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(Circulation. 1996;94:922-927.)
© 1996 American Heart Association, Inc.
Articles |
Cohort Study of Cytomegalovirus Infection as a Risk Factor for Carotid Intimal-Medial Thickening, a Measure of Subclinical Atherosclerosis
the Department of Epidemiology, The Johns Hopkins University School of Hygiene and Public Health (F.J.N., H.F., G.W.C., M.S.), Baltimore, Md; Division of Molecular Virology, Baylor College of Medicine (E.A., J.L.M.), Houston, Tex; and National Heart, Lung, and Blood Institute, National Institutes of Health (P.S.), Bethesda, Md.
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Abstract |
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Background Animal studies as well as clinical and cross-sectional epidemiological studies in humans have suggested a possible role of cytomegalovirus (CMV) and other herpesvirus infections in the development of cardiovascular disease.
Methods and Results The present report is based on a case-control study nested within a historical cohort. The case group comprised 150 individuals with elevated carotid intimal-medial thickness (IMT) measured by B-mode ultrasound at the first two examinations of the Atherosclerosis Risk in Communities (ARIC) Study (1987 through 1992). The control group comprised 150 age- and sex-matched individuals with low IMT. Antibody titers for CMV and herpesvirus 1 and 2 were determined in sera obtained in 1974 as part of a community-wide survey conducted in Washington County, Maryland. Case subjects had higher mean CMV antibody titers in 1974 sera than control subjects, although the difference was not statistically significant when adjusted for other cardiovascular risk factors. There was evidence of a graded relation between the odds of intimal-medial thickening and the levels of CMV antibodies that remained significant after adjustment for the main cardiovascular risk factors (P=.013). The adjusted odds ratio for a high CMV antibody titer (a positive/negative value 
20) compared with a positive/negative value <4 was 5.3 (95% confidence interval, 1.5 to 18.0).
Conclusions The results from this first population-based cohort study of CMV infection and carotid IMT are compatible with the hypothesis of a causal role of CMV in atherosclerosis.
Key Words: atherosclerosis • viruses • risk factors • carotid arteries • follow-up studies
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Introduction |
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Although initially formulated almost one century ago,1 2 the hypothesis that infectious agents might be implicated as causal agents in atherosclerosis received little attention until the late 1970s, when Fabricant et al3 showed that chickens experimentally infected with an avian herpesvirus developed pathological changes of the arteries very similar to human atherosclerosis.
Both antigens and nucleic acid sequences of CMV have been detected in smooth muscle cells from carotid artery plaques removed from patients during endarterectomy.4 5 Recent studies6 7 8 that used polymerase chain reaction demonstrated CMV DNA in arterial samples from vascular surgery patients more frequently than from control subjects.
Epidemiological studies9 showed that antibodies against CMV were elevated significantly in patients with angiographically defined coronary artery disease compared with control subjects. Previous cross-sectional analyses from the ARIC study10 showed moderate associations between antibodies to CMV and carotid IMT, a measure of subclinical atherosclerosis.11
The present report extends the previous analyses by adding a temporal component to the current evidence. Frozen sera collected in 1974 were available from a subset of participants from the Washington County, Maryland, subcohort of the ARIC study who participated in a county-wide survey.12 We report on the association of antibody titers to CMV and HSV in 1974 with IMT measured 13 to 18 years later as part of the ARIC study (1987 through 1992).
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Methods |
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Study Population
The ARIC study is a prospective investigation of the natural history and determinants of clinical and subclinical atherosclerosis. As detailed elsewhere,13 15 800 participants from four US communities were recruited, interviewed, and examined between 1987 and 1989. A total of 4020 participants were recruited in Washington County, Maryland. Of these, 3694 (94% of those alive) returned 3 years later for a second examination, conducted between 1990 and 1992.
Additional information came from a county-wide campaign conducted by the Johns Hopkins University Training Center for Public Health Research in the fall of 1974 to collect blood for a serum bank.12 A total of 21 061 adult residents of Washington County participated in this campaign by completing a brief health questionnaire, having their blood pressure determined, and donating 15 mL of nonfasting blood.14
An ad hoc computer program was used to link both databases on the basis of exact matches on both birth date and name (first and last or maiden name among women). As presented schematically in the Figure
, a total of 1410 individuals were identified among participants in the 1974 campaign and the ARIC baseline examination. Among these individuals, valid ultrasound measurements in both the baseline and the first follow-up ARIC visits were available for 1191 participants. Primarily because their serum samples had already been used for other nested case-control studies, 242 participants were excluded. The remaining 949 individuals constituted the source population for the selection of 150 cases of carotid atherosclerosis and 150 frequency-matched controls. The sample size was chosen on the basis of availability of resources, optimization of use of the serum specimens, and power calculations. For relatively frequent exposures (prevalence of 25% to 50%), a sample size of 150 per group provides adequate statistical power (80%) to detect an OR of 
2 or higher.
