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(Circulation. 2000;102:2335.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Chlamydia pneumoniae, Herpes Simplex Virus Type 1, and Cytomegalovirus and Incident Myocardial Infarction and Coronary Heart Disease Death in Older Adults
The Cardiovascular Health Study
Presented in part at the American Heart Association Council on Epidemiology and Prevention Scientific Sessions, Santa Fe, NM, March 1998.
From the Departments of Medicine (D.S.S., B.M.P., L.C.), Epidemiology (D.S.S., B.M.P., S.M.S., J.T.G.), Health Services (B.M.P.), Pathobiology (J.T.G., S.P.W.), Biostatistics (R.A.K.), and Laboratory Medicine (L.C., R.A.), University of Washington and Fred Hutchinson Cancer Research Center (S.M.S., L.C.) (Seattle); Department of Epidemiology (L.H.K.), University of Pittsburgh, Pittsburgh, Pa; and Department of Pathology (R.P.T.), University of Vermont (Burlington).
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Abstract |
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Background—Whether serological evidence of prior infection with Chlamydia pneumoniae, herpes simplex virus type 1 (HSV-1), and cytomegalovirus (CMV) is associated with myocardial infarction (MI) and coronary heart disease (CHD) death remains a source of controversy.
Methods and Results—We conducted a nested case-control study
among participants in the Cardiovascular Health Study,
a cohort study of persons aged 
65 years. Cases experienced an
incident MI and CHD death (n=213). Control subjects were matched to
cases by age, sex, clinic, year of enrollment, and month of blood draw
(n=405). Serum was analyzed for IgG antibodies to C
pneumoniae, HSV-1, and CMV. After adjustment for other risk
factors, the risk of MI and CHD death was associated with the presence
of IgG antibodies to HSV-1 (odds ratio [OR] 2.0, 95% CI 1.1 to 3.6)
but was not associated with the presence of IgG antibodies to either
C pneumoniae (OR 1.1, 95% CI 0.7 to 1.8) or CMV (OR
1.2, 95% CI 0.7 to 1.9). Although there was little association with
low to moderate C pneumoniae antibody titers (
1:512),
high-titer (1:1024) C pneumoniae antibody was associated
with an increased risk (OR 2.2, 95% CI 1.1 to 4.4).
Conclusions—Among older adults, the presence of IgG antibodies to HSV-1 was associated with a 2-fold increase in the risk of incident MI and CHD death. For C pneumoniae, only high-titer IgG antibodies were associated with an increased risk of MI and CHD death. The presence of IgG antibodies to CMV was not associated with risk among the elderly.
Key Words: bacteria • viruses • myocardial infarction • coronary heart disease • aging
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Introduction |
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The role of viruses and other infectious agents, such as Chlamydia pneumoniae, in the development of atherosclerosis and incident myocardial infarction (MI) and coronary heart disease (CHD) death has long been an area of investigative interest.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Animal/experimental, pathological, and cross-sectional seroepidemiological studies conducted among middle-aged populations provide some support for the hypothesis that infections with herpes simplex virus type 1 (HSV-1), cytomegalovirus (CMV), and C pneumoniae are associated with the development of atherosclerosis and CHD.5 6 7 8 9 10 11 12 13 14 15 16 However, recent reports from several prospective studies failed to demonstrate consistent associations between the presence of IgG antibodies to C pneumoniae, HSV-1, and CMV and incident MI.17 18 19 20 21 22
Given both the high prevalence of IgG antibodies to these agents and
the high incidence of cardiovascular disease among
older adults, it is particularly important to determine whether
serological evidence of prior infection with these agents, assessed
late in life, is associated with incident MI and CHD death. We examined
this question in an ancillary study to the
Cardiovascular Health Study (CHS), a cohort study of
men and women aged 65 years.23
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Overview
We conducted a nested case-control study within the CHS cohort.24 25 26 27 28 29 30 31 Cases (n=213) were defined by the occurrence of an incident fatal or nonfatal MI (n=167) or CHD death (n=46) that occurred from 0.1 to 4.3 years after a blood draw. The median time to event was 2.1 years (interquartile range 1.3 to 3.1 years. Approximately 2 control subjects (n= 405) were individually matched to each case (patient) by age, sex, field center, and date (year and month) of blood draw. Sera from cases and control subjects were tested for IgG antibodies to C pneumoniae, HSV-1, and CMV.
