(Stroke. 2001;32:855.)
© 2001 American Heart Association, Inc.
Original Contribution |
Presence of Chlamydia pneumoniae in Human Symptomatic and Asymptomatic Carotid Atherosclerotic Plaque
From the Stroke Branch (R.LaB., S.A., S.S., T.J.DeG.), National Institute of Neurological Disorders and Stroke; Biostatistics & Clinical Epidemiology Service (D.K.), Clinical Center, National Institutes of Health; National Institute of Allergy and Infectious Diseases (T.Q.); Infectious Diseases Division (C.G.), Johns Hopkins University; National Naval Medical Center (S.A., G.K., T.J.DeG.); and Uniformed Services University of the Health Sciences (T.J.DeG.).
Correspondence to Thomas J. DeGraba, MD, Stroke Branch, NINDS, NIH, Bldg 36/Room 4A–03, 36 Convent Dr, MSC 4128, Bethesda, MD 20892-4128.
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Abstract |
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MethodsResultsDiscussionConclusionsReferences |
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Background—Chlamydia pneumoniae has been identified in atherosclerotic plaques of patients with cerebrovascular and cardiovascular disease. However, the direct causative effect of C pneumoniae infection in the activation of atherosclerotic plaque to a prothrombotic state remains to be established. The aim of the present study is to examine the correlation between intraplaque presence of chlamydiae and symptomatic carotid disease in humans.
Methods—Plaques from 37 symptomatic and 57 asymptomatic consenting patients undergoing carotid endarterectomy were snap-frozen, and the tissue was prepared for polymerase chain reaction analysis for Chlamydia pneumoniae per Institutional Review Board–approved protocol. Blood was drawn from each patient at the time of surgery for serological analysis.
Results—The overall
rate of plaques positive for C
pneumoniae was 14.82%, with 5 of 37 (13.5%) plaques from
symptomatic patients and 9 of 57 (15.8%) from
asymptomatic patients, which revealed a definitive presence
of the organism. No association existed between
C pneumoniae presence and
symptomatic disease
(P=1.0). Also, no association
existed between presence of C
pneumoniae and severity of stenosis. Finally,
seropositivity for anti-chlamydial IgG, IgA, and IgM anti-chlamydial
antibodies did not correlate with identification of
C pneumoniae in the plaques.
However, high-serum anti-chlamydial IgA levels (
1:128) were
associated with occurrence of symptomatic disease
(P=0.03; odds ratio, 2.86; 95%
CI, 1.12 to 7.28).
Conclusions—Presence of C pneumoniae as a single factor does not appear to be sufficient to explain the occurrence of cerebrovascular symptoms. Low sensitivity of seropositivity for IgG, IgA, or IgM associated with PCR-identified C pneumoniae presence in the plaque makes it unlikely to be valuable as the single determining factor for actively infected plaque. Association of high-level anti-chlamydial IgA with symptomatic disease suggests that chronic or acute chlamydial infection anywhere in the body could play a role in atherosclerotic plaque activation and be used as a marker to target populations in future stroke prevention trials.