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Case-Control Definition
Subclinical carotid atherosclerosis was defined on the basis of measurements of the IMT of the carotid arteries obtained by B-mode ultrasound.11 Measurements were obtained by trained sonographers at three sites (common, bifurcation, and internal carotid) on both sides of the neck. Results were sent on magnetic tapes to the central ultrasound reading center.13 Between-reader and within-reader coefficients of reliability for average IMT in the three segments were all 0.90.15 For the present study, carotid atherosclerosis was defined on the basis of the average IMT for all measurements taken at the ARIC baseline and follow-up visits. The 150 participants with the highest overall mean IMT were included in the case group. Control subjects were the participants with the lowest mean IMT within 10-year age and sex strata. To guarantee an adequate overlap in the age and sex distribution of subjects in the case and control groups to ensure that further adjustment by use of multiple regression models would be feasible, the number of control subjects selected from each age-sex stratum was matched to the number of case subjects in that stratum.
Antibody Measurements
The serum samples collected in 1974 were frozen at -73°C. In August 1994, the samples were thawed, fractionated, and shipped with dry ice to the laboratory at the Division of Molecular Virology, Baylor College of Medicine, Houston, Tex. Antibodies were measured as described previously.9 16 17 Briefly, solid-phase radioimmunoassay was used for the detection of antibodies. The whole antigen of CMV strain AD169 and the major type-specific glycoproteins VP123 for HSV1 and VP119 for HSV2 were used as capture antigens. P/N values represent the ratio of the average counts of the test serum with viral antigen to the average counts of the test serum with control antigens from uninfected cells; the latter were always <2.
Serum samples were tested in pairs of one case and one control subject on the same plate. Laboratory personnel were blinded regarding the case-control status of each sample. Different cutoff points for P/N values were used to estimate the optimal definition of positive antibody status. Eight blind replicates of sera were submitted to the laboratory to evaluate laboratory reliability. The Pearson correlation coefficients between replicate pairs were .93, .86, and .74 for CMV, HSV1, and HSV2 P/N values, respectively.
Previous cross-sectional analyses from the ARIC study included carotid ultrasound case and control subjects selected among participants from among all four ARIC cohorts.10 Of the 300 Washington County participants selected as case and control subjects for the present study, 36 had been included in that previous study10 in which antibody status was determined by use of the same technique by the same laboratory from sera collected at the baseline ARIC examination (1987 through 1989). The pairwise Pearson's correlation coefficient between the 1974 and 1987 through 1989 CMV P/N values was .66. The corresponding correlations for HSV1 and HSV2 were r=.87 and r=.43, respectively.
Of the 300 serum samples, 6 had been thawed previously for other studies and refrozen. Although mean antibody titers in these samples were slightly lower than in the remaining samples, the difference was not statistically significant. Furthermore, when these 6 samples were excluded, the results were virtually identical to those presented in "Results" (data not shown).
Measurements of Covariates
Potential confounders or effect modifiers were assessed from histories taken at the time of the baseline ARIC visit in 1987 through 1989 (Figure
).13 Information on education (highest grade completed), cigarette smoking, and presence of diagnosed cardiovascular disease or diabetes was obtained by interview. Medication use was assessed by asking the participants to bring to the clinic all medications taken in the previous 2 weeks. Blood pressure measurements, anthropometry, and venipuncture were performed after participants had fasted for 12 hours. Blood pressures were measured with a standardized Hawksley random-zero sphygmomanometer after the subjects had been seated and resting for 5 minutes. The average of the second and third of three blood pressure measurements (with 30 seconds' rest between them) is used in the present report.