Setting
Briefly, CHS is a prospective cohort study of 5888 men and women
65 years old who were randomly selected from Medicare eligibility
lists in 4 communities: Forsyth County, NC; Sacramento County, Calif;
Washington County, Md; and Allegheny County, Pa. In 1989 through 1990,
5201 participants were recruited and examined; in 1992 to 1993, 687
additional black participants were recruited and examined.
Baseline Examination
The baseline examination, which was conducted in 1989 to 1990,
consisted of standard questionnaires that were used to assess risk
factors and medical history23 24 and a clinic examination
that included seated blood pressure, anthropometric measures,
venipuncture, resting ECG, spirometry, ankle-arm
systolic blood pressure index, and carotid
sonography.25 26 27 28 29 Fasting serum glucose, plasma lipids and
lipoproteins, serum fibrinogen, C-reactive protein, and white blood
cell count were measured. During an examination in 1992 to 1993, the
baseline examination described here was repeated for the initial (1989
to 1990) cohort and was conducted for the first time for the
supplemental black (1992 to 1993) cohort.
Follow-Up and Classification of Events
Details of the follow-up for events are described
elsewhere.31 All participants were contacted every 6
months, and the contacts alternated between a telephone interview and
an in-clinic examination. At each 6-month contact, participants were
asked about cardiovascular events and all
hospitalizations. Discharge summaries and diagnoses were obtained for
all hospitalizations. For all potential cardiovascular
events, additional information, including cardiac enzymes and serial
ECGs, was collected from the medical records. The algorithms for
classification of MI and definite fatal CHD are described
elsewhere.31
Selection of Cases and Control Subjects
The cases and matched control subjects were selected for this
ancillary study in 2 phases, on the basis of the first available serum
specimen, with each phase defined according to the source of the blood
specimen used to test for antibodies. For the first phase, the source
of the blood specimen was the baseline CHS examination (1989 to 1990),
and we selected all cases of incident MI or CHD death that occurred
during the initial 5.5 years of follow-up after the baseline
examination. For the second phase, the source of the blood specimen was
the 1992 to 1993 clinical examination, and we selected all cases of
incident MI or CHD death that occurred during 3.5 years of follow-up
among participants in that examination and whose events had not already
been selected in the first phase. From each phase, we excluded a
participant if he or she (1) had reported or had been diagnosed with
MI, angina pectoris, stroke, or transient ischemic attack or
had undergone CABG or coronary angioplasty before the blood
draw; (2) had ECG evidence of an MI before the blood draw; or (3) was
found during follow-up after the blood draw to have had an MI that
predated the blood draw. Incident MI or CHD deaths that were the
consequence of a procedure, such as surgery or angioplasty, were not
included.
Serological Evidence of Prior Infection
Sera obtained at baseline or at the 1992 to 1993 clinic
examinations were shipped to the University of Washington (Seattle) for
testing. The samples were batch-analyzed with case-control
pairs retained in random order within the same batch. The laboratories
were blinded to case-control status of the paired sera.
IgG antibody to C pneumoniae was measured with a microimmunofluorescence antibody test.32 Sera were screened for a positive antibody response at a dilution of 1:8, and those with a positive response were further tested at dilutions of 1:8, 1:16, 1:32, 1:64, and 1:1024. Based on an earlier report,14 an IgG antibody titer of at least 1:8 was considered diagnostic of past C pneumoniae infection a priori. Prior duplicate testing demonstrated that the percent agreement with a cut point of 1:8 as a positive antibody response was 100%.
IgG antibody to HSV-1 was assessed with a Western blot test. Because HSV titers are not associated with reactivation of latent HSV or with clinical disease,33 we focused on the presence or absence of antibody to HSV-1 and did not measure antibody titers. The methods and criteria for assay of the presence of HSV-1 antibody have been described in detail elsewhere.34 The assay discriminates between HSV-1 and HSV-2.
Antibody to CMV was assessed with a passive latex agglutination assay (CMVScan; Becton Dickinson). This test has been shown to be both sensitive and specific compared directly with other test formats for CMV antibody.35 36 Because of variation in end point titers between runs, the result of considerable run-to-run variability in the performance of the test for the antigen, we focused on the presence or absence of antibody to CMV, rather than on CMV antibody titers.
