(Stroke. 2000;31:2127.)
© 2000 American Heart Association, Inc.
Original Contributions |
Are Morphological or Functional Changes in the Carotid Artery Wall Associated With Chlamydia pneumoniae, Helicobacter pylori, Cytomegalovirus, or Herpes Simplex Virus Infection?
From the 2nd Department of Medicine (C.E.-K., H.-J.R., S.B., C.B., H.K., U.P., J.M.), the Institute for Medical Statistics and Documentation (G.R.), and the Institute for Clinical Chemistry and Laboratory Medicine (G.H.), Johannes-Gutenberg University, Mainz, Germany.
Correspondence to Christine Espinola-Klein, MD, 2nd Department of Medicine, Johannes-Gutenberg-University Mainz, Langenbeckstrasse 1, 55101 Mainz, Germany. E-mail espinola{at}mail.uni-mainz.de
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Abstract |
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Background and Purpose—Chronic infection with Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus (CMV), and herpes simplex virus (HSV) has been implicated in the pathogenesis of atherosclerosis. The carotid intima-media thickness (IMT) can be taken to indicate early atherosclerosis, the presence of a carotid stenosis is a marker of a manifest carotid atherosclerosis, and an increase in arterial stiffness is used as marker of structural and functional changes in an atherosclerotic vessel wall.
Methods—In 504 patients (75% men; mean age 62.9 [SD 10] years), we measured the IMT and the elastic pressure modulus (EP; n=445) of the common carotid artery and the prevalence of a internal or external carotid artery stenosis. Blood samples were taken, and antibodies against C pneumoniae, H pylori, CMV, and HSV types 1 and 2 were evaluated. Statistical evaluation was performed with regression procedures and multivariate logistic regression analyses.
Results—Seropositivity for C pneumoniae was an independent predictor for a combined end point of highest category of IMT and carotid artery stenosis (OR 1.8, 95% CI 1.1 to 3.1; adjusted) for IgG titers. Independently, CMV increased the risk for the combined end point (OR 1.7, 95% CI 1.1 to 2.8; adjusted) for IgG titers and for IgA titers (OR 2.3, 95% CI 1.1 to 4.9; adjusted). We found a significant correlation between IgG antibodies against CMV and EP; HSV type 2 IgG titers were associated with IMT and carotid stenosis, but the latter results were no longer significant after adjustment. There was no association with H pylori or HSV type 1.
Conclusions—We found a significant association of IgG antibodies against C pneumoniae and CMV with early and advanced carotid atherosclerosis. CMV was also correlated to functional changes of the carotid artery, but this could not be confirmed after adjustment.
Key Words: atherosclerosis • bacterial infections • carotid arteries • viruses
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There is accumulating evidence that certain infectious agents play a role in the pathogenesis of atherosclerosis. An association of viral infection with atherosclerosis was first reported in the 1970s, when experimental infection of germ-free chickens with an avian herpesvirus was found to produce arterial disease.1 There is also circumstantial evidence that cytomegalovirus (CMV) and herpes simplex virus (HSV) may contribute to the pathogenesis of atherosclerosis. The first such association, reported in relation to CMV, was later followed by reports of similar associations between atherosclerosis and HSV.2 3 Associations of human atherosclerosis with Gram-negative bacteria, has since been reported also, and there is increasing evidence that Chlamydia pneumoniae may play a important role. C pneumoniae was shown to be involved with coronary and carotid atherosclerosis in several trials.4 5 Helicobacter pylori has also been suggested to be involved in the atherosclerotic process; and in one seroepidemiological study, both H pylori and C pneumoniae infections were linked with coronary heart disease (CHD).6 7 Moreover, C pneumoniae and CMV were not only detected in human atherosclerotic lesions but were also shown to exacerbate lesion development in animal models of atherosclerosis and restenosis.8 9 10 A number of investigators have evaluated the association of different agents with advanced atherosclerosis, such as coronary artery disease (CAD) or carotid artery stenosis, and others have examined early carotid atherosclerosis; at present, however, little information is available about the influence of any bacterial or viral infection on functional wall changes, such as the stiffness of the carotid artery.5 11 12 Few investigators measured antibodies to more than one of these infectious agents in the same population.13 14 No data have been published about the association of C pneumoniae, H pylori, CMV, and HSV 1 and 2 with both functional and morphological changes of the carotid artery.
Therefore, we evaluated the intima-media thickness (IMT), the prevalence of a carotid stenosis, and the pressure-strain elastic modulus (EP) of the carotid artery and correlated these data with antibodies against C pneumoniae, H pylori, CMV, and HSV types 1 and 2.
