CLINICAL STUDIES
Cytomegalovirus in the pathogenesis of atherosclerosis
The role of inflammation as reflected by elevated C-reactive protein levels
Jianhui Zhu, MD, PhD*,
Arshed A. Quyyumi, MD, FACC ,
James E. Norman, PhD ,
Gyorgy Csako, MD and
Stephen E. Epstein, MD, FACC*
* Cardiovascular Research Foundation, Washington Hospital Center, Washington, DC, USA
Cardiology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
National Institutes of Health, Bethesda, Maryland, USA
Manuscript received September 10, 1998;
revised manuscript received June 14, 1999,
accepted August 5, 1999.
Reprint requests and correspondence: Dr. Stephen E. Epstein, Cardiovascular Research Foundation, Suite 4B-1, Washington Hospital Center, 110 Irving Street, NW, Washington, DC 20010
OBJECTIVES
We hypothesized that cytomegalovirus (CMV) infection: 1) stimulates an inflammatory response, reflected by elevated C-reactive protein (CRP) levels, and 2) predisposes to coronary artery disease (CAD), in part, through CMV-induced inflammation.
BACKGROUND
Although some studies show an association between CMV and atherosclerosis, others do not. We believed that CMV exerted an atherogenic effect by inducing inflammation, and the disparate results may derive partly from individual variability in the capacity to control CMV inflammatory activity.
METHODS
Blood samples were tested for CMV seropositivity and CRP levels from 238 individuals being evaluated for CAD by coronary angiography.
RESULTS
An elevated CRP level (>0.5 mg/dl) was a significant CAD determinant even after adjustment for traditional CAD risk factors (odds ratio [OR] = 2.4; p = 0.02). Moreover, CMV seropositivity was significantly associated with increased CRP levels (p = 0.04 after adjustment for CAD risk factors), suggesting that CMV could evoke a subclinical inflammatory response. However, considerable host variation existed in this response to CMV. When adjusted for CAD risk factors, the OR for CAD were 1.3 in the subgroup with CMV seropositivity alone (p = 0.7), 2.3 in the subgroup with elevated CRP levels alone (p = 0.2), and 4.3 in the subgroup with combined CMV seropositivity and elevated CRP levels (p = 0.01).
CONCLUSIONS
Our results suggest that 1) CMV elicits a subclinical inflammatory response, but only in certain individuals, and 2) individuals with an inflammatory response appear susceptible to the atherogenic effects of CMV, whereas those without appear resistant. These results may partly explain the disparate results of studies attempting to relate CMV to atherogenesis.
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Abbreviations and Acronyms
| | CAD | = coronary artery disease | | CMV | = cytomegalovirus | | CRP | = C-reactive protein | | OR | = odds ratio |
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|
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|
|
|
|
|
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|
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|
|
|
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