Statistical Analysis
We used conditional logistic regression, and we estimated the
odds ratio (OR) and 95% CIs associated with serological evidence of
prior infection, as reflected by the presence of IgG antibodies.
Separate multivariate models were used to examine the
association between each infection and incident MI and CHD death. We
also examined the associations with prior infection when the 3 agents
were considered simultaneously in the same logistic model.
For C pneumoniae, we also examined the associations of
antibody titers with incident MI and CHD death. In addition, we
explored whether the time to event influenced the risk associated with
either the presence (for HSV-1 and CMV) or titer (for C
pneumoniae) of IgG antibody. To determine whether the association
between antibodies and incident MI and CHD death was modified by other
factors, we estimated the relative risk in both the presence and
absence of other risk factors, markers of chronic inflammation, and
measures of subclinical atherosclerotic disease. All probability values
represent 2-sided tests.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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The cases and control subjects were similar with respect to age (mean 74 years) and sex (63% were men) (Table 1
). Diabetes, hypertension, and former
cigarette smoking were more common among the cases, and higher
educational attainment and good or excellent self-assessed health were
more common among the control subjects. Mean systolic blood
pressure and serum glucose, triglyceride, and fibrinogen
levels were higher, and mean HDL cholesterol,
FEV1, and energy expended in leisure-time
physical activity were lower among the cases than the control subjects.
The mean body mass index (BMI), LDL cholesterol, C-reactive
protein, and serum albumin levels were similar among the cases
and control subjects.
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Table 2 shows the prevalence of IgG
antibodies to HSV-1, CMV, and C pneumoniae among cases and
control subjects and the adjusted odds ratios. As expected, the
prevalence of IgG antibodies was 82% to HSV-1, 84% to CMV, and 83%
to C pneumoniae among control subjects. After adjustment for
the matching factors (age, sex, field center, and month and year of
blood draw) and for cigarette smoking, diabetes, hypertension, HDL
cholesterol, BMI, physical activity, and years of
education, the presence of IgG antibodies to HSV-1 was associated with
an increased risk of MI and CHD death (for HSV-1, OR 2.0, 95% CI 1.1
to 3.6), but the presence of IgG antibodies to C pneumoniae
and CMV was not associated with an increased risk of MI and CHD death
(for C pneumoniae, OR 1.1, 95% CI 0.7 to 1.8; for CMV,
OR 1.2, 95% CI 0.7 to 1.9). The findings were altered only slightly
both after inclusion of the 3 agents in a single conditional logistic
regression model and after exclusion of CHD deaths.
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For C pneumoniae, there was little evidence of an
association between IgG antibody titers of 1:512, but the prevalence
of an IgG antibody titer of 1:1024 was higher among cases (15.1%) than
among control subjects (8.7%) (Table 3).
After adjustment for other risk factors, the presence of a C
pneumoniae titer of 1:1024 was associated with a 2-fold increase
in risk compared with the absence of IgG antibodies (OR 2.2, 95% CI
1.1 to 4.4). There also was some evidence that the risk associated with
high-titer IgG antibodies for C pneumoniae varied
according to the time to event (Table 4).
When we stratified the data by the median time to event of 2.1 years,
the increased risk of MI and CHD death associated with a high C
pneumoniae titer was restricted to early events (for early events,
OR 4.2, 95% CI 1.7 to 10.7; for later events, OR 1.3, 95% CI 0.7 to
2.7; P for interaction=0.045). In contrast, there was little
evidence that the risk associated with the presence of HSV-1 antibodies
was greater for early than for late events (P for
interaction=0.733) and that the presence of CMV antibody was associated
with either early or late events.
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There was little evidence that the presence of other risk factors, markers of chronic inflammation (serum fibrinogen, C-reactive protein, white blood cell count, and albumin), and subclinical atherosclerosis (common carotid artery intimal-medial thickness, ankle-arm systolic blood pressure index, and Cardiac Infarction Injury Score) were important modifiers of the association of HSV-1 with MI and CHD death. There also was little evidence that these other clinical characteristics modified the risk of MI and CHD death associated with either antibodies to C pneumoniae or CMV. In addition, the association of HSV-1 antibodies and MI and CHD death was altered only slightly when we included terms that represented markers of inflammation and subclinical vascular disease in the multivariate models.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Among older adults, the presence of antibodies to HSV-1, measured late in life, was associated with a 2-fold increase in the risk of MI and CHD death overall. In contrast, the presence of IgG antibodies to C pneumoniae and CMV was not associated with incident MI or CHD death. However, there was some evidence that high-titer C pneumoniae antibody was associated with an increased risk, and the association of high titer with risk was particularly large for events that occurred within the first 2.1 years after the blood draw. Multivariate adjustment for other factors that might bias the associations and potential mediators altered the findings only slightly.
