(Circulation. 2001;103:45.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Prospective Study of Pathogen Burden and Risk of Myocardial Infarction or Death
From the Cardiovascular Research Institute (J.Z., S.E.E.), MedStar Research Institute, Washington Hospital Center, Washington, DC; Department of Epidemiology (F.J.N.), The Johns Hopkins University School of Public Health, Baltimore, Md; and LDS Hospital and University of Utah (B.D.H, J.L.A., J.B.M.), Salt Lake City.
Correspondence to Dr Stephen E. Epstein, CRI, Washington Hospital Center, 110 Irving St, NW, Suite 4B-1, Washington, DC 20010..
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Abstract |
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Background—We previously demonstrated that the risk of coronary artery disease (CAD) increased in relation to the number of pathogens (the "pathogen burden") in a cross-sectional study. In the present prospective study with a different patient cohort, we evaluated the effect of pathogen burden on the risk of myocardial infarction (MI) or death among CAD patients.
Methods and Results—IgG antibodies to cytomegalovirus (CMV), hepatitis A virus (HAV), herpes simplex virus type 1 (HSV1), HSV type 2 (HSV2), Chlamydia pneumoniae and Helicobacter pylori, and C-reactive protein (CRP) levels were tested in baseline blood samples from 890 patients who had significant CAD on angiography. The mean follow-up period was 3 years. The baseline prevalence of antibodies directed against CMV, HAV, HSV1, or HSV2, but not C pneumoniae and H pylori, was significantly higher among patients who subsequently developed MI or death than among control subjects. After adjustment for traditional risk factors, number of diseased vessels, and clinical presentation, relative hazards (95% confidence limits) for MI or death were 2.0 (1.4 to 3.2) for CMV, 1.6 (1.1 to 2.3) for HAV, and 1.5 (1.0 to 2.2) for HSV2. Increasing pathogen burden was significantly associated with increasing risk of MI or death in a dose-response fashion. Adjusted relative hazards of MI or death associated with pathogen burden were significant among individuals with low or high CRP levels.
Conclusions—The results suggest that infection plays an important role in incident MI or death and that the risk posed by infection is independently related to the pathogen burden.
Key Words: pathogens • antibodies • coronary disease • myocardial infarction
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Introduction |
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Despite accumulating evidence that infection predisposes to the development of atherosclerosis,1 2 3 4 5 6 7 8 9 10 several controversial areas remain11 12 13 14 ; these areas include the continued reports of seroepidemiological studies that fail to show an association between infection and atherosclerosis and the question of which (if any) of the several pathogens associated with atherosclerosis, including cytomegalovirus (CMV), Chlamydia pneumoniae, Helicobacter pylori, and herpes simplex virus (HSV), pose a true risk.
We reasoned that if infection is in fact causally related to coronary artery disease (CAD), it would be unlikely that a single agent plays a unique role. Rather, we considered that multiple infectious agents contribute to atherosclerosis and hypothesized that the risk of cardiovascular disease posed by infection is related to the number of pathogens to which an individual has been exposed (the "pathogen burden").15 We evaluated that hypothesis in a group of individuals under evaluation for CAD and found that CAD risk increased significantly in relation to pathogen burden.16 We also demonstrated for the first time that exposure to hepatitis A virus (HAV), as demonstrated by IgG anti-HAV antibodies, was significantly associated with increased CAD risk.16
Although these results were intriguing, the study was cross-sectional in design. To determine the validity of the original observation, in the present study we examined prospectively, and in an entirely different population, the hypothesis that the risk of myocardial infarction (MI) or death among CAD patients relates to pathogen burden and that HAV is one of the pathogens that contributes to this risk.
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Methods |
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Patients
The patient cohort consisted of 890 individuals undergoing coronary angiography at LDS Hospital, Salt Lake City, Utah. Each patient gave informed consent; the study was approved by the hospital institutional review board. Blood was drawn at angiography, and patient follow-up ranged from 1.8 to 4.3 years (mean 3 years).
Clinical Evaluation
All patients underwent a clinical examination. A
patient was defined as having CAD if there was angiographic evidence of
atherosclerosis (
70% stenosis of 1 major coronary artery).
Myocardial infarction (MI) reported during study follow-up was
confirmed if medical record review demonstrated symptoms consistent
with MI and the presence of either diagnostic ECG changes or cardiac
enzymes. It was not possible to confirm a cardiovascular basis for all
deaths. Therefore, the total number of deaths, uncensored relative to
presumed cause, was used in our analyses.