Key Words: atherosclerosis • carotid arteries • chlamydia • immunoglobulin • symptoms
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Introduction |
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TopAbstractIntroductionSubjects and
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The role of inflammation in the initiation, maturation, and activation of atherosclerotic plaque is emerging as a pivotal component that requires further investigation.1 Infectious agents have been postulated to be triggers to each of the major phases of atherosclerosis.2 3 4 Organisms such as the herpesvirus family, in particular cytomegalovirus, and Chlamydia pneumoniae have been the focus of research associating infection with atherosclerotic disease. This is in part due to the ability of these organisms to cause a chronic infectious state and to upregulate cytokines and adhesion molecules.5 6 7 C pneumoniae was chosen for the present study because it is an obligate intracellular parasite that commonly infects mononuclear phagocytes. Macrophages derived from monocytes characteristically are localized in human atherosclerotic plaque and provide a mechanism for entry of the organism into the vessel wall.8 Additionally, evidence exists for infection with Chlamydia species to create a persistent nonlethal infection, which can lead to a chronic inflammatory state9 by means of a variety of mechanisms. Endotoxin release and chlamydial heat-shock protein 60 have been associated with the increase of tumor necrosis factor-
and matrix metalloproteinase from
macrophages.7
Chlamydial heat-shock protein 60 causes oxidation of LDL, which alters
LDL to its highly atherogenic
form.10 Finally, chlamydiae
can activate CD4 and CD8+ T-lymphocytes through major
histocompatibility complexes I and
II.11 These factors
demonstrate the propensity and ability of
Chlamydia to localize in
atherosclerotic plaque and exacerbate, if not initiate, the
atherosclerotic inflammatory process. Animal studies have demonstrated an association between inoculation of C pneumoniae and rapid development of atherosclerotic disease in New Zealand White rabbits.12 13 Also, the atherosclerotic process has been demonstrated to be accelerated in apolipoprotein E–deficient mice with injection of C pneumoniae.14
Numerous studies have been reported to show an association between chlamydial infection by immunohistochemical staining, polymerase chain reaction (PCR), and serological positive studies and coronary artery15 16 17 18 or cerebrovascular19 20 21 22 disease. Despite the association, no definitive proof exists that presence of Chlamydia species or other infectious agents causes either initiation of atherosclerosis or progression of atherosclerotic plaque to a symptomatic state in humans. Preliminary studies with antibiotics for secondary prevention of coronary disease have been performed, with mixed results.23 24 25 However, criteria for similar studies in cerebrovascular disease are not well defined. The aim of the present study was to examine the association between presence of C pneumoniae in human carotid atherosclerotic plaque and occurrence of ischemic symptoms. We also studied the predictive value of anti-chlamydial antibody seropositivity for plaque infection and its association with symptomatic disease.
Given the potential for enhancing proinflammatory mediators that could lead to plaque rupture or luminal thrombosis, we hypothesized that C pneumoniae would be present in a significantly larger percentage of symptomatic versus asymptomatic carotid atherosclerotic plaque. We further hypothesize that elevated anti-chlamydial antibodies would be associated with presence of C pneumoniae in the plaque and symptomatic disease. To test these hypotheses, carotid plaque specimens from symptomatic and asymptomatic patients were examined by PCR for chlamydial DNA. Serological analysis also was performed to determine whether circulating anti-chlamydial antibodies are markers for symptomatic disease and C pneumoniae presence in the plaque.
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Subjects and Methods |
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Subjects
Ninety-four patients undergoing carotid endarterectomy at the National Naval Medical Center consented to participate in this Institutional Review Board–approved protocol to study presence of C pneumoniae in symptomatic versus asymptomatic patients. Patients were identified as candidates for carotid endarterectomy according to standard medical practices of the vascular surgery service at the participating hospital, following the North American Symptomatic Carotid Endarterectomy Trial (NASCET)26 and Asymptomatic CArotid endarterectomy Study (ACAS)27 criteria. Patients were invited to participate in the protocol after the decision was made for the patient to undergo endarterectomy. Full history of prior medical conditions was taken, and neurological examination was performed and recorded by a neurologist from the Stroke Branch/National Institute of Neurological Disorders and Stroke (NINDS). Patients were classified as symptomatic (prior transient ischemic attack or stroke within 6 months) or asymptomatic (no prior history of cerebral ischemic event). Computed tomographic scans were obtained on all patients before surgery, and imaging studies were used to rule out silent infarcts in the "asymptomatic" population.
Stroke risk factors for hypertension (blood pressure
>140/90 mm Hg for 1 year), past history of smoking (5
pack-years), diabetes (oral agent or insulin dependent for >1 year),
and hypercholesterolemia (LDL
cholesterol >160 mg/dL untreated, fasting
triglycerides >200 mg/dL, or on
cholesterol-lowering medications for >1 year), were
recorded in all patients. Patients with atrial fibrillation or
other conditions highly suspected to be cardiac sources of emboli were
excluded from the symptomatic group to avoid possible
confusion between a cardiac versus a carotid source of ischemic
events. A screening for fasting blood glucose and a lipid profile were
performed on all patients who had no known history of diabetes or
hypercholesterolemia.