Several limitations must be considered in interpretation of these findings. We used the presence of IgG antibodies (and for C pneumoniae, IgG titer) measured on a single occasion late in life to characterize prior infection. Other clinical characteristics not considered in our analyses might have biased the observed associations, and we may have had inadequate statistical power to detect an 80% to 90% increase in the risk of MI or CHD death associated with the presence of prior infection with C pneumoniae and CMV. In addition, the findings from this study may not be generalizable to young and middle-aged adults.
To our knowledge, this is the first prospective report of an association of recent, high-titer C pneumoniae antibodies with the risk of incident MI and CHD death among elderly persons. These preliminary findings suggest that high-titer C pneumoniae antibodies were associated with an increased risk, particularly for events that occurred during the initial 2.1 years after the blood draw. Of note, in a nested case-control study of incident CHD among the middle-aged persons followed for 3 years in the Atherosclerotic Risk in Communities Study, the prevalence of high-titer antibodies (both 1:512 and 1:1024) was higher among patients with CHD than among control subjects. Whether recently measured high-titer antibodies to C pneumoniae are more likely to reflect the etiologically relevant aspect of exposure to this agent, such as chronic infection or reinfection, rather than merely past infection remains unknown.
The data suggest a possible association between HSV-1 seropositivity and incident MI and CHD death among older adults. Although a similar association of HSV-1 antibodies with incident MI and CHD death was reported recently from the Helsinki Heart Study,20 an association between HSV-1 antibodies and incident MI and stroke was not observed in several prospective studies.21 22 Whether differences in study design or in the populations studied, such as the prevalence of other risk factors, account for the differences in findings remains unknown. In contrast, the absence of an association with CMV antibodies in this report is consistent with the findings from other prospective studies.20 21 22
This epidemiological study does not provide information about the potential mechanisms for the association of HSV-1 and acute cardiac events. One hypothesis relates to the potential reactivation of HSV-1 in autonomic nerves that innervate the coronary arteries, subsequent endothelial injury, and the initiation of an acute thrombotic event. HSV-1 reactivation is more frequent and more severe among persons who are immunocompromised; older persons are more likely to be immunocompromised; endothelial cells can be infected with HSV-1; and infection results in cell death and a leukocytoclastic vasculitis-like picture, including the conversion of the endothelial surface from antithrombotic to prothrombotic.37 38 39 40 Furthermore, mural thrombi have been described in the coronary arteries of chickens infected with Marek’s disease virus.5 Given the role of plaque disruption and the formation of occlusive thrombi in the occurrence of MI and CHD death, it is possible that reactivation of HSV-1 may result in endothelial injury that may increase the risk of thrombosis in the setting of atherosclerotic coronary disease. Unfortunately, because HSV-1 reactivation is not associated with consistent alterations in IgM, IgA, or IgG subclass antibody responses or in quantitative changes in HSV-1–specific antibodies, in this epidemiological study, we could not directly address this hypothesis.
This report is the first to examine the associations of IgG antibodies to C pneumoniae, HSV-1, and CMV, measured late in life, with incident MI and CHD death among older adults. The finding of a possible association of the presence of antibody to HSV-1, assessed latter in life, with incident MI and CHD among older adults is of potential importance, given the high incidence of CHD and the high prevalence of IgG antibody to HSV-1 among older adults. In addition, the association of recent high-titer IgG antibodies to C pneumoniae with the risk of acute cardiac events among older adults must be confirmed in other studies. Several large-scale secondary prevention trials that examine the effect of macrolide antibiotic therapy for C pneumoniae among patients with known coronary heart disease are now in progress, but these trials have not targeted older persons with high-titer IgG antibodies. Additional clinical trials should be considered to determine more fully the potential clinical and public health implications of the associations reported herein.