Risk Factors
Risk factors considered in this study included age,
male sex, cigarette smoking, diabetes, hyperlipidemia, hypertension,
family history of coronary heart disease, levels of C-reactive protein
(CRP), and seropositivity status to CMV, C
pneumoniae, H pylori, HAV, HSV1, and HSV2. A history of past
and current smoking was obtained. A patient who stopped smoking >20
years ago and who was <30 years of age when smoking was stopped was
considered not to have smoking as a risk factor. A patient was
considered to have diabetes if he or she was taking insulin or oral
hypoglycemic agents or had previously received such treatment and was
currently using dietary modification to control the condition. A
patient was considered to have hyperlipidemia if he or she had a serum
cholesterol value of >240 mg/dL (6.2 mmol/L) or was receiving
antihyperlipidemic treatment. A patient was considered to have
hypertension if he or she had received the diagnosis or was being
treated with antihypertensive medications or dietary
modification.
Infectious Serology
Serum obtained from patients was frozen at -80°C,
and aliquots were thawed only when specific tests were performed.
Commercially available ELISA kits were used to determine serum IgG
antibodies to CMV, HSV1, and HSV2 (Wampole), to
H pylori (Meridian
Diagnostics), to HAV (ETI-AB-HAVK; DiaSorin Inc), and to
C pneumoniae (Savyon
Diagnostics). (The latter IgG ELISA had 
95% sensitivity compared
with the microimmunofluorescence assay.)
CRP Level
Serum CRP was measured with a fluorescence
polarization immunoassay (TDxFLEx analyzer; Abbott Labs); 95% of
healthy individuals (n=202) had a CRP level of 
0.5 mg/dL and 98% had
a level of 1.0 mg/dL (Abbott Laboratories Diagnostic Division, list
No. 9550, January 1996). The between-run coefficient of variation of
this assay (n=31) was 4.3% and 2.2% at a mean level of 1.10 and 2.94
mg/dL, respectively.
Statistical Analysis
Categorical data were analyzed by the
2 test. All statistical tests were
2-sided. Covariates that were considered were age, sex, smoking,
diabetes, hyperlipidemia, hypertension, family history, and
seropositivity status to CMV, C
pneumoniae, H
pylori, HAV, HSV1, and HSV2, as well as the aggregate number
of seropositive tests. All covariates were examined as predictors of MI
or death in univariate analyses. A multivariate Cox regression analysis
of these covariates as predictors of increased incidence of MI or death
was made with an SAS software system (SAS Institute) for PC Windows.
Relative hazard was used as a measure of risk of incident events in
patients with a given risk factor compared with those without that
factor or as a multiplicative factor for each unit increase in age or
pathogen burden. The presence of statistically significant linear
trends of increasing relative hazards with increasing pathogen burden
was assessed by entering pathogen burden as a single ordinal covariate
in the Cox regression and using the standard Wald statistic to test the
statistical significance of the corresponding regression
coefficient.
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Results |
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Patient Characteristics
A total of 890 study subjects were followed for a mean of 3 years after CAD diagnosis. Men constituted 77% of the cohort. Most participants were Utah residents, a population that ethnically is primarily of northern European descent. Ages ranged from 34 to 95 years (mean age 65 years). Baseline clinical characteristics and prevalence of IgG antibodies against the pathogens in these subjects are presented in Table 1
. Only 8 (0.9%) patients tested negative for all 6
pathogens, whereas 427 (48%) were positive for 5 or all 6
pathogens.
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During follow-up, 76 (9%) of 890 patients developed MI, 104
(12%) died, and 167 (19%) experienced an MI or death.
Table 1
shows the distribution of risk factors, baseline
prevalence of infection, and pathogen burden according to eventual
outcome (MI or death). In these univariate analyses, seropositivity
prevalence for infectious pathogens, especially CMV and HAV, was
significantly higher in patients with events than in those without
events. Pathogen burden was also significantly higher in patients who
experienced incident MI or death (of whom 65% were positive for 5 or
all 6 pathogens).
Multivariate Analyses of Anti-Pathogen IgG
Antibodies and MI or Death
Cox multivariate regression analysis revealed
significant relative hazards of MI or death associated with baseline
seropositivity to CMV, HAV, and HSV2
(Table 2). In contrast, significant relative hazards for
seropositivity to H pylori were
found for MI but not for the combined end point. No significant
associations were found for seropositivity to
C pneumoniae in either
individual or combined end points.