Blood specimens were drawn and processed according to a protocol described in detail elsewhere.18 19 Aliquots were centrifuged, frozen at -70°C, and shipped with dry ice to the ARIC central laboratories. Total cholesterol was measured by use of enzymatic methods.20
Statistical Analyses
Atherosclerosis case patients and control subjects were compared according to demographic characteristics and the presence of cardiovascular risk factors at the baseline ARIC examination. The associations of serum antibody levels with the covariates of interest were examined. Given their skewed distribution, mean P/N values were compared on a logarithmic scale (geometric mean). Comparison of mean log P/N values while controlling for covariates was performed by use of multiple linear regression methods. ORs that expressed the relation between 1974 antibody status and carotid atherosclerosis in 1987 through 1992 were obtained from multiple logistic regression models, adjusting for the frequency-matched variables (sex and age group). Additional logistic regression models were used to adjust for other potential confounders. We obtained trend tests by testing the statistical significance (Wald statistic) of the logistic regression coefficient for antibody levels as an ordinal single covariate in the logistic regression.
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Results |
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By design, the number of case and control subjects in each 10-year age- and sex-matched group was identical (Table 1
). On average, however, control subjects were somewhat younger than case subjects because of residual differences within the broad age groups used for matching: mean (SD) ages were 58.3 (4.8) and 56.7 (4.7) for case and control subjects, respectively. Reflecting the overwhelming predominance of whites in Washington County, all subjects were white except one case and one control subject who were black. Table 1 also shows the mean and range of IMT measurements in case and control subjects.
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As in previous cross-sectional studies from ARIC,21 the main coronary heart disease risk factors were all significantly associated with subclinical carotid atherosclerosis in the present study. The ORs for cigarette smoking (current versus never), hypercholesterolemia, hypertension, diabetes, and overweight at the baseline examination were 2.3, 3.2, 2.6, 3.5, and 2.8, respectively (all P<.01).
Table 2 shows the association between CMV antibody status in the 1974 sera and the presence of cardiovascular risk factors at the ARIC baseline examination. Elevated P/N values for CMV antibodies were significantly more common among women, those with lower educational attainment, hypercholesterolemic subjects, and hypertensives. Smokers, diabetics, and overweight or older individuals had elevated P/N values, but the differences were not statistically significant. Age (as a continuous variable) was only weakly correlated with CMV antibody titers (Pearson r=.08). The associations between HSV1 and HSV2 titers and cardiovascular risk factors tended to be weaker and statistically not significant (data not shown).
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The mean CMV P/N value was significantly higher in case subjects than in control subjects (Table 3). However, after adjustment for potential confounders, the difference diminished slightly and became statistically nonsignificant. When these analyses were stratified by hypercholesterolemia status, the highest CMV antibody levels were found among hypercholesterolemic case subjects (geometric mean of age-adjusted P/N ratio, 8.7). The relative difference in P/N ratio geometric mean between case and control subjects was slightly higher among hypercholesterolemic subjects (38%) than among those without hypercholesterolemia (27%). However, this possible interaction between hypercholesterolemia and CMV infection was not statistically significant (P=.23). No significant differences in the P/N values for HSV1 and HSV2 antibodies were found (data not shown).
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There was a pattern of increased odds of subclinical carotid atherosclerosis with increasing CMV P/N values (Table 4). The trend test was statistically significant even after adjustment for the main cardiovascular risk factors (P=.013). A high CMV P/N value of 20 was associated with an adjusted OR of >5 compared with low (<4) P/N values.
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The definition of case-control status in the present study was based solely on carotid IMT, regardless of the presence of clinical evidence of cardiovascular disease. However, 19 case subjects and 3 control subjects had prevalent coronary disease by use of clinical criteria (ECG Q wave or history of a myocardial infarction, coronary angioplasty, or coronary bypass). CMV antibody levels were higher among the 19 case subjects who had some evidence of clinical disease (age-adjusted geometric mean, 7.8) than among those without clinical disease (age-adjusted geometric mean, 7.3), although the difference was not statistically significant as a result of the small sample size. When the analyses presented in Table 4 were repeated after exclusion of the individuals with prevalent disease, the results were virtually identical (data not shown).