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Acknowledgments |
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This work was supported by an NHLBI Shannon Award (R55-HL-46900) and by contracts NO1-HC-87079, NO1-HC-87080, NO1-HC-87081, NO1-HC-87082, NO1-HC-87083, NO1-HC-87084, NO1-HC-87085, NO1-HC-87086, and AI-30731.
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Footnotes |
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Reprint requests to David S. Siscovick, MD, MPH, Cardiovascular Health Research Unit, 1730 Minor Ave, Suite 1360, Seattle, WA 98101.
1 See the Appendix for a list of participating institutions and principal staff. 
Dr Psaty has received a Merck/SER Clinical Fellowship and also serves on the Events Committee for the HERS Trial (Wyeth Ayerst).
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Participating Institutions and Principal Staff
Forsyth County, NC, Wake Forest University School of Medicine: Gregory L. Burke, Sharon Jackson, Alan Elster, Curt D. Furberg, Gerardo Heiss, Dalane Kitzman, Margie Lamb, David S. Lefkowitz, Mary F. Lyles, Cathy Nunn, Ward Riley, John Chen, Beverly Tucker. Forsyth County, NC, Wake Forest University, ECG Reading Center: Farida Rautaharju, Pentti Rautaharju. Sacramento County, Calif, University of California, Davis: William Bonekat, Charles Bernick, Michael Buonocore, Mary Haan, Calvin Hirsch, Lawrence Laslett, Marshall Lee, John Robbins, William Seavey, Richard White. Washington County, Md, Johns Hopkins University: M. Jan Busby-Whitehead, Joyce Chabot, George W. Comstock, Adrian Dobs, Linda P. Fried, Joel G. Hill, Steven J. Kittner, Shiriki Kumanyika, David Levine, Joao A. Lima, Neil R. Powe, Thomas R. Price, Jeff Williamson, Moyses Szklo, Melvyn Tockman. Washington County, Md, Johns Hopkins University, MRI Reading Center: Norman Beauchamp, R. Nick Bryan, Douglas Fellows, Melanie Hawkins, Patrice Holtz, Naiyer Iman, Michael Kraut, Cynthia Quinn, Grace Lee, Carolyn C. Meltzer, Larry Schertz, Earl P. Steinberg, Scott Wells, Linda Wilkins, Nancy C. Yue. Allegheny County, Pa, University of Pittsburgh: Diane G. Ives, Charles A. Jungreis, Laurie Knepper, Lewis H. Kuller, Elaine Meilahn, Peg Meyer, Roberta Moyer, Anne Newman, Richard Schulz, Vivienne E. Smith, Sidney K. Wolfson. University of California, Irvine, Echocardiography Reading Center (baseline): Hoda Anton-Culver, Julius M. Gardin, Margaret Knoll, Tom Kurosaki, Nathan Wong. Georgetown Medical Center, Echocardiography Reading Center (follow-up): John Gottdiener, Eva Hausner, Stephen Kraus, Judy Gay, Sue Livengood, Mary Ann Yohe, Retha Webb. New England Medical Center, Boston, Mass, Ultrasound Reading Center: Daniel H. O’Leary, Joseph F. Polak, Laurie Funk. University of Vermont, Central Blood Analysis Laboratory: Elaine Cornell, Mary Cushman, Russell P. Tracy. University of Arizona, Tucson, Pulmonary Reading Center: Paul Enright. University of Washington, Seattle, Coordinating Center: Alice Arnold, Annette L. Fitzpatrick, Richard A. Kronmal, Bruce M. Psaty, David S. Siscovick, Will Longstreth, Patricia W. Wahl, David Yanez, Paula Diehr, Susan Heckbert, Corrine Dulberg, Bonnie Lind, Thomas Lumley, Ellen O’Meara, Jennifer Nelson, Charles Spiekerman. NHLBI Project Office: Robin Boineau, Teri A. Manolio, Peter J. Savage, Patricia Smith.
Received March 13, 2000; revision received June 16, 2000; accepted June 16, 2000.