Plaques were obtained at the time of surgery in a sterile fashion, and blood was drawn for serological testing. Carotid stenosis was measured on angiogram by use of NASCET criteria.26
DNA Isolation
Carotid atherosclerotic plaques were obtained from
symptomatic and asymptomatic patients
undergoing carotid endarterectomy at the National
Naval Medical Center, Bethesda, Md. DNA was isolated from approximately
5 to 10 serial sections of about 16-µm thickness from snap-frozen
excised tissues by use of the QIAamp tissue kit (Qiagen Inc)
according to the manufacturer’s instructions, except that DNA was
eluted in 2 steps of 50 µL each.
Care was taken to maintain aseptic handling of tissue samples. Patient samples and primary PCR reaction assembly were kept isolated in a separate laboratory to eliminate contamination of DNA samples by primary or secondary PCR products. The laboratory used to prepare the primary product was supplied separately from the main laboratory. Each sample was analyzed in duplicate or triplicate to insure reliability.
PCR Amplification
To detect C
pneumoniae DNA at the required level of sensitivity, a
2-step nested PCR protocol was implemented. The sequence of the 473-bp
PstI fragment was used as the
basis for this PCR, because it previously had been shown to have little
sequence similarity to other members of this genus by dot-blot
hybridization.28 Outer
primers for the primary PCR step were designated CP1-L
(5'-TTATTCACCGTCCTACAGCAGAAA-3') and CP2-R
(5'-GGGGGTTCAGGGATCATTTGT-3') and produced a 404-bp sequence that
corresponds to a chlamydial polymerase. Inner primers (nested)
contained within the 404-bp sequence were designated CPN1-L
(5'-TTACGAAACGGCATTACAACGGCTAGAAATCA-AT-3') and CPN1-R
(5'-TATGGCATATCCGCTTCGGGAA-CGAT-3') and were a
214-bp product.
After an initial 9-minute reaction at 95° to
activate the PCR enzyme, the outer PCR reaction was performed.
This reaction consisted of 40 cycles of 30 s at 95°C to melt,
50 s at 60°C to anneal, and 30 at 72°C to extend the primers;
was performed in 25 µL of PCR buffer, 50 nmol/L of each chlamydial
primer (5'-ATCG-3', 5'-ATCG-3'), and 0.25 U of AmpliTaq Gold (Perkin
Elmer Inc); and was templated with 1 µL of the DNA isolated from the
patient samples. The inner, nested PCR reaction was performed
with between 25 and 30 cycles of 15 s at 94°C to melt, 1 minute
at 60°C to anneal, and 15 s at 72°C to extend the primers, in
the same PCR reaction buffer as above. The nested reaction was
templated with 1 µL of the primary PCR product hot-started at
50°C. PCR products were visualized under 300 nm of UV
transillumination (Fotodyne Inc) after electrophoresis in 2% ultrapure
agarose, 1:10 000 SYBR Green II (Molecular Probes Inc). Specific
nested PCR product was identified by use of 5 to 15 ng of 
X174
DNA restricted with HaeIII as a
size marker. All PCR reactions were performed in a Perkin-Elmer model
9700 gene amplification PCR system (PE Applied
Biosystems).
Serological Testing
Microimmunofluorescence29
was performed on serum samples from 91 of 94 patients for anti-IgG,
anti-IgA, and anti-IgM for C
pneumoniae by use of formalin-treated whole elementary
bodies of organisms (Washington Research Foundation). This test is
considered to be the reference standard for determination of
anti-chlamydial IgG, IgM, and IgA antibody levels. Purified elementary
bodies from high-titer C
pneumoniae preparations were mixed with purified yolk sac
and applied to glass slides (The Washington Research Center) Only 1
serovar of C pneumoniae
existed, and purified antigen was made from strain AR39. Antigen dots
for C trachomatis also were
included in the series of antigen dots, so that specificity of the
anti–C pneumoniae antibody in
human serum could be confirmed. The highest-dilution serum that
demonstrated good, even fluorescence of the elementary bodies
was recorded as the titer for each group. The laboratory used for
the present study participates with others in quality assurance
studies for
microimmunofluorescence.30
(Adequate serum sample for serological testing was available for 91 of
94 [97%] of the patients.) Dilutions were initiated at ratios of 1:8
through 1:1024. A value of 1:16 was considered
positive.
