slowing heart disease and preventing heart attacks and cardiac-related death as lowering cholesterol, two teams of researchers are reporting today.

The studies, being published in The New England Journal of Medicine, provide the strongest evidence yet that the protein - known as CRP, for C-reactive protein - plays a role in heart disease.

The participants were patients with severe heart disease who were taking high doses of statin drugs, which reduce both cholesterol and CRP. Lower CRP levels, the researchers found, were linked to a slower progression of atherosclerosis and fewer heart attacks and deaths. And this effect was independent of the effect of lowering cholesterol.

"What we now have is hard clinical evidence that reducing CRP is at least as important as lowering cholesterol," said Dr. Paul Ridker of Brigham and Women's Hospital in Boston, the lead author of one of the studies.

But other heart disease researchers cautioned that more work was needed to prove that CRP directly causes heart disease. And most agreed that because the new studies involved only people with severe heart disease, it remained unknown whether healthy people would benefit from reducing their CRP levels.

Still, the study investigators said they suspected that the results would be shown to apply more broadly. If they are correct, a huge new market for the already popular statins could be opened among people whose cholesterol levels are normal but who have high levels of CRP. Of people stricken by heart attacks, half have normal cholesterol readings.

Dr. Ridker's study addressed the question of whether CRP levels independently predicted heart attacks and deaths.

The second study, by Dr. Steven E. Nissen of the Cleveland Clinic and his colleagues, asked whether CRP independently predicted heart disease progression.

In both cases, the investigators concluded, the answer was yes. (They, like most researchers in this field, have received support from drug companies, and Dr. Ridker is also an inventor of a test for CRP that his institution licensed. He and his laboratory profit from the use of the test.)

Some heart disease experts said the new studies offered persuasive evidence that doctors should focus on keeping CRP levels low in patients with severe heart disease.

"This is missing-link evidence," said Dr. Sidney Smith, a cardiologist at the University of North Carolina who is a past president of the American Heart Association and co-chairman of a committee of the heart association and the American College of Cardiology that sets treatment guidelines.

Others, though, said CRP could instead be a marker for something else being fought by statin drugs to reduce heart disease risk.

"These are very important papers," said Dr. James I. Cleeman, coordinator of the National Cholesterol Education Program at the National Heart, Lung and Blood Institute. "They are provocative. But we need to recognize that the relationship between CRP and heart disease is a developing story. This adds to the evidence, but I'm not sure it settles the issue."

CRP levels are low in healthy young people - usually less than one milligram per liter of blood - but they rise with age and with obesity, diabetes, smoking and a sedentary life. If people lose weight, stop smoking, exercise or take oral diabetes drugs, their CRP levels fall. But a third of the population has levels greater than three milligrams, and levels that high have been associated with heart disease risk, Dr. Ridker said.

Even before the new findings, evidence had been mounting that CRP and heart disease were somehow linked.

Scientists have developed hypotheses to explain why, proposing that the protein could cause plaque to develop in coronary arteries, lead plaque to burst open or bring on the formation of blood clots that then block arteries and cause heart attacks. Some drug companies have started programs to develop drugs that make a specific target of CRP and prevent its synthesis.