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 C. M. O'Connor, M. W. Dunne, M. A. Pfeffer, J. B. Muhlestein, L. Yao, S. Gupta, R. J. Benner, M. R. Fisher, and T. D. Cook Azithromycin for the Secondary Prevention of Coronary Heart Disease Events: The WIZARD Study: A Randomized Controlled Trial JAMA, September 17, 2003; 290(11): 1459 - 1466. [Abstract] [Full Text] [PDF]
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 E. A. Holly and P. M. Bracci Population-based Study of Non-Hodgkin Lymphoma, Histology, and Medical History among Human Immunodeficiency Virus-negative Participants in San Francisco Am. J. Epidemiol., August 15, 2003; 158(4): 316 - 327. [Abstract] [Full Text] [PDF]
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 Y. Agmon, B. K. Khandheria, I. Meissner, T. M. Petterson, W. M. O'Fallon, T. J. H. Christianson, D. O. Wiebers, T. F. Smith, J. M. Steckelberg, and A. J. Tajik Lack of association between Chlamydia pneumoniae seropositivity and aortic atherosclerotic plaques: A Population-Based transesophageal echocardiographic study J. Am. Coll. Cardiol., May 7, 2003; 41(9): 1482 - 1487. [Abstract] [Full Text] [PDF]
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 D. A. Hill, G. Gridley, S. Cnattingius, L. Mellemkjaer, M. Linet, H.-O. Adami, J. H. Olsen, O. Nyren, and J. F. Fraumeni Jr Mortality and Cancer Incidence Among Individuals With Down Syndrome Arch Intern Med, March 24, 2003; 163(6): 705 - 711. [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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 J.A. Erkens, O.H. Klungel, R.M.C. Herings, R.P. Stolk, J.A. Spoelstra, D.E. Grobbee, and H.G.M. Leufkens Use of fluorquinolones is associated with a reduced risk of coronary heart disease in diabetes mellitus type 2 patients Eur. Heart J., October 2, 2002; 23(20): 1575 - 1579. [Abstract] [Full Text] [PDF]
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L Wallby, B Janerot-Sjoberg, T Steffensen, and M Broqvist T lymphocyte infiltration in non-rheumatic aortic stenosis: a comparative descriptive study between tricuspid and bicuspid aortic valves Heart, October 1, 2002; 88(4): 348 - 351. [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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 S. W. Kerrigan, I. Douglas, A. Wray, J. Heath, M. F. Byrne, D. Fitzgerald, and D. Cox A role for glycoprotein Ib in Streptococcus sanguis-induced platelet aggregation Blood, June 28, 2002; 100(2): 509 - 516. [Abstract] [Full Text] [PDF]
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 D. G. Alber, P. Vallance, and K. L. Powell Enhanced Atherogenesis Is Not an Obligatory Response to Systemic Herpesvirus Infection in the ApoE-Deficient Mouse: Comparison of Murine {gamma}-Herpesvirus-68 and Herpes Simplex Virus-1 Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 793 - 798. [Abstract] [Full Text] [PDF]
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K. Miura, H. Nakagawa, and P. Greenland Invited Commentary: Height-Cardiovascular Disease Relation: Where to Go from Here? Am. J. Epidemiol., April 15, 2002; 155(8): 688 - 689. [Full Text] [PDF]
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 C. Stollberger and J. Finsterer Role of Infectious and Immune Factors in Coronary and Cerebrovascular Arteriosclerosis Clin. Vaccine Immunol., March 1, 2002; 9(2): 207 - 215. [Full Text] [PDF]
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 J. Boman and M. R. Hammerschlag Chlamydia pneumoniae and Atherosclerosis: Critical Assessment of Diagnostic Methods and Relevance to Treatment Studies Clin. Microbiol. Rev., January 1, 2002; 15(1): 1 - 20. [Abstract] [Full Text]
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 G. J. Blake and P. M. Ridker Novel Clinical Markers of Vascular Wall Inflammation Circ. Res., October 26, 2001; 89(9): 763 - 771. [Abstract] [Full Text] [PDF]
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H. J. Rupprecht, S. Blankenberg, C. Bickel, G. Rippin, G. Hafner, W. Prellwitz, W. Schlumberger, and J. Meyer Impact of Viral and Bacterial Infectious Burden on Long-Term Prognosis in Patients With Coronary Artery Disease Circulation, July 3, 2001; 104(1): 25 - 31. [Abstract] [Full Text] [PDF]
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P. K. Shah Link Between Infection and Atherosclerosis: Who Are The Culprits: Viruses, Bacteria, Both, or Neither? Circulation, January 2, 2001; 103(1): 5 - 6. [Full Text] [PDF]
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