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Discussion |
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In this nonconcurrent prospective study, elevated levels of CMV antibody titers in sera collected in 1974 were shown to be associated with an increased risk of carotid intimal-medial thickening 13 to 18 years later. Although the mean viral antibodies for CMV fell short of statistical significance after risk-factor adjustment (Table 3
), a graded association with antibody titers was found to be strong, independent of other major risk factors, and statistically significant (Table 4). With regard to why the mean CMV antibody levels lost statistical significance with multiple adjustment (Table 3), it is of interest that the absolute magnitude of the difference changed little from the statistically significant crude difference. The loss of statistical significance after adjustment could stem from colinearity between antibody status and some of the adjustment variables. In addition, it could indicate that one of these variables is in the causal pathway of the hypothesized relation between CMV and atherosclerosis. For example, if one of the mechanisms for atherogenesis due to CMV infection is its role in altering lipid metabolism (see below), analysis of cholesterol-adjusted levels is less appropriate than evaluation of nonadjusted differences. As in a previous cross-sectional analysis from the ARIC study,10 the definition of carotid atherosclerosis was based on the average IMT of the carotid arteries. Although the clinical relevance of IMT is not entirely clear, its correlation with intimal-medial measurements in pathological specimens has been demonstrated.11 Moreover, IMT is consistently associated with classic cardiovascular risk factors21 and with novel risk factors22 as well as with incident clinical coronary disease.23 24 One possible limitation of the present study, however, is that the case definition is not based on any clinically relevant cutoff point for carotid IMT. Because the study participants were free-living, healthy individuals, we considered those individuals with the thickest IMTs to be "cases." To maximize the difference, we selected as the comparison group ("controls") those individuals of comparable age and sex with the thinnest IMTs. Also, to reduce the possibility of misclassification due to measurement error, we used the grand mean of all IMT measurements at the first two visits in the ARIC study for the selection of case and control subjects.
Compared with previous investigations at the same laboratory that used the same technique for determination of viral antibodies,9 10 we found a substantially higher prevalence of positive CMV antibodies in the present study population, particularly for very high antibody titers. There was a high correlation between 1974 and 1987 through 1992 CMV antibody P/N values (r=.66) among the few participants for whom both measurements were available. However, the median P/N value for CMV in the 1974 samples among control subjects in the present study was 8.3 compared with 3.8 among the 109 Washington County ARIC participants selected as control subjects in the previous cross-sectional analyses that used sera from 1987 through 1989.10 All quintiles above the median were substantially higher in the 1974 samples than in the samples from 1987 through 1989, whereas quintiles below the median were similar (not shown). We can only speculate about the reasons for these differences in CMV antibody status between the two time periods. It is possible that there was an epidemic of CMV in Washington County in the early 1970s.
The surprisingly high CMV titers in this sample made us explore a wide range of possible cutpoints. Regardless of the cutpoint used, a higher CMV antibody was consistently associated with atherosclerosis, although the strength and the statistical significance of the association varied depending on the definition used (data not shown). The strong OR associated with very high antibody titers (Table 4) has never been reported before and thus should be interpreted with caution.
With the exception of newborns and immunosuppressed individuals, CMV causes mostly subclinical infections, but the sites of latency are not well known.25 Several different organs and cell types could be sites for CMV latency, including blood cells and smooth muscle cells.4 25 26 Reactivation of latent CMV infection can occur, usually associated with immunosuppression,25 although it could also be associated with other types of psychological and physical stress. The high antibody titers seen in the present study may indicate a higher risk of frequent reactivation of a latent CMV infection, which in turn may cause smooth muscle cell changes and proliferation.27
The results of the present study are consistent with previous epidemiological studies9 10 as well as with experimental evidence that points to CMV as a potential risk factor for atherosclerosis and cardiovascular disease.3 4 5 6 7 8 The present study adds a new dimension to the investigation of the relation between viral infections and atherosclerotic disease. In cross-sectional epidemiological studies9 10 and in virological studies demonstrating the presence of virus antigen and genome in the plaque4 5 6 7 8 or the coronary arteries of trauma victims,28 the temporal relation between infectious agents and atherosclerosis cannot be clearly established. The virus could be an opportunistic bystander in the atherosclerotic tissue.10 However, by showing that antibody status determined in 1974 is associated with carotid atherosclerosis measured 13 to 18 years later, we provide support for temporality, an important criterion for a causal relationship.29 Despite the lack of information about carotid atherosclerosis at the time the serum was obtained, the progressive natural history of atherosclerosis leads to the assumption that cases identified in 1987 through 1992 had less disease in 1974, which would support a temporal relation between CMV infection and atherosclerosis. The results presented here also support evidence from follow-up studies30 of immunosuppressed cardiac transplant patients that demonstrated an increased incidence of graft atherosclerosis and mortality associated with CMV infection after transplantation. Other criteria for causality met in the present study include the strength of the association denoted by the high OR for the high antibody titers as well as the strong suggestion of a dose-response relation (Table 4).29
The negative results regarding HSV1 and HSV2 antibodies in the present study are also consistent with the literature. Although there is limited evidence from pathology studies linking HSV to atherosclerosis,28 immunocytochemical studies4 and epidemiological studies suggest no association or only a weak association for HSV1 or HSV2. Adam et al9 found no association between HSV1 or HSV2 serum antibodies and coronary disease. Sorlie et al10 found a weak, nonstatistically significant association between HSV1 and carotid atherosclerosis and no association for HSV2.
