Researchers examined the hearts of people who had died suddenly to determine if they had stable or ruptured plaques in their blood vessels. They also determined C-reactive protein (CRP) levels from post-mortem blood samples and used a special staining technique to look at CRP levels in the plaque itself. Researchers found that people who had sudden cardiac death had higher levels of CRP in their blood and in their plaque than those who died from non-cardiac causes.
"Our research provides the first indication that CRP is a risk factor for atherosclerotic vascular disease and sudden death," says lead investigator Renu Virmani, M.D., a researcher with the U.S. Armed Forces Institute of Pathology in Washington, D.C.
Scientists have known for some time that elevated CRP in the blood indicates damage to arterial walls. However, until now it has not been known that blood levels also correlate to levels within plaque and its vulnerability to rupture, says Virmani.
"This is the first time it has been linked to sudden death from cardiovascular disease," she says. "If circulating CRP levels are elevated, there are more vulnerable plaques. It is that simple. It is very important to identify vulnerable plaques in order to begin treatment."
C-reactive protein can increase 1,000-fold in the bloodstream in response to acute infection, trauma, burns, and other inflammatory conditions. It is also released into the bloodstream when blood vessels leading to the heart are constricted or damaged.
Virmani and her colleagues examined post-mortem blood samples and arteries from 302 autopsies of men and women lacking any inflammatory conditions other than atherosclerosis. These included 73 deaths from arterial blockages caused by plaque rupture or erosion, 71 in persons with stable plaque, and 158 controls - people who died of non-cardiac sudden death without any conditions associated with elevated CRP levels.
Along with CRP levels in plaque and in blood serum, the overall plaque burden on the heart, total cholesterol, diabetes, smoking history, and body mass index was determined for each subject. The number of "thin-cap" plaques per heart also was determined. These plaques, also called atheroma, are composed of cholesterol, lipid materials and lipid macrophages - large cells within artery walls that ingest other microorganisms, cells and foreign matter. Those with thin caps are the least stable and most likely to rupture unexpectedly. CRP levels were compared and subjects were stratified into highest and lowest quintiles.
"It's exciting to think we may be able to detect the culprit lesion that might kill a patient," explains Virmani. "There are people walking around with high CRP levels who have no idea they are at risk because all the other signs appear normal. CRP is the only abnormality that gives rise to heightened risk of sudden death once factors such as pneumonia and other conditions that raise CRP levels are factored out."
The researchers found the median CRP was 3.2 micrograms per milliliter (ug/mL) in acute plaque rupture; 2.9 ug/mL in plaque erosion; 2.5 ug/mL in stable plaque; and 1.4 ug/mL in the control group.
In the study, 52.8 percent of people whose plaque had ruptured had serum CRP levels above 3 ug/mL, compared with 20 percent of controls. About 39 percent of people with eroded plaques had levels above 3 ug/mL, and 35 percent of individuals with stable plaque had levels above 3 ug/mL.
Previous studies have shown that baseline plasma levels of circulating CRP can predict risk of future stroke and heart attacks. In unstable angina, elevated CRP levels are associated with poorer disease prognosis. This study shows CRP is also significantly elevated in patients with coronary artery disease, both with and without acute coronary thrombosis.
The only other predictor of sudden cardiac death besides CRP was cigarette smoking. About 70 to 80 percent of people with eroded plaques were smokers compared with 40 percent of people with stable plaque.
"In the future, all patients should have their CRP levels checked. That way we can intervene with lifestyle counseling and drugs like statins and aspirin," Virmani says.
The special staining of CRP used in this study is still an experimental tool and only a few large hospital laboratories can perform the procedure, says Virmani.
This research was supported in part by a grant from the National Institutes of Health.
Co-authors of the study are Allen P. Burke, M.D.; Russell P. Tracy, Ph.D.; Frank Kolodgie, Ph.D.; Gray T. Malcolm, Ph.D.; Arthur Zieske, M.D.; Robert Kutys, M.S.; Joseph Pestaner, M.D.; and John Smialek, M.D.
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