Data Analysis
For comparisons of categorical variables,
Fisher’s Exact Test (2-sided P
value) was used. Continuous variables were compared by 2-sample
t tests. For exploration of
possible confounding risk factors, Mantel-Haenszel
2 was used for stratification
analysis of dichotomous variables, whereas logistic
regression was used in the analogous situation to control for
continuous variables. For a final multivariate
analysis, logistic regression was used, which modeled
symptomatic state as the dependent variable and all
other possible risk factors as covariates. For the logistic regression,
Wald 2 was used to determine
significance, and odds ratios and 95% confidence intervals were
calculated. For all tests, a value of
P
0.05 was considered
significant.
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Results |
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Major risk factors, age, and degree of stenosis were similar in both Chlamydia-positive and -negative groups (Table 1
). Only diabetes was nearly significant (Fisher’s
Exact Test,
P=0.07).
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PCR Detection of C
pneumoniae
DNA isolated from the carotid atherosclerotic plaques
of 94 endarterectomy patients were tested in a
2-stage nested PCR protocol. Plaques from 37 symptomatic
and 57 asymptomatic patients were studied. Overall rate of
plaques positive for C
pneumoniae was 15%; 5 of 37 (13.5%) plaques from
symptomatic patients and 9 of 57 (15.8%) from
asymptomatic patients revealed a definitive presence of the
organism. No association was observed between presence of
C pneumoniae and
symptomatic disease (Fisher’s Exact Test,
P=1.00).
Effect of
Chlamydia-positive or -negative
plaque on symptomatic state was explored further, and the
study was controlled for each of the possible confounding risk factors
listed in
Table 1
. These bivariate analyses did not
reveal any association between presence of
C pneumoniae and symptoms (all
P>0.58).
Serological Detection of
C pneumoniae
Serological studies of anti-chlamydial IgG, IgA, and
IgM revealed no association between seropositive samples and presence
of C pneumoniae within the
plaque as measured by PCR.
(Table 2). Only high anti-chlamydial IgA titers (1:128)
were associated with symptomatic versus
asymptomatic disease (Fisher’s Exact Test,
P=0.03;
Table 3). However, high titers of anti-chlamydial IgA,
similar to the other immunoglobulin levels, were not associated with
presence of intraplaque C
pneumoniae. Four of 14 (28.6%) patients with PCR-positive
plaque had high titers of IgA compared with 22 of 77 (28.6%) of
patients who were PCR negative (Fisher’s Exact Test,
P=1.00;
Table 2). No serological level of any antibody class was
associated with PCR-positive symptomatic plaque versus
patients who were PCR positive and asymptomatic (data not
shown; all P>0.58, Fisher’s
Exact Test).
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Multivariate
Analyses
To explore definitively whether any factor was
associated with symptoms, a logistic regression was modeled with
symptom presence or absence as the dependent variable and all other
possible risk factors (demographic, medical conditions, chlamydial PCR
status, and chlamydial serologies) as covariates. The only significant
variable was anti-chlamydial IgA titer 1:128 (Wald test
2, 4.836;
P=0.03). Odds ratio was 2.86
(95% confidence interval, 1.12 to
7.28).
