(Circulation. 1996;94:872-873.)
© 1996 American Heart Association, Inc.
Articles |
Does Atherosclerosis Have an Infectious Etiology?
the University of Texas–Houston Medical School.
Correspondence to L. Maximilian Buja, MD, Dean, The University of Texas–Houston Medical School, 6431 Fannin–MSB G.010, Houston, TX 77030. E-mail buja@dean.med.uth.tmc.edu.
Key Words: Editorials • atherosclerosis • viruses • follow-up studies
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Introduction |
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 Top Introduction References |
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Atherosclerosis develops as a response of the vessel wall to injury.1 Careful review of epidemiological studies indicates that the classic risk factors, eg, hypercholesterolemia, cigarette smoking, and hypertension, account for the majority but not the entirety of the etiology and pathogenesis of the clinical complications of atherosclerosis, including ischemic heart disease and acute myocardial infarction.2 3 Furthermore, exact knowledge regarding the mechanisms by which the various established risk factors contribute to the development and progression of lesions is incomplete. These facts have led investigators to pursue other possible etiologies and factors that may be involved in the etiology and pathogenesis of atherosclerosis and its complications.
An alternate explanation that recently has received considerable attention is the infectious theory of atherosclerosis. The hypothesis that infectious agents are causal agents in atherosclerosis originally was formulated in the first two decades of this century.4 5 However, this concept received little attention until the late 1970s, when Fabricant et al6 showed that chickens experimentally infected with an avian herpes virus developed florid vascular lesions similar to those of human atherosclerosis. Subsequently, many investigators have reported observations implicating certain infectious agents in human atherosclerotic disease. Specifically, observations have been presented implicating Chlamydia pneumoniae, Helicobacter pylori, HSV, and CMV as possible primary etiologic factors or cofactors in the pathogenesis of atherosclerosis, including ischemic heart disease and cerebrovascular disease.7 8 9 10 11 12 13 14 15 Two basic lines of evidence have been presented: (1) detection of the agent in atherosclerotic lesions by immunocytochemistry and molecular biology and (2) epidemiological evidence based on serological data implicating an association between atherosclerotic disease and positive serology.
Nevertheless, the proof for the etiologic role of a particular agent is incomplete to date, and the infectious etiology remains controversial. The simple demonstration of a prevalent microbe in atherosclerotic lesions does not prove a causal role for the agent. Furthermore, the high sensitivity of molecular techniques, including the polymerase chain reaction, raises concerns regarding the possibility of a high rate of false-positive reactions. Similarly, cross-sectional evidence of an association of positive serology and disease at a single point in time sheds little light on the potential causative role of the agent in disease progression. Also, the relative importance of infectious agents and other risk factors is not clear.16 17
In this issue of Circulation, Nieto and associates18 provide a new approach to the evaluation of the potential pathogenic role of one infectious agent, namely, CMV, in the pathogenesis of atherosclerosis. Specifically, Nieto and associates present the results of a cohort study of CMV infection as a risk factor for carotid intimal-medial thickening, a measure of subclinical atherosclerosis. Longitudinal data were obtained by use of a case-control methodology nested within a historical cohort. The case subjects were 150 individuals with elevated carotid IMT measured by B-mode ultrasound at the first two examinations of the Atherosclerosis Risk in Communities study (1987 through 1992). Control subjects were 150 age- and sex-matched individuals with low IMTs. Antibody titers for CMV and HSV1 and HSV2 were measured in sera obtained in 1974 as part of a community-wide survey conducted in Washington County, Maryland. The case subjects with high IMTs had higher mean CMV antibody titers in the 1974 sera than the control subjects, although the difference was not statistically significant when adjusted for other cardiovascular risk factors. However, the investigators found a graded relationship between the odds of intimal-medial thickening and the levels of CMV antibodies, and this relationship remained significant after adjustment for the major cardiovascular risk factors (P=.013). The adjusted odds ratio for a high CMV antibody titer (P/N value 
20) compared with a P/N value <4 was 5.3 (95% CI, 1.5 to 18.0). Interestingly, the associations between HSV1 and HSV2 titers, carotid IMT, and cardiovascular risk factors were weaker and not statistically significant. The authors conclude that the results from this first population-based cohort study of CMV infection and carotid intimal-medial thickening are compatible with the hypothesis of a causative role of CMV in atherosclerosis.
This study is noteworthy for several reasons. The population-based methodology with longitudinal follow-up of case and control subjects provides additional powerful evidence in favor of a relationship between a prior CMV infection and the subsequent development of atherosclerotic disease. Furthermore, the use of ultrasound provides serial noninvasive evaluation of the progression of atherosclerotic disease. However, there are certain cautions that must be considered to avoid overinterpretation of the significance of the study. The echocardiographic analysis provides indirect evidence of subclinical atherosclerotic disease in only one vascular bed. The presence or absence of atherosclerotic disease is regarded as an all-or-nothing phenomenon based on an arbitrary cutoff point. This obviously is an oversimplification of a continuum from normality to severe disease. Similarly, an arbitrary cutoff point is used for positivity or negativity for CMV infection. The strength of the association between intimal-medial thickening and a positive CMV titer was not so strong as to exert a statistically independent influence on the presence or absence of atherosclerotic disease when adjusted for other risk factors. However, the strongest evidence for an association with CMV infection is the fact that there was a graded relationship between the odds of intimal-medial thickening and the levels of CMV antibodies that remained significant even after adjustment for the main cardiovascular risk factors.
In summary, Nieto and associates have provided a novel approach to the evaluation of the pathogenic role of infectious agents in atherosclerosis. Demonstration of a longitudinal influence of prior CMV infection with the subsequent development of subclinical atherosclerotic disease in the carotid arteries strengthens the argument for a pathogenic role of CMV infection and possibly other pathogens in the progression of atherosclerotic disease. However, the study does not provide information regarding the cellular and subcellular events that may be involved. The data also suggest that progression of the disease requires an interaction between CMV infection and the influence of the other known risk factors. Also, the study is silent as to the potential relationship of prior CMV infection and progression to clinically overt atherosclerotic disease. Further studies building on this novel and provocative study are in order.
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Selected Abbreviations and Acronyms |
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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