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Subjects and Methods |
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Study Population
A total of 504 patients, treated at our department of cardiovascular medicine (university clinic), were recruited into the study between January 1997 and January 1998. Patients were randomly chosen every day. All patients had come to the hospital for various internal diseases: 283 patients (56%) had a stable and 90 patients (18%) an unstable coronary syndrome, 62 patients (12%) suffered from acute myocardial infarction, and 96 patients (14%) had come to the hospital for other internal diseases (for example, peripheral arterial disease [PAD] or valvular heart disease). In total, 436 patients (87%) had known CHD, proved by acute or previous myocardial infarction or by coronary angiography, and 169 patients (34%) had PAD, defined as either angiographically detected stenosis or a pathological ankle-arm index (blood pressure ankle/arm of <1). Patients who were admitted to the hospital for a new stroke or known cerebrovascular diseases were excluded from the evaluation. Informed consent was obtained from all participants before examination. Participants attended for a single visit. Cardiovascular risk factors such as familial history of cardiovascular diseases were assessed by interview (Table 1
). Diabetes mellitus was
diagnosed in patients with a history of dietary treatment or additional
oral antidiabetic or insulin medication; hypertension with history of
antihypertensive treatment; and hyperlipidemia in
patients with lipid-lowering medication or history of
cholesterol levels of 
240 mg/dL.
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Serology
Blood samples were drawn from each subject after an overnight
fasting period. Serum was centrifuged at 4000g for
10 minutes, immediately divided into aliquots, and frozen at -80°C
until analysis. Serum total cholesterol,
triglycerides, and high- and low-density lipoproteins were
evaluated immediately, and measurements of antibodies were performed
with the stored frozen samples. IgG antibodies against H
pylori, CMV, and HSV types 1 and 2 were measured by a commercial
ELISA test kit (EUROIMMUN; Lübeck, Germany). Because no
international reference serum exists, the calibration is performed in
relative units per milliliter (RU/mL). The recommended cutoff point of
20 RU/mL was considered positive. H pylori- and CMV-specific
IgA antibodies were evaluated by a commercial semiquantitative ELISA
assay (EUROIMMUN). Results are provided in the form of ratios, with a
ratio of >1.0 considered positive for both test kits, according to the
manufacturer. C pneumoniae IgA and IgG antibodies were also
measured by a commercial ELISA enzyme immunoassay (SeroCP IgA and IgG,
Hain Diagnostika GmbH). Results are provided by the manufacturer in the
form of indices, relative to the concentrations of antibodies. An
antibody index of >1.5 was considered positive and an index of >2.5
highly positive, according to the SeroCP manufacturers. The results of
antibody measurements are shown in Table 2.
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Ultrasound Imaging
B-mode ultrasonographic images of the carotid artery were
obtained with a 7.5-MHz transducer (Ultramark 9, Advanced Technology
Laboratories). Common carotid artery IMT was measured, in accordance
with previous reports,15 16 1 cm before the carotid
bifurcation at the far wall of the carotid artery. The distance between
the echoes arising from the blood-intima interface and the
media-adventitia interface was taken as the measure of IMT. Multiple
longitudinal and cross-sectional measurements of both common carotid
arteries were summarized, and the mean carotid IMT was calculated for
each individual. Patients were divided into 4 groups in accordance with
the quartiles of IMT, to which we will henceforth refer to as
categories.
The reader estimated the percent diameter stenosis for each internal and external carotid artery by using both color duplex imaging and Doppler peak systolic flow velocities. In accordance with previous reports, Doppler peak velocities <1.4 m/s were assumed to indicate the absence of significant lumen stenosis (diameter stenosis <60%).17 All patients with at least a 60% stenosis (46 patients, 9.1%) of the internal or external carotid artery were defined as having clinically advanced carotid artery disease.
The continuous variation in arterial diameter throughout
the cardiac cycle was measured ECG triggered from both common carotid
arteries by M-mode ultrasonographic imaging. The echoes corresponding
to the diametrically opposite blood-intima interfaces were identified
on a screen, and the minimal diastolic and maximal
systolic distances between these interfaces were evaluated.
Supine blood pressure was measured from the right brachial artery
during the ultrasound examination at both arms, and the mean
systolic and diastolic blood pressure was
calculated. The EP, measured in kilopascals, was calculated according
to the formula
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Patients were divided into 4 categories in accordance with the quartiles of EP. The EP has not yet been evaluated in the first 59 patients (12%).