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Multiple Infections (Pathogen Burden) and
MI or Death
We defined pathogen burden using seropositivity to all
6 pathogens tested: CMV, HAV, C
pneumoniae, H
pylori, HSV1, or HSV2. As shown in
Table 3, a graded dose-response relationship of increasing
relative hazards with increasing pathogen burden was observed. After
multivariate adjustment, those positive to 5 or 6 pathogens were >6
times more likely to have incident MI or death than were those with 0
or only 1 seropositive result. Because of the limited sample size in
the reference group (36 subjects), the 95% confidence limit
(CL) values were large, although a highly significant
dose-response trend test was observed even after multivariate analyses
(P=0.0005). In alternative
analyses, we used the 0 to 2 pathogens as reference group (total of 100
subjects); the relative hazards for individuals with 5 or 6 pathogens
(Table 3, last column) was >3 in multivariate analyses, now
with narrower 95% CL values that did not overlap 1.
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Additional analyses were conducted that defined pathogen
burden on the basis of 4 pathogens: CMV, HAV, HSV1, or HSV2. These 4
were chosen for the multivariate analysis because each was
significantly associated with the combined end point in the univariate
analysis. The
Figure
shows the MI- or death-free survival curves according to pathogen
burden defined according to positivity to the 4 pathogens. There is a
dose-response effect (P for
trend <0.05). The corresponding Cox regression analyses
(Table 3, bottom) showed significantly elevated relative
hazards in both univariate and multivariate analyses, with a graded
dose-response type of relationship, and a particularly strong
association present with high levels of pathogen burden. The adjusted
relative hazard of MI or death in a comparison of the seropositivity of
4 pathogens with none was 7.6 (95% CL 1.04, 55.7). Furthermore,
as demonstrated in the Cox regression analyses
(Table 4), an increased risk of either of the individual end
points (MI or death) and of the combined end point (MI or death) was
significantly related to the number of pathogens with which an
individual is infected.
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Because CMV and HAV are the pathogens most strongly associated with MI or death in this study, we repeated the analyses using the seropositive versus seronegative status of all 6 pathogens but excluded the results of either CMV or HAV. The relation between increasing pathogen burden with increasing frequency of the risk of MI or death remained significant (data not shown).
Pathogen Burden and CRP Levels
In our study population, the mean CRP level was 2.34
mg/dL and the median level was 1.4 mg/dL. Mean CRP levels were 1.76,
2.21, 2.28, 2.22, 2.42, and 2.61 mg/dL in patients exposed to 0 to 1,
2, 3, 4, 5, or 6 pathogens (P
for trend 0.05).
To determine whether the association between pathogen burden
and MI or death is modified by CRP, we analyzed 2 subgroups of
patients: all individuals with CRP below its mean (or median) value,
and those at or above this value
(Table 5). We found stronger associations among those with
lower CRP values, although a significant trend was present in both CRP
strata levels. These results provide further evidence that suggests
pathogen burden significantly predicts the combined end point of MI or
death independent of CRP.
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Discussion |
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In our previous cross-sectional study,16 we examined the relation between pathogen burden and the presence of angiographically documented CAD. We selected for study a panel of 6 pathogens because they shared 2 common characteristics: all were obligate intracellular pathogens, and all established persistent antibodies targeted to the pathogen. Five of the pathogens (CMV, C pneumoniae, H pylori, HSV1, and HSV2) are known to establish life-long latent or persistent infections, whereas 1 pathogen (HAV) is not currently recognized as establishing a persistent infection despite the life-long persistence of anti-HAV antibodies. The results of that study demonstrated that increasing pathogen burden was associated with increasing risk of CAD and, for the first time, that HAV was one of the pathogens that contributes to atherosclerosis.
The results of the present investigation confirm and extend
those findings. This study is prospective in design and involves an
entirely different patient cohort. We determined, for the first time,
whether pathogen burden predicts MI or death in a cohort with
angiographically documented CAD. The results demonstrated that a graded
dose-response relationship of increasing relative hazards for MI or
death was observed with increasing pathogen burden
(Table 3). The statistical association became even more
robust when the 4 pathogens (CMV, HAV, HSV1, and HSV2) were considered
(Table 3,
Figure).