Regarding the plausibility of a causal association between CMV and atherosclerosis, several mechanisms have been proposed to explain how viruses may be involved etiologically in atherogenesis.31 32 Herpesviruses alter lipid metabolism in cultured cells from chickens33 as well as in cultured human and bovine smooth muscle cells.34 The original experiments by Fabricant et al3 showed that the atherogenic effect of viral infection was stronger when combined with experimentally induced hypercholesterolemia. In the present study, the difference in CMV antibody levels between case and control subjects was greater in hypercholesterolemic individuals. The interaction between CMV infection and hypercholesterolemia was not statistically significant, however, mainly as a result of limited power for subgroup analysis in the present study. Viruses could also induce an immunologic injury due to deposit of antigen-antibody complexes in the vascular tissues.28 Furthermore, CMV replication destroys proliferating smooth muscle cells, possibly impairing vessel repair of atherosclerotic lesions.35 The virus might promote smooth muscle cell mutation and lead to cell proliferation and formation of atherosclerotic plaques.36
Finally, viral infection might induce endothelial injury, triggering the development of the atherosclerotic plaque.37 This is supported by experimental findings demonstrating that CMV infection of the endothelium increases the adherence of polymorphonuclear leukocytes, one of the earliest steps in the atherogenesis process.38 A recent study27 demonstrated that the presence of CMV in smooth muscle cells from atherectomy specimens was associated with enhanced p53 accumulation in patients who developed coronary restenosis after angioplasty.
CMV is highly prevalent in human populations.25 39 As with atherosclerosis, the prevalence of positive CMV antibodies increases with age and is >60% among adult blood donors in many parts of the world.25 26 31 If CMV and other herpesviruses were causally related to atherogenesis, the possible public health implications could be extremely important. In animal models, the lipid accumulation as well as the increased atherosclerosis induced by experimental herpesvirus infection is prevented by immunization.40 41 Given the ubiquitous presence of these agents in humans, the assumption of even a modest relative risk would imply a large potential for prevention.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The ARIC study is performed as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55020, N01-HC-55021, and N01-HC-55022. Dr Comstock is supported in part by NHLBI career research award HL-21670. The Washington County serum bank is supported by research grant CA 47503 from the National Cancer Institute. The authors thank Dr Richey Sharrett at the National Heart, Lung, and Blood Institute, for his encouragement and assistance in all phases of the development of this research. The authors also thank Linda Schramm and Sandra C. Hoffman, MPH, at The Johns Hopkins Training Center for Public Health Research, Hagerstown, Md, for their help in managing and handling the serum samples. The Washington County clinical center, central laboratories, and the ultrasound reading center of the ARIC Cooperative Group, their institutions, coinvestigators, and principal staff who contributed to this report are as follows: The Johns Hopkins University, Baltimore, Md—Carol Shearer, Rita Timmons, Joyce B. Chabot, and Carol Christman; University of Texas Medical School, Houston, Tex—Valerie Stinson, Pam Pfile, Hoang Pham, and Teri Trevino; The Methodist Hospital, Atherosclerosis Clinical Laboratory, Houston, Tex—Doris J. Epps, Charles E. Rhodes, and Selma M. Soyal; Bowman Gray School of Medicine, Ultrasound Reading Center, Winston-Salem, NC—Christy Jones, Kathy Joyce, Mary Louise Lauffer, and Suzanne Pillsbury; and the University of North Carolina, Chapel Hill, Coordinating Center—Ken Kaufman, PhD, Ho Kim, MS, Charmaine M. Marquis, and Alison Meyer.
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Footnotes |
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Reprints requests to Dr F. Javier Nieto, Department of Epidemiology, The Johns Hopkins University School of Hygiene and Public Health, 615 N Wolfe St, Baltimore, MD 21205. E-mail jnieto@phnet.sph.jhu.edu.
Received January 16, 1996; revision received April 24, 1996; accepted May 6, 1996.