Statistical Analysis
All ultrasonographic measurements were taken with blinding to
clinical details and serological results. Serological assays were
performed with blinding to clinical details and the results of
ultrasound examinations. The intraclass correlation coefficient (ICC)
for interobserver variability (n=40, 2 investigators) was 0.994 (95%
CI 0.991 to 0.998) for IMT and 0.945 (95% CI 0.920 to 0.986) for EP
measurements. ICC for intraobserver variability (n=40) was 0.996 (95%
CI 0.993 to 0.998) for IMT and 0.973 (95% CI 0.949 to 0.985) for EP
measurements. Testing for statistical trends was performed with
regression analysis for categories of IMT, categories of EP,
and for patients with and without carotid artery stenosis.
Multivariate logistic regression analysis was
performed including age, sex, cardiovascular risk
factors, presence of CHD or PAD, and seropositivity for each infectious
agent. To reduce the problem of multiple testing, we limited our
evaluation to 1 multivariate model and to 1 combined
end point, including patients who were in the maximal category of IMT
or had a significant carotid artery stenosis. Confidence
intervals at the 95% level were calculated for the odds ratios. A
value of P
0.05 was considered significant.
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Results |
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Intima-Media Thickness
There was a significant increase in IgG antibodies against C pneumoniae with increasing categories of carotid IMT (P<0.02, Table 3
). There was
no significant association between elevated C pneumoniae IgA
antibody levels and increased carotid IMT. We also found significant
associations between elevated IgG and IgA antibodies against CMV and
increased carotid IMT (CMV IgG P<0.001, CMV IgA
P<0.02). There was a significant elevation of IgG
antibodies against HSV type 2 with increased carotid IMT
(P<0.0001). We could not find any correlation between
elevated antibodies against H pylori or HSV type 1 and
increasing categories of carotid IMT.
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Pressure-Strain Elastic Modulus
There was a significant association between elevated levels of IgG
antibodies against CMV and increased categories of EP
(P=0.05, Table 4). These
results were altered after controlling for age, gender, CAD, PAD, and
cardiovascular risk factors in the
multivariate regression analysis
(P=0.13). There was no association between common carotid
artery elasticity and IgA antibodies against CMV. We could not find any
association of antibodies against C pneumoniae, H pylori,
and HSV type 1 or 2 with increased categories of EP.
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Carotid Artery Stenosis
Using univariate methods of analysis, there
was a borderline significant association between C
pneumoniae IgG seropositivity and the presence of relevant carotid
stenosis (IgG P=0.053, Table 5). Patients with carotid
stenosis had significantly higher levels of IgA antibody titers
against C pneumoniae (P<0.02) and IgG antibody
titers against CMV (P<0.05). However, there was no
association between CMV IgA antibodies and the prevalence of a
significant carotid stenosis in the univariate
model. We also found a significant increase in IgG antibody levels
against HSV type 2 in patients with versus patients without carotid
atherosclerosis (P<0.04). There was no
association between the presence of a carotid stenosis and
antibodies against H pylori or HSV type 1.
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Logistic Regression Analysis
In view of a combined end point of elevated carotid IMT and the
presence of carotid stenosis, a significant association for
high C pneumoniae IgG seropositivity was confirmed in the
logistic regression analysis adjusted for age, gender, CAD,
PAD, and cardiac risk factors (OR 1.8, 95% CI 1.1 to 3.1,
P=0.03; Table 6). After
adjustment the association between carotid
atherosclerosis and C pneumoniae IgA
seropositivity could not be confirmed.
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For CMV IgG antibody titers, the significant association with carotid atherosclerosis continued to be significant after logistic regression analysis (OR 1.7, 95% CI 1.1 to 2.8, P=0.03). Using the combined end point of the highest category of IMT and the presence of a carotid stenosis in the multivariate model, there was still an independent relationship with seropositivity for IgA antibodies against CMV (OR 2.3, 95% CI 1.1 to 4.9, P=0.04).