Furthermore, in addition to the combined end point, pathogen burden
also significantly predicted an increased risk of both individual end
points (MI or death)
(Table 4).
Although the primary thrust of this investigation was to
determine whether pathogen burden predicted cardiovascular events, the
results related to the individual pathogens are of interest. We found
that the baseline prevalence of antibodies directed against CMV, HAV,
HSV1, or HSV2, but not C
pneumoniae and H
pylori, was significantly higher among patients who
subsequently developed MI or death
(Table 1). After multivariate adjustment, CMV, HAV, and HSV2
demonstrated positive relative hazards for MI or death
(Table 2). It is possible that different populations will
exhibit different relationships among the pathogens and CAD events.
However, the results do point out that it cannot be taken for granted
that C pneumoniae
seropositivity will be an important risk factor for future events in a
patient population with known CAD, an assumption implicit in the
numerous prospective trials that are under way in which the effects of
macrolide antibiotics on future event rate are being
assessed.17
Our results also suggest that prior HAV infection influences the course of atherosclerosis. In our initial study, HAV was selected as one of the pathogens to be studied because, like the others, it is an obligate intracellular pathogen and anti-HAV antibodies persist throughout the life of the host. The basis for such selection criteria was derived from our belief that infection predisposes to CAD, at least in part through immune responses and perhaps infection-induced autoimmune responses that could involve molecular mimicry.18 We thought that a persistent antibody response could reflect a process compatible with immunopathology and autoimmune disease. It is unknown whether the persistent antibody response to HAV represents persistent infection with HAV, reflects consistent exposure to cross-reactive self-antigens, or reflects intermittent exposure of the host to other pathogens that contain antigens that are cross-reactive with HAV antigens. Regardless of the precise mechanism, the fact that HAV is associated with both CAD and cardiovascular events suggests that other pathogens that share these characteristics may also contribute to the atherosclerotic process.
Importantly, we found that increasing pathogen burden is associated with increasing CRP levels. An elevated CRP level, believed to reflect underlying inflammation, is a risk factor for cardiovascular events.19 20 21 Therefore, our results suggest that one of the mechanisms by which pathogen burden contributes to cardiovascular events is through the inflammatory response elicited by infection with multiple pathogens. However, in stratified analyses of the relation between pathogen burden and MI or death on the basis of the median CRP value, we found stronger associations among those with lower CRP values (although a significant trend was present in both strata of CRP levels). These results provide further evidence that suggest pathogen burden significantly predicts the combined end point of MI or death independent of CRP.
Of interest, we found in our particular cohort, which
consists of patients with angiographically documented CAD, that some of
the risk factors traditionally associated with CAD did not predict risk
of incident events. This may be in part due to the fact that once CAD
is diagnosed, it is likely that treatable risk factors will be
aggressively treated, thereby moderating any future risk they may
cause. This could explain the fact that smoking, hyperlipidemia, and
hypertension were not identified as risk factors for incident events in
the present study. Importantly, in this context, we found that pathogen
burden is not an inconsequential risk factor. The predictive values of
CMV, HAV, and HSV infection on MI or death were of comparable or
greater magnitude than those of the major CAD risk factors as
traditionally defined
(Table 2). As an example of the relative risk posed by
infection, according to the point estimates of the adjusted Cox
regression coefficients, each of these pathogens has an independent
association with MI or death equal in magnitude to that of an age
increase of 15.6, 10.6, and 9.2 years, respectively.
Despite the strong associations between pathogen burden and
MI or death, it is possible that pathogen burden does not causally
relate to the precipitation of such events. It may, for example, be a
surrogate marker of other factors, not considered in the present
investigation, that are the true causal factors that contribute to the
identified association. The likelihood that pathogen burden is not just
a surrogate marker for some other factor or factors is suggested by the
extremely high risk posed
(Table 3) and the many mechanistic studies that demonstrate
pathogens evoke cellular changes that in themselves could account for
the development of atherogenesis and for the precipitation of the acute
complications of
atherosclerosis.22 23 24
One potential confounding influence not evaluated in the present study that could influence our conclusions is the impact of socioeconomic status (SES). Unfortunately, we cannot address this issue definitively because information related to SES was not obtained as part of the database. However, several considerations make this possibility unlikely. First, most of the patients in this investigation lived in Utah, which has a very homogeneous population that is ethnically primarily of northern European descent. Moreover, all study participants had some degree of access to health care, as evidenced by the fact that all of them had, by definition, diagnostic arteriography at study inception; hence, extremes of SES probably play no role in outcome. Also, arguing against an important confounding influence of SES is the disparity in the associations we observed between the individual pathogens and outcome events. Although we found strong associations between events and seropositivity to HAV and CMV, we found no association between outcome events and seropositivity to H pylori or C pneumoniae. The frequency of each of these latter infections is strongly influenced by low SES. It therefore would be likely that if low SES was the confounder that influenced outcome, each of these pathogens would have been found to be associated with outcome, but this possibility appears unlikely.