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B. Reinhardt, T. Mertens, U. Mayr-Beyrle, H. Frank, A. Luske, K. Schierling, and J. Waltenberger HCMV infection of human vascular smooth muscle cells leads to enhanced expression of functionally intact PDGF {beta}-receptor Cardiovasc Res, July 1, 2005; 67(1): 151 - 160. [Abstract] [Full Text] [PDF]
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M. Charakida, A. E. Donald, M. Terese, S. Leary, J. P. Halcox, A. Ness, G. D. Smith, J. Golding, P. Friberg, N. J. Klein, et al. Endothelial Dysfunction in Childhood Infection Circulation, April 5, 2005; 111(13): 1660 - 1665. [Abstract] [Full Text] [PDF]
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M. S. Smith, G. L. Bentz, P. M. Smith, E. R. Bivins, and A. D. Yurochko HCMV activates PI(3)K in monocytes and promotes monocyte motility and transendothelial migration in a PI(3)K-dependent manner J. Leukoc. Biol., July 1, 2004; 76(1): 65 - 76. [Abstract] [Full Text] [PDF]
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M. Smieja, J. Gnarpe, E. Lonn, H. Gnarpe, G. Olsson, Q. Yi, V. Dzavik, M. McQueen, S. Yusuf, and for the Heart Outcomes Prevention Evaluation (HOPE Multiple Infections and Subsequent Cardiovascular Events in the Heart Outcomes Prevention Evaluation (HOPE) Study Circulation, January 21, 2003; 107(2): 251 - 257. [Abstract] [Full Text] [PDF]
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A. Prasad, J. Zhu, J. P.J. Halcox, M. A. Waclawiw, S. E. Epstein, and A. A. Quyyumi Predisposition to Atherosclerosis by Infections: Role of Endothelial Dysfunction Circulation, July 9, 2002; 106(2): 184 - 190. [Abstract] [Full Text] [PDF]
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P. B. Gorelick Stroke Prevention Therapy Beyond Antithrombotics: Unifying Mechanisms in Ischemic Stroke Pathogenesis and Implications for Therapy: An Invited Review Stroke, March 1, 2002; 33(3): 862 - 875. [Abstract] [Full Text] [PDF]
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I. Buerger, J. Reefschlaeger, W. Bender, P. Eckenberg, A. Popp, O. Weber, S. Graeper, H.-D. Klenk, H. Ruebsamen-Waigmann, and S. Hallenberger A Novel Nonnucleoside Inhibitor Specifically Targets Cytomegalovirus DNA Maturation via the UL89 and UL56 Gene Products J. Virol., October 1, 2001; 75(19): 9077 - 9086. [Abstract] [Full Text] [PDF]
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S. Blankenberg, H. J. Rupprecht, C. Bickel, C. Espinola-Klein, G. Rippin, G. Hafner, M. Ossendorf, K. Steinhagen, and J. Meyer Cytomegalovirus Infection With Interleukin-6 Response Predicts Cardiac Mortality in Patients With Coronary Artery Disease Circulation, June 19, 2001; 103(24): 2915 - 2921. [Abstract] [Full Text] [PDF]
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S. F. Ameriso, E. A. Fridman, R. C. Leiguarda, G. E. Sevlever, and J. D. Spence Detection of Helicobacter pylori in Human Carotid Atherosclerotic Plaques Editorial Comment Stroke, February 1, 2001; 32(2): 385 - 391. [Abstract] [Full Text] [PDF]
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J. Zhu, F. J. Nieto, B. D. Horne, J. L. Anderson, J. B. Muhlestein, and S. E. Epstein Prospective Study of Pathogen Burden and Risk of Myocardial Infarction or Death Circulation, January 2, 2001; 103(1): 45 - 51. [Abstract] [Full Text] [PDF]
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E. Speir, Z.-X. Yu, K. Takeda, V. J. Ferrans, and R. O. Cannon III Antioxidant Effect of Estrogen on Cytomegalovirus-Induced Gene Expression in Coronary Artery Smooth Muscle Cells Circulation, December 12, 2000; 102(24): 2990 - 2996. [Abstract] [Full Text] [PDF]
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C. Espinola-Klein, H.-J. Rupprecht, S. Blankenberg, C. Bickel, H. Kopp, G. Rippin, G. Hafner, U. Pfeifer, and J. Meyer Are Morphological or Functional Changes in the Carotid Artery Wall Associated With Chlamydia pneumoniae, Helicobacter pylori, Cytomegalovirus, or Herpes Simplex Virus Infection? Stroke, September 1, 2000; 31(9): 2127 - 2133. [Abstract] [Full Text] [PDF]