The relationships between early and advanced carotid atherosclerosis and seropositivity for HSV type 2 IgG did not persist after adjustment.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Inflammatory mechanisms have been implicated in the pathogenesis of atherosclerosis. Elevated levels of C-reactive protein, a marker of systemic inflammation, or fibrinogen have been found among individuals with stable and unstable angina pectoris, PAD, and carotid artery stenosis.20 21 Several plasma markers of inflammation have also been evaluated as potential tools for prediction of myocardial infarction and stroke.22 23 Multiple investigators have demonstrated that infectious agents evoke cellular and molecular changes that might cause, trigger, or accelerate an atherosclerotic process. The fact that multiple pathogens have been associated with atherosclerosis implies that many pathogens exist, and recent data suggest that the risk of atherosclerosis relates to the number of atherogenic pathogens with which the individual is infected; however, the role of each infectious agent remains unclear.24 25
Over the last years the role of C pneumoniae in the development of atherosclerosis has been widely discussed. We found a significant increase in C pneumoniae IgG with early and advanced atherosclerosis, and this relationship persisted after adjustment. There was also an association between elevated IgA antibodies against C pneumoniae and carotid artery stenosis, but after adjustment this was not significant any more. Markus et al reported similar results with regard to C pneumoniae IgA seropositivity and the presence of carotid stenosis in the univariate but not the multivariate analysis.11 The presence of IgA antibodies against C pneumoniae is considered to indicate a chronically recurrent infection, because of its half-life of 9 days and since relevant prospective data have been reported only for IgA.25 This could explain the positive association between advanced carotid atherosclerosis and IgA seropositivity. In contrast to our results, Markus et al11 found no association between carotid IMT and IgG antibodies against C pneumoniae. This discrepancy can probably be explained by the different patient collectives. Markus et al included a normal population, and participants were on average 10 years younger than those in our study; therefore, we suggest that carotid atherosclerosis is more advanced in our older patients at cardiovascular risk. Our results also agree with the results of other trials reporting a significant association of a chronic C pneumoniae infection with carotid atherosclerosis and an increased risk of stroke and transient ischemic events.26 27 28 There is no conclusive evidence yet that C pneumoniae causes atherosclerosis or precipitates acute coronary or cerebrovascular syndromes. The detection of C pneumoniae DNA in other nonrespiratory sites, such as aortic valves or skin granulomata, suggests that the organism may merely be an "innocent bystander" in inflamed tissue.29 Conversely, C pneumoniae in atherosclerotic vessels might promote local injury and elicit an autoimmune inflammatory response.30 It is interesting that after adjustment for age, gender, and risk factors (including smoking), the independent relationship between C pneumoniae seropositivity and carotid atherosclerosis remained only for patients with high levels of antibody titers. Patients with low antibody counts likely only had a previous respiratory disease, and those with very high antibody titers also had an infection of the arterial walls with C pneumoniae. It is also possible that both high antibody titers to a bacterial infection and atherosclerosis are independent signs of an increased inflammatory response in a particular individual.
We found no association between antibodies against H pylori and carotid artery disease. Evidence for a moderate association between H pylori and atherosclerosis is difficult to interpret even in population-based studies, because residual confounding factors related to socioeconomic status are probably present.14 The role of H pylori is controversial, with some studies reporting negative results and others showing a significant correlation with coronary or carotid artery disease; often, however, results cannot be confirmed after adjustment for risk factors and socioeconomic status.7 14 31 32 33 34
Histopathological studies have reported evidence of CMV and HSV particles within the whole human vascular tree, and the presence of CMV genomic sequences is usually associated with CMV seropositivity.3 35 36 We found a significant association between IgG seropositivity for CMV and the presence of early and advanced atherosclerosis, even after adjustment, consistent with the results of previous serological studies. The Atherosclerosis Risk in Communities (ARIC) study12 documented a significant association between elevated carotid IMT and the level of CMV antibodies. Several authors found associations with clinically advanced atherosclerotic disease, such as CHD or significant carotid atherosclerosis; others did not.37 38 39 40 Zhou et al could show an increased risk for restenosis in patients with prior infection with CMV 6 months after atherectomy.10 In contrast, other authors reported negative predictive values of CMV seropositivity for the progress of cardiovascular diseases after a longer follow-up period, such as Strachan et al40 in the Caerphilly prospective and Ridker et al41 in the Physician Health study, with a follow-up period of >10 years. Zhu et al42 explained the discrepancy between positive and negative study results as follows: individuals with an inflammatory response appear to be susceptible to the atherogenic effects of CMV, whereas those without appear to be resistant. It is possible that in some patients an atherosclerotic response of a vessel wall tends to develop after viral infection; a previous infection with CMV or another virus probably alters the function of cells permanently without persistence of the agent. It is known that human smooth muscle cells can be infected by CMV, and in some cases viral arteritis may furnish the substrate for an atheroma, perhaps in combination with traditional risk factors.43 We also found significantly elevated antibodies against CMV with increased carotid artery stiffness. The loss of significance after adjustment could stem from colinearity between antibody status and some of the adjustment variables, and it is known from the ARIC trial that patients with atherosclerosis, especially diabetics, have stiffer arteries than normal subjects of the same age.18
With regard to HSV, we found a significant association of early as well as advanced atherosclerosis with the HSV type 2, but this result could not be confirmed after adjustment. We found no association with HSV type 1. In the literature the role of HSV is controversial with regard to CAD.2 44 Although there is limited evidence from pathological studies linking HSV to carotid atherosclerosis, epidemiological studies suggest no or only a weak association for HSV type 1 or, as in our trial, for HSV type 2 with carotid atherosclerosis.44 There was no correlation of carotid IMT with antibodies directed against HSV type 1 or type 2 antigens in the ARIC trial.2 12 Moderated-sized effects may, however, have been missed in populations with very high rates of seropositivity to HSV, and in our trial 91% of the patients have antibodies against HSV type 1.
