By KATHLEEN FACKELMANN
A surprising report now suggests that a simple blood test may foreshadow heart attacks up to a decade in advance. That knowledge may encourage individuals to adopt a more healthful lifestyle.
The study also adds to evidence that the body's inflammatory response plays a crucial role in the clogging of the heart's vessels. The new findings "may turn out to have great importance in the future," says Charles H. Hennekens of Harvard Medical School in Boston. His team suggests that anti-inflammatory drugs may prevent a heart attack from ever happening.
The stakes are high. According to the Dallas-based American Heart Association, heart attacks kill nearly 500,000 people in the United States each year.
Researchers had long suspected that inflammation plays a central role in atherosclerosis, the buildup of the fatlike substance called cholesterol and other debris on the interior surface of the artery wall. However, they lacked supporting evidence from a large epidemiological study.
That's where Paul M. Ridker, a cardiologist at Harvard, comes in. Ridker and his coworkers knew that people who have just suffered a heart attack have a chemical marker of inflammation, called C-reactive protein, in their blood. The researchers wondered whether the protein could serve as an indicator of risk in healthy people.
The team turned to the Physicians' Health Study, an investigation of more than 22,000 male physicians. The group focused on 1,086 of the participants, half of whom had developed heart disease over the course of the 14-year study. All had had blood collected and stored at the beginning of the research effort. Ridker's group decided to measure concentrations of C-reactive protein in this blood. The protein is a naturally produced inflammatory substance that sends white blood cells to the site of an injury or infection. If prolonged or excessive, however, this response can harm body tissues.
Not surprisingly, since all of the men were healthy at the study's onset, the concentrations of C-reactive protein were considered normal. The researchers discovered, however, that men with readings in the top 25 percent of the test group had a much higher risk of heart attack or stroke than men with lower concentrations.
"People with high-normal values ended up over the next 10 years of their lives having three times as many heart attacks and twice as many strokes as did those who had lower levels of this particular protein," Ridker says. "What that's telling us is that inflammation is present 5, 6, 8, 10 years in advance of the heart attack," he adds.
The correlation between this protein and a future heart attack is independent of known risk factors such as smoking, hypertension, or even high cholesterol, the authors note in the April 3 New England Journal of Medicine (NEJM).
"It is truly remarkable that they were able to find a correlation between this marker of inflammation and events many years later," comments Peter Libby, an inflammation researcher at Harvard. "That's the real surprise for me."
In an editorial in the same issue of NEJM, Attilio Maseri of the Catholic University of the Sacred Heart in Rome calls the study's findings intriguing. "The time has come to reexamine the pathogenic components of [a heart attack]," he says.
The Harvard team's results hint that researchers may soon have a novel heart attack predictor. By measuring the concentration of C-reactive protein, doctors may flag people who, despite normal cholesterol counts, face a higher-than-average chance of stroke or heart attack in the coming years.
"We may have a new method of detecting risk in this group," Ridker says. Such a test might add weight to the widespread public health admonitions to eat a low-fat diet, exercise regularly, and stop smoking--habits thought to avert heart and blood vessel disease.
A lot of people ignore such recommendations because they believe a heart attack's not likely to happen to them. "But are they really at low risk?" Ridker asks. "This [test] might change their perception."
The study also suggests that certain people may benefit from drugs to reduce inflammation. At the start of the Physicians' Health Study, the researchers placed participants at random in one of two groups. Volunteers in the first group took an aspirin every other day. The rest took a dummy pill on the same schedule. The researchers designed this part of the study to test aspirin's ability to ward off heart attacks. In 1988, they reported that aspirin dramatically cut the risk of a first heart attack in middle-aged men (SN: 1/30/88, p. 68).
The new analysis elaborates on aspirin's ability to prevent heart attack. Among the men with the highest C-reactive protein concentrations at the beginning of the study, taking aspirin correlated with a large, statistically significant reduction in heart attack rate. For men with the lowest concentrations, the correlation was not statistically significant.
"The very people who were getting the biggest benefit from aspirin had the most inflammation," Ridker says.