In conclusion, our investigation provides further evidence that infection plays an important role in cardiovascular disease. Given the study results that the risk of incident MI or death occurring in CAD patients is independently related to the pathogen burden, it may seem somewhat paradoxical that the traditional incidence of CAD has been very low in areas of the world in which infection with multiple pathogens occurs at a very high rate. However, any effect of infection on the incidence of CAD must be considered in the context of coexisting CAD risk factors. In this regard, CAD is reaching epidemic proportions in rapidly developing Third World countries,25 as the populations adopt Western diets and a high-stress lifestyle typically associated with a high incidence of CAD. Thus, the impact of infection on the incidence of CAD and its complications in such populations will probably become all too evident during the next several decades.
Received June 12, 2000; revision received August 21, 2000; accepted August 21, 2000.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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1. 1. Adam E, Probtsfield JL, Burek J, et al. High levels of cytomegalovirus antibody in patients requiring vascular surgery for atherosclerosis. Lancet. 1987;2:291–293.[Medline] [Order article via Infotrieve]
2.
Zhou YF, Leon MB,
Waclawiw MA, et al. Association between prior cytomegalovirus infection
and the risk of restenosis after coronary atherectomy.
N Engl J Med. 1996;335:624–630.
3.
Nieto FJ, Adam E,
Sorlie P, et al. Cohort study of cytomegalovirus infection as a risk
factor for carotid intimal-medial thickening, a measure of subclinical
atherosclerosis. Circulation. 1996;94:922–927.
4. Saikku P, Leinonen M, Mattila K, et al. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet. 1988;2:983–986.[Medline] [Order article via Infotrieve]
5.
Thom DM, Grayston
JT, Siscovitch DS, et al. Association of prior infection with
Chlamydia pneumoniae and
angiographically demonstrated coronary artery disease.
JAMA. 1992;268:68–72.
6. Saikku P, Leinonen M, Tenkanen L, et al. Chronic Chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart Study. Ann Intern Med. 1992;16:273–278.
7. Muhlestein JB, Hammond EH, Carlquist JF, et al. Increased incidence of Chlamydia species within the coronary arteries of patients with symptomatic atherosclerotic versus other forms of cardiovascular disease. J Am Coll Cardiol. 1996;27:1555–1561.[Abstract]
8.
Mendall MA, Goggin
PM, Molineaux N, et al. Relation of
Helicobacter pylori infection
and coronary heart disease. Br Heart
J. 1994;71:437–439.
9.
Pasceri V,
Cammarota G, Patti G, et al. Association of virulent
Helicobacter pylori strains
with ischemic heart disease.
Circulation. 1998;97:1675–1679.
10. Sorlie PD, Adam E, Melnick SL, et al. Cytomegalovirus/herpesvirus and carotid atherosclerosis: the ARIC study. J Med Virol. 1994;42:33–37.[Medline] [Order article via Infotrieve]
11.
Havlik RJ,
Blackwelder WC, Kaslow R, et al. Unlikely association between
clinically apparent herpesvirus infection and coronary incidence at
older ages. Arteriosclerosis. 1989;9:877–880.
12. Adler SP, Hur JK, Wang JB, et al. Prior infection with cytomegalovirus is not a major risk factor for angiographically demonstrated coronary artery atherosclerosis. J Infect Dis. 1998;177:209–212.[Medline] [Order article via Infotrieve]
13. Weiss SW, Roblin PM, Gaydos CA, et al. Failure to detect Chlamydia pneumoniae in coronary atheromas of patients undergoing atherectomy. J Infect Dis. 1996;173:957–963.[Medline] [Order article via Infotrieve]
14.
Ridker PM,
Hennekens CH, Buring JE, et al. Baseline IgG antibody titers to
Chlamydia pneumoniae, Helicobacter
pylori, herpes simplex virus, and cytomegalovirus and the
risk for cardiovascular disease in women.