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Discussion |
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Infection with Chlamydia represents a plausible and intriguing factor leading to atherosclerotic plaque progression and activation. As an obligate parasite, it can persist in a chronic state, increasing inflammatory mediator release and resulting in oxidation of LDL, among other mechanisms. The possibility that chlamydial infection increases the risk of stroke is so compelling that preliminary trials with antibiotics for primary prevention have been initiated. However, in the present study, no clear preponderance of occurrence of C pneumoniae presence in carotid atherosclerotic plaque could be associated with symptomatic patients. In fact, frequency of occurrence of Chlamydia was nearly identical between symptomatic and asymptomatic patients. No risk factor for stroke that is positively identified as a covariate in symptomatic disease appears to exist. At face value, these data would suggest that C pneumoniae does not play a major role in converting atherosclerotic plaque to the symptomatic state. If C pneumoniae could cause symptomaticity solely based on its presence, one could assume that a majority if not most of the plaques with C pneumoniae would fall in the symptomatic category. However, the presence of contributory factors may increase susceptibility of plaque to respond to infectious agents in an enhanced proinflammatory fashion in certain patient populations. For example, a potential scenario of plaque activation by foreign antigen is the proliferation of T cells, which are known components of atherosclerotic plaques. Plaques that possess resident T cells that have been previously sensitized to C pneumoniae would have a greater propensity for inflammatory activation and symptomaticity if reexposed. Symptomaticity could be mediated through increased risk of plaque rupture or increased luminal thrombosis.
Elevated anti-chlamydial IgA titers were significantly associated with symptomatic versus asymptomatic disease. Elevated anti-chlamydial IgA levels are believed to occur with reinfection of C pneumoniae.18 31 32 33 These titers will begin to decline within weeks to several months after reinfection. Persistently elevated levels are believed to be associated with a chronic infection state and have been noted to be associated with both chronic and acute coronary disease.18 However, no association was seen between presence of C pneumoniae in atherosclerotic plaques and immunoglobulin titers. More than 70% of patients with plaque positive for C pneumoniae by PCR did not have high anti-chlamydial IgA titers. This lack of association makes anti-chlamydial IgA titer levels a poor indicator for demonstrable intraplaque presence of C pneumoniae. Because elevated anti-chlamydial IgA levels are associated with symptomatic disease, as previously reported in other studies,34 35 but not with intraplaque C pneumoniae presence, elevation of anti-chlamydial IgA may represent a more general chronic infection state, which might result in a greater likelihood of activation of generalized atherosclerotic plaque by circulating activated leukocytes. Another possible explanation for association of IgA levels to Chlamydia and symptomatic disease is the potential for a generalized increased immunoglobulin response to antigens not specific for Chlamydia. Persons who have been previously infected with Chlamydia could display an elevated anti-chlamydial IgA after exposure to a variety of antigens. This supports the hypothesis that generalized inflammatory response can activate atherosclerotic plaque, with anti-chlamydial IgA acting only as a marker and not as an indicator of the specific antigen exposure. Further studies that focus on intraplaque differences between symptomatic and asymptomatic patients in presence of C pneumoniae need to be performed to identify any potential causative effect of infectious agents in thromboembolic atherosclerotic disease.
Several other findings and techniques necessitate brief discussion. First, the observed overall occurrence of intra-plaque C pneumoniae by PCR in our population is lower than previously reported. The probes used in the present study were highly reproducible. Potential reasons are lack of sensitivity of the technique, although dilutional studies would indicate that this was not the case. Great care was taken to avoid contamination both from external sources and during initial amplification of the chlamydial DNA. The use of nested PCR was chosen to heighten the sensitivity of identifying Chlamydia within the atherosclerotic plaques. To avoid false-positives, primary PCR was performed in a separate laboratory with separate equipment. The technique of nested PCR is beneficial for reducing the likelihood that inhibitors within the tissue used would prevent identification of Chlamydia within the plaque.
Additionally, other studies used immunohistochemical staining, PCR, and serological testing as indicators of C pneumoniae presence. Another potential influencing factor of chlamydial presence in the plaque is that the population studied, which is characterized by military retirees and their dependents, has had consistent health care, resulting in a higher incidence of successfully treated respiratory infections.
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Conclusions |
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TopAbstractIntroductionSubjects and
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In conclusion, presence of C pneumoniae in carotid atherosclerotic plaque is not associated with the symptomatic state and therefore is unlikely to be sufficient as a single factor to cause thromboembolic stroke. C pneumoniae serological studies reveal that elevated anti-chlamydial IgA microimmunofluorescence was found to be a predictor of symptomatic disease but not a marker for presence of C pneumoniae in plaques as identified by PCR. Chlamydia still could be a modifier of atherosclerosis. However, future studies need to be performed to identify mechanisms by which C pneumoniae presence may be associated with the symptomatic state. Even if it is found that C pneumoniae, under some circumstances, enhances a proinflammatory and prothrombotic state in atherosclerotic plaques, our data suggest that it affects 5% to 15% of patients in our population. Future trials along this vein will need either to identify a surrogate marker that is consistent with intraplaque infection or to hypothesize one, given that our data suggest that reducing chronic infection with Chlamydia at any site in the body may be beneficial for reducing activation of atherosclerotic plaque.
