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(Stroke. 2003;34:2518.)
© 2003 American Heart Association, Inc.
Progress Review |
From the Department of Neurology, Helsinki University Central Hospital, and Neuroscience Program, Biomedicum Helsinki, Helsinki, Finland (P.J.L.), and Neurologische Klinik, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany (A.J.G.).
Correspondence to Dr Perttu J. Lindsberg, Neuroscience Program, Biomedicum Helsinki, PO Box 700, 00290 Helsinki, Finland. E-mail perttu.lindsberg{at}hus.fi
| Abstract |
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Summary of Review Several traditional vascular risk factors are associated with proinflammatory alterations, including leukocyte activation, and predispose cerebral vasculature to thrombogenesis on inflammatory stimulation. Furthermore, accumulation of inflammatory cells, mainly monocytes/macrophages, within the vascular wall starts early during atherogenesis. During later disease stages, their activation can lead to plaque rupture and thrombus formation, increasing stroke risk. Inflammatory markers (eg, leukocytes, fibrinogen, C-reactive protein) are independent predictors of ischemic stroke. Chronic infections (eg, infection with Chlamydia pneumoniae or Helicobacter pylori) were found to increase the risk of stroke; however, study results are at variance, residual confounding is not excluded, and causality is not established at present. In case-control studies, acute infection within the preceding week was a trigger factor for ischemic stroke. Acute and exacerbating chronic infection may act by activating coagulation and chronic infections and may contribute to atherogenesis. Genetic predisposition of the inflammatory host response may be an important codeterminant for atherogenesis and stroke risk.
Conclusions Inflammation contributes to stroke risk via various interrelated mechanisms. Infectious diseases, traditional risk factors, and genetic susceptibility may cooperate in stimulating inflammatory pathways. Final proof of a causal role of infectious/inflammatory mechanisms in stroke pathogenesis is still lacking and will require interventional studies.
Key Words: anticholesteremic agents chlamydia human experimentation infection inflammation leukocytes NF-kappa B stroke
| Introduction |
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In this report we summarize the current knowledge of the role of inflammation and infection in the pathogenesis of ischemic stroke, and, because the fields are interrelated, we also review mechanisms of inflammatory vessel disturbance as a pathogenetic pathway in atherogenesis and stroke. The main focus is on clinical evidence, and only key observations from animal experiments and basic science are included. It is one of our general hypotheses that infection/inflammation, specific genetic predispositions, and traditional risk factors interact with each other and may cooperatively enhance the risk of stroke. Therefore, one focus is to examine the current knowledge of the relationship between these conditions to develop an integrated view on how they influence stroke risk. We attempt to apply generally accepted external criteria to determine whether the link between the 2 entities is of causal or merely associative nature.7 This review begins with local inflammatory alterations at the vessel wall and finally deals with systemic inflammatory changes, with acceptance of the concept that both features are closely connected to each other.
| Inflammatory Conversion of Cerebral Vasculature |
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(MIP-1
) have binding sites along the parenchymal surface of human cerebral microvessels.13 These factors can be released by resident glial cells and transported to receptors on the vascular endothelium. Chemotactic factors and molecules mediating leukocyte adhesion exert chemotaxis and transmigration across the BBB and orchestrate cell entry to perivascular/subendothelial spaces.