Ann Intern Med. 1999;131:573–577.
15.
Nieto FJ.
Infections and atherosclerosis: new clues from an old hypothesis?
Am J Epidemiol. 1998;148:937–948.
16. Zhu J, Quyyumi AA, Norman JE, et al. Effects of total pathogen burden on coronary artery disease risk and C-reactive protein levels. Am J Cardiol. 2000;85:140–146.[Medline] [Order article via Infotrieve]
17.
Jackson LA,
Stewart DK, Wang SP, et al. Safety and effect on
anti-Chlamydia pneumoniae
antibody titers of a 1 month course of daily azithromycin in adults
with coronary artery disease. J Antimicrob
Chemother. 1999;44:411–414.
18.
Epstein SE, Zhou
YF, Zhu J. Infection and atherosclerosis: emerging mechanistic
paradigms. Circulation. 1999;100:e20–e28.
19.
Ridker PM,
Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of
cardiovascular disease in apparently healthy men.
N Engl J Med. 1997;336:973–979.
20.
de Beer FC, Hind
CR, Fox KM, et al. Measurement of serum C-reactive protein
concentration in myocardial ischemia and infarction.
Br Heart J. 1982;47:239–243.
21.
Liuzzo G,
Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive
protein and serum amyloid A protein in severe unstable
angina. N Engl J Med. 1994;331:417–424.
22. Hajjar DP, Pomerantz KB, Falcone DJ, et al. Herpes simplex virus infection in human arterial cells: implications in arteriosclerosis. J Clin Invest. 1987;80:1317–1321.
23. Jacob HS, Visser M, Key NS, et al. Herpes virus infection of endothelium: new insights into atherosclerosis. Trans Am Clin Climatol Assoc. 1992;103:95–104.[Medline] [Order article via Infotrieve]
24. Speir E, Modali R, Huang ES, et al. Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. Science. 1994;256:391–394.
25.
Reddy S, Yusuf S.
Emerging epidemic of cardiovascular disease in developing countries.
Circulation. 1998;97:596–601.
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J. Ngeh and C. Goodbourn Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila in Elderly Patients With Stroke (C-PEPS, M-PEPS, L-PEPS): A Case-Control Study on the Infectious Burden of Atypical Respiratory Pathogens in Elderly Patients With Acute Cerebrovascular Disease Stroke, February 1, 2005; 36(2): 259 - 265. [Abstract] [Full Text] [PDF]
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 M. J. Zibaeenezhad, A. Amanat, A. Alborzi, and A. Obudi Relation of Chlamydia Pneumoniae Infection to Documented Coronary Artery Disease in Shiraz, Southern Iran Angiology, January 1, 2005; 56(1): 43 - 48. [Abstract] [PDF]
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J Sheehan, P M Kearney, S O Sullivan, C Mongan, E Kelly, and I J Perry Acute coronary syndrome and chronic infection in the Cork coronary care case-control study Heart, January 1, 2005; 91(1): 19 - 22. [Abstract] [Full Text] [PDF]
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 A. Kato, T. Takita, Y. Maruyama, and A. Hishida Chlamydial infection and progression of carotid atherosclerosis in patients on regular haemodialysis Nephrol. Dial. Transplant., October 1, 2004; 19(10): 2539 - 2546. [Abstract] [Full Text] [PDF]
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D. Sander, K. Winbeck, J. Klingelhofer, T. Etgen, and B. Conrad Progression of Early Carotid Atherosclerosis Is Only Temporarily Reduced After Antibiotic Treatment of Chlamydia pneumoniae Seropositivity Circulation, March 2, 2004; 109(8): 1010 - 1015. [Abstract] [Full Text] [PDF]
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 P. L. Nerheim, J. L. Meier, M. A. Vasef, W.-G. Li, L. Hu, J. B. Rice, D. Gavrila, W. E. Richenbacher, and N. L. Weintraub Enhanced Cytomegalovirus Infection in Atherosclerotic Human Blood Vessels Am. J. Pathol., February 1, 2004; 164(2): 589 - 600. [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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 A. van der Ven, R. van Diest, K. Hamulyak, M. Maes, C. Bruggeman, and A. Appels Herpes Viruses, Cytokines, and Altered Hemostasis in Vital Exhaustion Psychosom Med, March 1, 2003; 65(2): 194 - 200. [Abstract] [Full Text] [PDF]
