By William J. Cromie

Gazette Staff

It's not only smoking, eating large amounts of cheesecake, and lack of exercise that leads to heart attacks. It could very well be a long, slow process of inflammation, according to new evidence found by researchers at the Medical School.

Their study links relatively high levels of a substance in blood that increases the "stickiness" of blood vessels to atherosclerosis and heart attacks. The researchers tied the sticky stuff to heart attacks that killed 474 medical doctors participating in the study. These sticky molecules occur naturally as a means of fighting infection, but they can also accelerate formation of deposits that close off arteries bringing blood to the heart.

"This a gradual, long-term process lasting 20 to 25 years," says Paul Ridker, associate professor of medicine. "But it ends in minutes or seconds with a heart attack. It provides a clue as to why people start to develop atherosclerosis at a young age."

Last year, Ridker and his colleagues found another compound, called C-reactive protein, which raises the risk of heart attacks and stroke in men. Both it and the sticky molecules are markers of the inflammatory process by which the body responds to injury and heals itself.

Their presence may account for heart attacks that strike people who don't have high blood pressure, elevated cholesterol, and other obvious risks factors. For example, as many as half of all heart attacks occur in men and women who don't have high cholesterol.

"By measuring the inflammatory process in blood vessels, we might be able to better predict heart disease," Ridker notes cautiously. Once detected, lifestyle changes and drugs might slow the inevitable march to heart disease. Aspirin, for example, reduces both blood clotting and inflammation, as do other more expensive drugs.

Unsolved is the mystery of what starts the hidden inflammation in the first place. One theory implicates viruses, bacteria, and other microbes. Suspects include herpes and other viruses, the bacteria responsible for ulcers, and Chlamydia pneumoniae, a common cause of respiratory illness.

This theory raises the frightening possibility that people might catch heart disease in the same way they are infected by viruses and bacteria that cause flu or tuberculosis. Microbes have been found in atherosclerotic plaque scraped from human blood vessels, but no one has proved that one caused the other. Those who don't dismiss the idea say it might account for only a small percentage of heart disease. Ridker calls it this an area that needs more research.

Living Linings

Scientists refer to the sticky molecules as CAMs, or cellular adhesion molecules. They reside in the thin lining of blood vessels. Such linings were once thought of as mere biological Saran Wrap, existing for the sole purpose of preventing blood from leaking out of arteries and veins. But many years of research at the Medical School has shown that vessel linings are dynamic organs that play a major role in fighting infection.

"Rather than passive tubes through which the heart pumps blood, these vessels continuously secrete molecules necessary to combat infections and to keep arteries from becoming clogged," notes Michael Gimbrone, Friedman Professor of Pathology.

Working at Brigham and Women's Hospital in Boston, Ridker and his team are the first to link a CAM called ICAM-1, or intercellular adhesion molecule type 1, to future risk of a heart attack.

They measured levels of this molecule in the blood of medical doctors whom they followed for nine years. All were healthy at the start of the experiment, but 474 of the physicians suffered a first heart attack during the followup. These men were matched with 474 doctors who did not develop heart disease.

"Those with higher levels of ICAM-1 increase their risk of a first heart attack by 80 percent," Ridker explains. "I want to emphasize that such men don't have a disease. They aren't sick or abnormal. Their levels of ICAM-1 merely sit at the high end of the normal range."

Ridker's group also discovered that men with the highest levels of C-reactive protein in their blood had three times the risk of heart attack, and two times the risk of stroke, compared to those with the lowest levels. Studies are being done to determine if the same holds true for women.

"We're well along the way to completing a study that will answer this question," Ridker says. There doesn't appear to be any reason why adhesion molecules would act differently in women.

"C-reactive protein tells us there's a problem," Ridker says. "ICAM-1 gives us insight into exactly what's happening."

Adhesion molecules can pick white cells out of blood as they float by. These white cells, called monocytes and macrophages, destroy invading microbes like viruses and bacteria. The first step in getting them to the site of an infection involves a union with an adhesion molecule.

Apparently, there is a harmful side to this healing process. In some people, sticky white cells get stuck between the blood vessel lining and the layer of muscles behind the lining. They start building what are called foam cells, which become collection points for oxidized low-density cholesterol, clumps of blood platelets, decaying muscle cells, fibrous tissue, and even hard calcium deposits. This arterial refuse then causes raised patches, or plaques, that disrupt, then block, flow of blood.

A Clear Warning

The longer inflammation is at work, the greater the risk of heart attack. "The predictive value of increased ICAM-1 levels didn't appear until two to four years into our nine-year followup," Ridker reported in the British medical journal Lancet. "During years four to eight, the effect became more prominent."

The kind of warnings provided by relatively high levels of ICAM-1 and C-reactive protein "should motivate people to take risk factors they can control more seriously," Ridker adds. Some scientists speculate that benefits of lowering high cholesterol levels and elevated blood pressure, not smoking, exercising, and eating properly could be substantially greater for people with elevated inflammation than for those without it.

"An aspirin every other day provides an inexpensive defense against blood clotting and inflammation," Ridker notes. "We're also excited about new cholesterol-lowering drugs such as pravastatin (Pravachol)."

Drugs have been developed at Harvard and elsewhere to prevent adhesion molecules and white cells from sticking together. Such agents block sites on the white cells where the adhesion molecules dock.

"We hope the results of our research will spur further investigation of these experimental drugs," Ridker says.

Meanwhile, he and his colleagues are trying to answer some basic questions. What starts the smoldering inflammation? They are checking the blood of the physicians in their study for evidence of chronic viruses, bacteria, and other microbes like Chlamydia pneumoniae.

If these infectious microbes aren't responsible for the heart-stopping buildups, what is? One suspect is cytokines, molecules that transmit signals among cells and direct the traffic of white cells to infection sites. "If cytokines are overactive, perhaps we can use drugs already available to slow their activity," Ridker speculates.

To help support such research, Ridker has just been awarded a $900,000, three-year grant from the National Heart, Lung, and Blood Institute.