Aspirin is known to discourage the formation of blood clots. Such action helps prevent heart attacks, which strike when a blood clot gets lodged in a plaque-clogged artery. The new findings suggest that aspirin's ability to subdue inflammation is also valuable in fighting heart attacks, Ridker says.
The classic view of atherosclerosis needs an overhaul. For years, cardiologists thought of the artery as a rigid tube with cholesterol and other goo piling up inside, much as a bathroom pipe gets clogged with debris.
Today, increasing evidence shows that atherosclerosis isn't simply a mechanical plugging of the pipes. "It's now clearly recognized that an atherosclerotic plaque is a much more dynamic set of circumstances," inflammation researcher Stephen Prescott of the University of Utah in Salt Lake City told Science News. Indeed, the data suggest that inflammation is "central to the pathogenesis" of atherosclerosis, he says.
In the 1970s, Russell Ross of the University of Washington School of Medicine in Seattle put forth the theory that an injury to the blood vessel wall kicks off the insidious process of inflammation and plaque formation. Various agents may cause such an injury. People with high cholesterol concentrations also have high concentrations of carrier molecules called lipoproteins, which can oxidize into dangerous compounds known as free radicals. Free radicals also harm the blood vessels of people who smoke cigarettes. Finally, some researchers think that infectious microbes damage the blood vessel wall and trigger atherosclerosis (see sidebar).
In any event, the body mounts an inflammatory response to the injury. If the cause of that injury persists, the protective action of the white blood cells goes awry, says Ross, and inflammation becomes excessive.
The inflammation-causing chemicals released by white cells can further harm the blood vessel wall. White cells congregate at the site of the injury, becoming engorged with fat molecules and forming the first signs of atherosclerosis--the fatty streaks that develop as early as the teenage years (SN: 1/20/90, p. 37).
The body tries to heal that damage by sending in smooth muscle cells to cover the fatty streak and repair the wall. Over the years, layers of fat and cells are deposited on the once-pristine artery surface. By the fifth or sixth decade of life, many people have hardened plaque that significantly narrows the blood vessel.
For years, researchers have been building the basic framework for this view of atherosclerosis. Now, Ridker's team has added epidemiological support.
What's next on the research agenda? The aspirin data hint at a bold new approach to the prevention of heart disease: Quench the chronic inflammation of the blood vessels. This approach "clearly needs to get tested," Ridker says, adding that other drugs may prove more effective than aspirin.
Indeed, a team at Harvard led by Charles N. Serhan has used current knowledge of how aspirin works to design two new anti-inflammatory compounds. Serhan says these agents are much more powerful than aspirin. They stop inflammation by telling white cells to quit migrating to the site of injury, he explains. Could such research lead to drugs that safely stop inflammation in the arteries of people with atherosclerosis? "That would be my biggest dream come true," Serhan says. So far, however, his team has tested these agents on inflammation only in mouse ears, not the coronary arteries of people. He reports his findings in the May 5 Journal of Experimental Medicine.
The goal of such research is to find a defense against atherosclerosis itself. "Is it possible that taking a particular agent over a period of time would keep the disease at such a low-grade level that it would never prove to be a problem?" Ross asks. "I don't know the answer to that."
Such an antidote could rewrite the future for an estimated 2.2 million people in the United States who harbor plaque-clogged arteries.
Epstein, S., et al. 1996. Association between prior cytomegalovirus infection and the risk of restenosis after coronary atherectomy. New England Journal of Medicine 335(Aug. 29):624.
Ridker, P., et al. 1997. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. New England Journal of Medicine 336(April 3):973.
Serhan, C., et al. 1997. Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: Evidence for anti-inflammatory receptors. Journal of Experimental Medicine 185(May 5):1693.
Libby, P. 1995. Molecular bases of the acute coronary syndromes. Circulation 91(June 1):2844.
Raloff, J. 1997. Unclogging arteries? Radiation helps. Science News 151(June14):364.
Ross, R. 1993. The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature 362(April 29):801.
Charles H. Hennekens
Brigham and Women's Hospital
900 Commonwealth Avenue
Boston, MA 02215-1204
Brigham and Women's Hospital
900 Commonwealth Avenue
Boston, MA 02215-1204
Department of Pathology
University of Washington School of Medicine
Seattle, WA 98195
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