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S. E. Epstein, J. Zhu, M. S. Burnett, Y. F. Zhou, G. Vercellotti, and D. Hajjar Infection and Atherosclerosis : Potential Roles of Pathogen Burden and Molecular Mimicry Arterioscler Thromb Vasc Biol, June 1, 2000; 20(6): 1417 - 1420. [Abstract] [Full Text] [PDF]
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F. J. Nieto, M. Szklo, P. D. Sorlie, P. M. Ridker, C. H. Hennekens, M. J. Stampfer, and F. Wang Cytomegalovirus Infection and Coronary Heart Disease • Response Circulation, December 21, 1999; 100 (25): e139 - e139. [Full Text] [PDF]
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J. Zhu, A. A. Quyyumi, J. E. Norman, G. Csako, and S. E. Epstein Cytomegalovirus in the pathogenesis of atherosclerosis: The role of inflammation as reflected by elevated C-reactive protein levels J. Am. Coll. Cardiol., November 15, 1999; 34(6): 1738 - 1743. [Abstract] [Full Text] [PDF]
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S. E. Epstein and J. Zhu Lack of Association of Infectious Agents With Risk of Future Myocardial Infarction and Stroke : Definitive Evidence Disproving the Infection/Coronary Artery Disease Hypothesis? Circulation, September 28, 1999; 100(13): 1366 - 1368. [Full Text] [PDF]
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A. E. Hak, C. D. A. Stehouwer, M. L. Bots, K. H. Polderman, C. G. Schalkwijk, I. C. D. Westendorp, A. Hofman, and J. C. M. Witteman Associations of C-Reactive Protein With Measures of Obesity, Insulin Resistance, and Subclinical Atherosclerosis in Healthy, Middle-Aged Women Arterioscler Thromb Vasc Biol, August 1, 1999; 19(8): 1986 - 1991. [Abstract] [Full Text] [PDF]
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P.-Y. Lovey, A. Morabia, D Bleed, O Péter, G Dupuis, and J Petite Long term vascular complications of Coxiella burnetii infection in Switzerland: cohort study BMJ, July 31, 1999; 319(7205): 284 - 286. [Abstract] [Full Text]
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J. S. Yudkin, C. D. A. Stehouwer, J. J. Emeis, and S. W. Coppack C-Reactive Protein in Healthy Subjects: Associations With Obesity, Insulin Resistance, and Endothelial Dysfunction : A Potential Role for Cytokines Originating From Adipose Tissue? Arterioscler Thromb Vasc Biol, April 1, 1999; 19(4): 972 - 978. [Abstract] [Full Text] [PDF]
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D P Strachan, D Carrington, M A Mendall, B K Butland, P M Sweetnam, and P C Elwood Cytomegalovirus seropositivity and incident ischaemic heart disease in the Caerphilly prospective heart disease study Heart, March 1, 1999; 81(3): 248 - 251. [Abstract] [Full Text]
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B. Fagerberg, J. Gnarpe, H. Gnarpe, S. Agewall, and J. Wikstrand Chlamydia pneumoniae but Not Cytomegalovirus Antibodies Are Associated With Future Risk of Stroke and Cardiovascular Disease : A Prospective Study in Middle-Aged to Elderly Men With Treated Hypertension Stroke, February 1, 1999; 30(2): 299 - 305. [Abstract] [Full Text] [PDF]
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L. E. Rohde, R. T. Lee, J. Rivero, M. Jamacochian, L. H. Arroyo, W. Briggs, N. Rifai, P. Libby, M. A. Creager, and P. M. Ridker Circulating Cell Adhesion Molecules Are Correlated With Ultrasound-Based Assessment of Carotid Atherosclerosis Arterioscler Thromb Vasc Biol, November 1, 1998; 18(11): 1765 - 1770. [Abstract] [Full Text] [PDF]
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R. M. Presti, J. L. Pollock, A. J. Dal Canto, A. K. O'Guin, and H. W. Virgin IV Interferon {gamma} Regulates Acute and Latent Murine Cytomegalovirus Infection and Chronic Disease of the Great Vessels J. Exp. Med., August 3, 1998; 188(3): 577 - 588. [Abstract] [Full Text] [PDF]
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