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ecent Columbia research has shown that blacks, Hispanics, and whites have different risk factors for stroke. Using data from the Northern Manhattan Stroke Study, an 11-year ongoing study of stroke and stroke risk factors in approximately 2,000 ethnically diverse stroke patients and controls in the area, researchers found that high blood pressure and diabetes are more significant risk factors for stroke in African-Americans and Hispanics. Irregular heart rhythms and coronary artery disease, though, are more important factors for whites.

But to better understand stroke and its causes, a more complete picture of atherosclerosis or hardening of the arteries is needed, especially in light of growing evidence that inflammation plays an important part. For the past decade, researchers have begun to clarify how arteries harden and thicken not simply because of high cholesterol but because of inflammation, which can lead ultimately to clots forming in the blood vessels.

To learn more about inflammation’s role in atherosclerosis and ultimately in stroke, a group of Columbia Health Sciences researchers, led by Dr. Mitchell Elkind, assistant professor of neurology (in the Gertrude H. Sergievsky Center), investigated eight inflammatory markers in 279 individuals free of stroke from the NIH-funded Northern Manhattan Stroke Study. The researchers found that two markers in people under age 70 were strong indicators of atherosclerosis. The higher the level in the blood of the two markers—tumor necrosis factor receptors 1 and 2—the more likely the person was to have thicker carotid plaque, which is increasingly being viewed as a “pre-clinical disease” marker for atherosclerosis. The findings were published in the January issue of Stroke.

The presence of plaque in the carotid arteries, which bring blood to the brain, is associated with strokes, either by transmitting blood clots to the brain or by stopping blood flow and causing stroke. People with atherosclerotic carotid arteries also are more likely to have atherosclerosis in the coronary arteries and throughout the circulatory system, making them more susceptible to heart attack, too.

Tumor necrosis factor and its receptors are markers for inflammation that become elevated in the blood in a variety of infectious, inflammatory, and autoimmune diseases. Experimental evidence suggests that immune processes and inflammation play a role in the development of artery thickening. Elevated levels of tumor necrosis factor receptors may be a reflection of the inflammatory processes operating in the formation of plaques.

These receptor markers someday may allow doctors to diagnose atherosclerosis earlier and put preventive actions in place. Although Dr. Elkind says it is too soon to make treatment recommendations based on this research, the findings suggest anti-inflammatory drugs in the future might be used to prevent atherosclerosis and stroke.

Dr. Elkind’s group chose to look at eight inflammation markers: C-reactive protein, interleukin 1, interleukin 2, interleukin 2 receptor, interleukin 6, tumor necrosis factor-alpha, and tumor necrosis factor receptors 1 and 2. The researchers measured the levels of these markers in the blood and, using ultrasound technology, carotid artery plaque thickness. Statistical methods allowed them to correlate inflammation marker levels with the amount of thickening of the artery. No association between the markers and racial and ethnic groups could be found, perhaps because the sample was too small.

Co-investigator Dr. Ralph Sacco, associate professor of neurology at P&S and associate professor of epidemiology (in the Gertrude H. Sergievsky Center) in the Mailman School of Public Health, says he was surprised to find the relationship between tumor necrosis factor receptors and carotid artery plaque even in such a small sample size. “Getting these results from a small study implies the association was strong,” says Dr. Sacco, who is also associate chairman of neurology and director of the Northern Manhattan Stroke Study.

Although the study findings are interesting, they are limited because the scientists only analyzed data at one point in time and do not know if the markers will be predictive of stroke. But the Northern Manhattan Stroke Study is longitudinal, allowing the researchers to follow participants over time. Dr. Elkind and his colleagues are now measuring other inflammatory markers, such as tumor necrosis factor-alpha and the tumor necrosis factor receptors, in the blood collected from 125 patients and 250 controls in the stroke study for the past 11 years. The researchers will then see if any of the markers are associated with stroke. Other markers being investigated are Chlamydia pneumoniae and cytomegalovirus titers.

Following people over time also will allow the researchers to get a better sense of the sequence of events concerning inflammation and carotid artery plaque. “We believe that inflammation comes first and then carotid artery plaque is next, but what if it’s the other way around?” says Dr. Sacco, who added that more work is also being done on stroke risk factors. In a study of 3,300 stroke-free community residents, conventional risk factors such as high blood pressure and diabetes as well as emerging risk factors are being measured so that if a participant has a stroke, the researchers will be able to go back to investigate which factors were related to the stroke.

It remains unclear why the relationship for tumor necrosis factor receptors was not as strong for people over age 70. But Dr. Elkind speculates that as people get older and develop more plaque, the tumor receptors might be less important as indicators of atherosclerosis than other factors, such as diabetes, high blood pressure, or high cholesterol.

“The correlation between tumor necrosis factor receptors and carotid artery plaque is just one piece of the whole view of atherosclerosis and stroke,” Dr. Elkind says. “But it could be an important piece, especially if it leads to greater understanding and better treatments, although it probably will take some time to get to that point.”

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