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 J. P. Higgins Chlamydia pneumoniae and Coronary Artery Disease: The Antibiotic Trials Mayo Clin. Proc., March 1, 2003; 78(3): 321 - 332. [Abstract] [PDF]
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J. B. Muhlestein and J. L. Anderson Infectious Serology and Atherosclerosis: How Burdensome Is the Risk? Circulation, January 21, 2003; 107(2): 220 - 222. [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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B. D. Horne, J. B. Muhlestein, J. F. Carlquist, T. L. Bair, T. E. Madsen, N. I. Hart, J. L. Anderson, and for the Intermountain Heart Collaborative (IHC) St Statin Therapy Interacts With Cytomegalovirus Seropositivity and High C-Reactive Protein in Reducing Mortality Among Patients With Angiographically Significant Coronary Disease Circulation, January 21, 2003; 107(2): 258 - 263. [Abstract] [Full Text] [PDF]
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M. V. Kalayoglu, P. Libby, and G. I. Byrne Chlamydia pneumoniae as an Emerging Risk Factor in Cardiovascular Disease JAMA, December 4, 2002; 288(21): 2724 - 2731. [Abstract] [Full Text] [PDF]
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M. Prager, Z. Turel, W. S. Speidl, G. Zorn, C. Kaun, A. Niessner, G. Heinze, I. Huk, G. Maurer, K. Huber, et al. Chlamydia pneumoniae in Carotid Artery Atherosclerosis: A Comparison of Its Presence in Atherosclerotic Plaque, Healthy Vessels, and Circulating Leukocytes From the Same Individuals Stroke, December 1, 2002; 33(12): 2756 - 2761. [Abstract] [Full Text] [PDF]
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D. Sander, K. Winbeck, J. Klingelhofer, T. Etgen, and B. Conrad Reduced Progression of Early Carotid Atherosclerosis After Antibiotic Treatment and Chlamydia pneumoniae Seropositivity Circulation, November 5, 2002; 106(19): 2428 - 2433. [Abstract] [Full Text] [PDF]
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C. Espinola-Klein, H.-J. Rupprecht, S. Blankenberg, C. Bickel, H. Kopp, A. Victor, G. Hafner, W. Prellwitz, W. Schlumberger, and J. Meyer Impact of Infectious Burden on Progression of Carotid Atherosclerosis Stroke, November 1, 2002; 33(11): 2581 - 2586. [Abstract] [Full Text] [PDF]
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M. Gabrielli, L. Santarelli, A. Gasbarrini, C. Espinola-Klein, H. J. Rupprecht, S. Blankenberg, C. Bickel, H. Kopp, J. Meyer, G. Rippin, et al. Role for Chronic Infections in Atherosclerosis? * Response Circulation, August 13, 2002; 106 (7): e32 - e32. [Full Text] [PDF]
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J. A. Vita and J. Loscalzo Shouldering the Risk Factor Burden: Infection, Atherosclerosis, and the Vascular Endothelium Circulation, July 9, 2002; 106(2): 164 - 166. [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. Blankenberg, L. Tiret, C. Bickel, D. Peetz, F. Cambien, J. Meyer, H. J. Rupprecht, and for the AtheroGene Investigators Interleukin-18 Is a Strong Predictor of Cardiovascular Death in Stable and Unstable Angina Circulation, July 2, 2002; 106(1): 24 - 30. [Abstract] [Full Text] [PDF]
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R K Singh, A D McMahon, H Patel, C J Packard, B J Rathbone, and N J Samani Prospective analysis of the association of infection with CagA bearing strains of Helicobacter pylori and coronary heart disease Heart, July 1, 2002; 88(1): 43 - 46. [Abstract] [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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 S. E. Epstein The Multiple Mechanisms by Which Infection May Contribute to Atherosclerosis Development and Course Circ. Res., January 11, 2002; 90(1): 2 - 4. [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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J. Sinisalo, K. Mattila, V. Valtonen, O. Anttonen, J. Juvonen, J. Melin, H. Vuorinen-Markkola, M. S. Nieminen, and for the Clarithromycin in Acute Coronary Syndrome Effect of 3 Months of Antimicrobial Treatment With Clarithromycin in Acute Non-Q-Wave Coronary Syndrome Circulation, April 2, 2002; 105(13): 1555 - 1560. [Abstract] [Full Text] [PDF]
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