Although the reason for the early entry of inflammatory cells into "subendothelial" or "perivascular" domains of cerebrovascular tissue is not clear, they can powerfully signal to endothelial cells (EC) and smooth muscle cells (SMC), eg, by releasing proliferative or proteolytic substances during systemic challenges. Presumably these cells (macrophage/monocyte lineage cells, T lymphocytes) receive receptor stimulation and activate humoral changes and then influence the inflammatory state of that vascular segment by releasing inflammatory mediators or growth factors, such as interleukins, tumor necrosis factor-
(TNF-
), interferons, and transforming growth factor-ß (TGF-ß). Some of these mediators fuel the inflammatory process further and can make the luminal EC surface adherent (eg, by upregulation of intercellular adhesion molecule-1 [ICAM-1] and E-selectin) and procoagulant (eg, by upregulation of tissue factor [TF] and plasminogen activator inhibitor-1 [PAI-1] and downregulation of thrombomodulin and tissue plasminogen activator).14 Experimental data suggest that induction of immunological tolerance in lymphocytes by repeated expression of E-selectin can render them able to inhibit this early local inflammation of vascular segments.12 At this pivotal point, novel gene expression has occurred, and the EC have been activated to express immunologically provoking molecules. This early inflammatory step presumably can also occur in small vessels. Accordingly, plasma levels of soluble adhesion molecules (sICAM-1, sE-selectin) were observed to be increased both in large-intracranial-artery disease and small-artery disease.15
Link Between Traditional Stroke Risk Factors and Inflammation
Inflammatory cells positioned in vascular locations are capable of responding to known long-term risk factors for human stroke such as hypertension, hyperlipidemia, diabetes mellitus, obesity, and smoking, which have been linked to markers of EC inflammatory changes (eg, increased sICAM-1) in subjects with and without a history of cerebral infarction.1619 Prevalent cardiovascular risk factors increase systemic levels of TNF-
,20,21 which strongly augments adhesion moleculedependent transendothelial migration of lymphocytes in human cerebral endothelium in vitro.22 Circulating monocytes regulate the level of plasma TNF-
and may cause a similar response in vivo. Once the circulating monocyte has become a stationary tissue macrophage, oxidized LDL inhibits its chemotaxis, presumably to prevent its departure from the vascular domain.23 Cholesterol is also a factor that activates monocytes and is gradually accumulated in them as they mature into macrophages and eventually into foam cells. Hypercholesterolemia has been shown to increase several markers of activation in both inflammatory cells and endothelium.24 This may stem from an increase of nuclear transcription factor-
B (NF-
B), which regulates many of the inflammatory vascular effects in hypercholesterolemia as well.25
Arterial hypertension is perhaps the sturdiest stroke risk factor; accordingly, antihypertensives are most potent in stroke prevention. The association of chronically or acutely elevated blood pressure with markers of inflammation is well documented. Circulating levels of sICAM-1, soluble vascular cell adhesion molecule-1 (sVCAM-1), and sE-selectin have been reported to be increased in patients with essential hypertension.26,27 Acute hypertension induced by cold pressor test in normotensive and hypertensive patients increased serum levels of sICAM-1, sVCAM-1, and sE-selectin but did not influence the expression of adhesion molecules in circulating monocytes and lymphocytes.28 Chronic hypertension involving structural organ remodeling is also associated with signs of activation in monocytes obtained from peripheral blood.29 Interestingly, another study suggested that circulating monocytes from patients with hypertension are preactivated compared with those in nonhypertensive controls.30 On stimulation with lipopolysaccharide (LPS) or angiotensin II, these preactivated monocytes released more TNF-
than those from normotensives. Risk factors may perturb vascular function through additive, "ping-pong," or even synergistic effects, which involve systemic inflammation. Indeed, cross-sectional observations are consistent with the hypothesis that abnormal vascular function in type 2 diabetes in hypertensive subjects is at least in part secondary to increased inflammation, with associated EC and platelet activation.31
Cigarette smoking is generally held to be immunosuppressive, but, in association with a prohemostatic risk factor, smoking may be a proinflammatory factor. Monocyte expression of TF was found to be increased in smoking women and even more so in those using oral contraceptives, which was based on induction of NF-
B in monocytes.32 Smoking increased circulating levels of sICAM-1 and decreased the number of activated circulating monocytes, which may indicate augmented cell-cell adhesion.33 In a population already harboring ischemic cerebrovascular disease, those who smoked had increased levels of sICAM-1 and sE-selectin.15 Cross-sectional studies also showed associations between vascular risk factors, including diabetes mellitus, smoking, and hyperlipidemia, and inflammatory indexes such as leukocyte count, C-reactive protein (CRP), and fibrinogen.34,35
In experimental studies, Hallenbeck and coworkers36 showed that aged, hypertensive, or diabetic rats but rarely young and healthy rats develop ischemic stroke on intrathecal LPS application, which indicated that conventional vascular risk factors may predispose to inflammation-induced procoagulant mechanisms. Further work by the same group supported the hypothesis that perivascular immunoreactive cells are more abundant and capable of exaggerated cytokine signaling to the endothelium in animals with stroke risk factors.37,38 These findings are instrumental for understanding the longitudinal link between traditional risk factors, inflammatory mechanisms, thrombosis, and stroke.