Received August 9, 2000; revision received December 20, 2000; accepted December 28, 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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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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S. F. Ameriso, A. R. Villamil, C. Zedda, J. C. Parodi, S. Garrido, M. I. Sarchi, M. Schultz, J. Boczkowski, and G. E. Sevlever Heme Oxygenase-1 Is Expressed in Carotid Atherosclerotic Plaques Infected by Helicobacter pylori and Is More Prevalent in Asymptomatic Subjects Stroke, September 1, 2005; 36(9): 1896 - 1900. [Abstract] [Full Text] [PDF]
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 M. M. Ieven and V. Y. Hoymans Involvement of Chlamydia pneumoniae in Atherosclerosis: More Evidence for Lack of Evidence J. Clin. Microbiol., January 1, 2005; 43(1): 19 - 24. [Full Text] [PDF]
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B. Maraha, H. Berg, M. Kerver, S. Kranendonk, J. Hamming, J. Kluytmans, M. Peeters, and A. van der Zee Is the Perceived Association between Chlamydia pneumoniae and Vascular Diseases Biased by Methodology? J. Clin. Microbiol., September 1, 2004; 42(9): 3937 - 3941. [Abstract] [Full Text] [PDF]
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V. Y. Hoymans, J. M. Bosmans, D. Ursi, W. Martinet, F. L. Wuyts, E. Van Marck, M. Altwegg, C. J. Vrints, and M. M. Ieven Immunohistostaining Assays for Detection of Chlamydia pneumoniae in Atherosclerotic Arteries Indicate Cross-Reactions with Nonchlamydial Plaque Constituents J. Clin. Microbiol., July 1, 2004; 42(7): 3219 - 3224. [Abstract] [Full Text] [PDF]
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 K. He, A. Merchant, E. B Rimm, B. A Rosner, M. J Stampfer, W. C Willett, and A. Ascherio Dietary fat intake and risk of stroke in male US healthcare professionals: 14 year prospective cohort study BMJ, October 4, 2003; 327(7418): 777 - 782. [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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 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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K. Kohara, Y. Tabara, Y. Yamamoto, M. Igase, and T. Miki Chlamydia pneumoniae Seropositivity Is Associated With Increased Plasma Levels of Soluble Cellular Adhesion Molecules in Community-Dwelling Subjects: The Shimanami Health Promoting Program (J-SHIPP) Study Stroke, June 1, 2002; 33(6): 1474 - 1479. [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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P. B. Gorelick Stroke Prevention Therapy Beyond Antithrombotics: Unifying Mechanisms in Ischemic Stroke Pathogenesis and Implications for Therapy: An Invited Review Stroke, March 1, 2002; 33(3): 862 - 875. [Abstract] [Full Text] [PDF]
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S. C. Johnston, L. M. Messina, W. S. Browner, M. T. Lawton, C. Morris, and D. Dean C-Reactive Protein Levels and Viable Chlamydia pneumoniae in Carotid Artery Atherosclerosis Stroke, December 1, 2001; 32(12): 2748 - 2752. [Abstract] [Full Text] [PDF]
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P. Thiagarajan Atherosclerosis, Autoimmunity, and Systemic Lupus Erythematosus Circulation, October 16, 2001; 104(16): 1876 - 1877. [Full Text] [PDF]
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Z. G. Nadareishvili, D. E. Koziol, B. Szekely, C. Ruetzler, R. LaBiche, R. McCarron, T. J. DeGraba, and S. Jander Increased CD8+ T Cells Associated With Chlamydia pneumoniae in Symptomatic Carotid Plaque Editorial Comment Stroke, September 1, 2001; 32(9): 1966 - 1972. [Abstract] [Full Text] [PDF]
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