By William J. Cromie

Gazette Staff

An easy, inexpensive way to detect those most likely to suffer a future heart attack or stroke has been discovered by Medical School researchers. The method is independent of smoking, high blood pressure, high cholesterol, being overweight, and other common risk factors.

The researchers also found that aspirin significantly reduces the chance of a first heart attack and stroke in those at highest risk.

"We made very sensitive measurements of a common indicator of inflammation in the blood, called plasma C-reactive protein, and found that men with the highest levels had three times the risk of heart attack compared to those with the lowest levels," said Paul Ridker, assistant professor of medicine. "Risk for ischemic stroke was two times higher." Ischemic stroke occurs when clots plug arteries bringing blood to the brain.

"The higher the level of this inflammation factor, the more the risk is reduced by aspirin," Ridker added. "This raises the possibility that other anti-inflammatory agents may help to prevent heart disease and stroke."

Common brand names of such agents include Advil, Excedrin, Motrin, and Nuprin.

Cutting the Risk

Ridker and his colleagues recruited men who participate in the Physicians' Health Study, a joint effort of the Medical School and Brigham and Women's Hospital. This is the same study that showed, eight years ago, that an aspirin every other day cuts the risk of first heart attack almost in half (44 percent). Later Harvard studies found the same is very likely to be true in women.

Tests have already begun to determine whether the protein serves as a useful predictor for women as well as for men. The researchers probably would be surprised if it didn't.

Men in the test, all of whom had no history of heart attack or stroke, were split into four groups. One took an aspirin every other day, one a vitamin pill, one took both, and one took neither. About 15,000 of these men submitted blood samples for measurements of their levels of the inflammation marker.

Five hundred forty-three of them had a heart attack, stroke, or blood clots in their veins during the succeeding eight years. They were matched with 543 others who remained healthy, and levels of marker protein and aspirin use in the two groups were compared.

Those with the highest levels of the protein suffered the most heart attacks and strokes. Their risk was independent of other factors known to predispose men to cardiovascular disease, such as smoking, high blood pressure, and a diet high in fat.

"That's an important point," said Ridker. "Such risk factors only detect about half of the people who have heart attacks and strokes. Both can occur without the presence of any of these factors."

Those at highest risk, as measured by the new predictor, cut their chances of having a heart attack by more than half (56 percent) when they took aspirin regularly. Those with less of the protein in their blood did not lower their risk as much.

"Everyone benefited from the aspirin," Ridker noted. "Those with the highest levels of inflammation benefited the most."

The reduction in risk is not much greater than that found in the earlier studies of men and women, which did not account for the C-reactive protein. However, the important point is that a promising new way has been discovered to predict who is at highest risk for heart attack and stroke, two of three biggest killers in the industrial world. Heart attacks kill about 500,000 Americans every year; another 150,000 die from strokes or brain attacks.

A major next step is to determine details of the link between inflammation and the thickening of artery walls that leads to clogging of blood vessels serving the heart and brain. Ridker notes that such studies are already under way.

When you become injured or ill, your levels of C-reactive protein rise as the immune system reacts. That activity produces inflammation as blood cells and plasma rush to act in the body's defense. Measurements of such inflammation are routinely made in clinics and hospitals.

"But the levels we work with are much lower than those associated with acute injury or disease," Ridker explained in an interview. "I call the condition 'micro-inflammation.' It's a chronic irritation in otherwise healthy people. We don't know yet what causes the inflammation or exactly how it's associated with atherosclerosis."

Ridker and his collaborators at the Medical School, the School of Public Health, and the University of Vermont report details of their studies and conclusions in today's New England Journal of Medicine. An editorial in the same issue by Attilio Maseri, of Catholic University of the Sacred Heart in Rome, congratulates the Ridker team for venturing beyond accepted ideas about inflammation and atherosclerosis and exploring the medical equivalent of the "hidden side of the moon." "The study by Ridker et al.," he writes, "provides convincing evidence that among normal men, [blood plasma] levels of C-reactive protein are predictive of heart attack and ischemic stroke."