Limitations
We did not included socioeconomic status, a known important
confounder, especially with regard to H pylori infection,
and this is a limitation for the interpretation of the results. Because
a number of statistical tests were calculated in this study, a
multiplicity problem arises. However, multiple testing adjustments were
not considered, and thus the results should be interpreted
carefully.
Conclusions
The present data support the association of cerebrovascular
disease with previous CMV and C pneumoniae infections. It is
possible that chronic infection with HSV type 2 is associated with
carotid atherosclerosis, but this result could not be
confirmed after statistical adjustment. We found no evidence that
H pylori– or HSV type 1–positive serology is associated
with early or advanced carotid atherosclerosis, nor was
there an independent relationship between decreased carotid elasticity
and any infectious agents.
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Acknowledgments |
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The authors acknowledge the EUROIMMUN GmbH, Lübeck, Germany, for evaluation of the H pylori, CMV, and HSV antibody titers.
Received March 3, 2000; revision received May 23, 2000; accepted May 23, 2000.
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 L. B. Goldstein, R. Adams, M. J. Alberts, L. J. Appel, L. M. Brass, C. D. Bushnell, A. Culebras, T. J. DeGraba, P. B. Gorelick, J. R. Guyton, et al. Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline. Circulation, June 20, 2006; 113(24): e873 - e923. [Abstract] [Full Text] [PDF]
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 L. B. Goldstein, R. Adams, M. J. Alberts, L. J. Appel, L. M. Brass, C. D. Bushnell, A. Culebras, T. J. DeGraba, P. B. Gorelick, J. R. Guyton, et al. Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline. Stroke, June 1, 2006; 37(6): 1583 - 1633. [Abstract] [Full Text] [PDF]
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 I. Volanen, M. J. Jarvisalo, R. Vainionpaa, M. Arffman, K. Kallio, S. Angle, T. Ronnemaa, J. Viikari, J. Marniemi, O. T. Raitakari, et al. Increased Aortic Intima-Media Thickness in 11-Year-Old Healthy Children With Persistent Chlamydia pneumoniae Seropositivity Arterioscler Thromb Vasc Biol, March 1, 2006; 26(3): 649 - 655. [Abstract] [Full Text] [PDF]
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A. K. Njamnshi, K. N. Blackett, J. N. Mbuagbaw, F. Gumedze, S. Gupta, and C. S. Wiysonge Chronic Chlamydia pneumoniae Infection and Stroke in Cameroon: A Case-Control Study Stroke, March 1, 2006; 37(3): 796 - 799. [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. J. Lindsberg and A. J. Grau Inflammation and Infections as Risk Factors for Ischemic Stroke Stroke, October 1, 2003; 34(10): 2518 - 2532. [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. 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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T. Vainas, H. A.J.M. Kurvers, W. H. Mess, R. d. Graaf, R. Ezzahiri, J. H.M. Tordoir, G.-W. H. Schurink, C. A. Bruggeman, and P. J.E.H.M. Kitslaar Chlamydia pneumoniae Serology Is Associated With Thrombosis-Related but Not With Plaque-Related Microembolization During Carotid Endarterectomy Stroke, May 1, 2002; 33(5): 1249 - 1254. [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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 M. L. C. Tondella, D. F. Talkington, B. P. Holloway, S. F. Dowell, K. Cowley, M. Soriano-Gabarro, M. S. Elkind, and B. S. Fields Development and Evaluation of Real-Time PCR-Based Fluorescence Assays for Detection of Chlamydiapneumoniae J. Clin. Microbiol., February 1, 2002; 40(2): 575 - 583. [Abstract] [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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C. Espinola-Klein, H. J. Rupprecht, S. Blankenberg, C. Bickel, H. Kopp, G. Rippin, A. Victor, G. Hafner, W. Schlumberger, and J. Meyer Impact of Infectious Burden on Extent and Long-Term Prognosis of Atherosclerosis Circulation, January 1, 2002; 105(1): 15 - 21. [Abstract] [Full Text] [PDF]
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