To summarize, stroke risk factors may influence the interaction between inflammatory cells and the surrounding resident cerebrovascular cells, leading to increased susceptibility to inflammatory stimulation and to the formation of atheromatous plaques in large arteries and intimal thickening with local thrombosis in smaller arterioles (Figure). Inflammatory and prothrombotic alterations in arterial vessel walls due to stroke risk factors may also add to our understanding of why risk factors are linked with stroke, particularly in patients with atherosclerosis that is not yet discernible.
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Continuous Inflammation in Matured Atherosclerotic Plaques
As noted by Virchow,39 development of atherosclerotic vascular lesions includes an immune-mediated inflammatory response. Migration of inflammatory cells, mononuclear cells, mast cells, and lymphocytes into the vascular wall is today held as a hallmark of a human atherosclerotic plaque in cerebrovasculature as in other vessels4044 (reviewed in Reference 6). This ongoing process is fortified by the progressive deposition of modified lipids in the subendothelial layers. When LDL is caught in an artery, it becomes oxidized and phagocytosed by macrophages, which leads to the formation of lipid peroxides and the accumulation of cholesterol esters and the formation of foam cells.6,45 Oxidized LDL stimulates chemotactic effects and can increase the expression of macrophage colony-stimulating factor and MCP-1 synthesized by EC.46,47 Oxidized LDL can also upregulate the expression of adhesion molecules on human EC48 and promote the transmigration of monocytes.49 LDL may thus augment the inflammatory response by stimulating chemokines and recruiting new monocytes into the atheromatous lesion, as part of an ongoing process.
Some individuals with mature carotid artery disease have a systemic predisposition to irregularity and rupture of atherosclerotic plaques that is independent of traditional vascular risk factors, which was concluded after an analysis of 5393 carotid bifurcation angiograms from 3007 patients.50 Mechanisms involving inflammation may explain this. Continued dysfunction of vascular endothelium in the presence of macrophages and T cells leads to compensatory vascular changes, SMC proliferation, and recruitment of more macrophages and lymphocytes from the blood to eventually multiply within the atherosclerotic lesion. This further enhances the inflammatory changes of the endothelium and plaque maturation by locally released factors such as cytokines, chemokines, and growth factors.6 As the atherosclerotic lesion grows, this leads to formation of the so-called fibrous cap encapsulating the lipid-laden plaque core.51 Asymptomatic carotid plaques are more commonly morphologically so-called fibrous "hard" plaques, whereas symptomatic plaques are more commonly lipid-laden "soft" plaques,52,53 although this view has been disputed.54 However, it is believed that the formation of a fibrous "cap" in human carotid arteries may be associated with increased intimal expression of adhesion molecules,55 may protect the plaque from rupturing and in situ thrombosis, and perhaps may also inhibit inflammatory cell fluxes. In human carotid arteries, mast cells capable of releasing matrix-degrading proteases, such as metalloproteinases and elastase, are present in the "shoulder" region of the fibrous cap and may thus contribute to plaque rupture.43,44 Clearly, much more abundant macrophages may also play an important role in plaque destabilization. Furthermore, plasma cells capable of releasing large amounts of immunoglobulins have been found in atherosclerotic plaques.56
Microbial Agents in the Pathogenesis of Atherosclerotic Cerebrovascular Disease and Stroke
Chlamydia pneumoniae
Infectious agents and mainly viruses have been implicated in atherogenesis for several decades.57 The present discussion on microbial agents and atherosclerosis is mainly centered on Chlamydia pneumoniae, a gram-negative intracellular bacterium that is distributed worldwide. Saikku et al58 first associated serological evidence of C pneumoniae infection with myocardial infarction. Thereafter, >40 studies addressed the same question. Most of them reported positive associations,59 but publication bias may be involved. With the use of such diverse techniques as polymerase chain reaction, immunohistochemistry, and electron microscopy, >40 studies detected C pneumoniae in coronary and carotid plaques but only rarely or not at all in normal vessel walls.59 However, the prevalence of positive findings varied widely between studies,6068 and not all studies reported positive results,69 eg, the agent was not detectable in Australian patients.70 C pneumoniae was also detected in atherosclerotic plaques of intracerebral arteries.71 In some61 but not in other studies,67 C pneumoniae was particularly associated with more advanced atherosclerotic lesions and with plaque thrombosis.62 Viability of C pneumoniae was shown by detection of specific mRNA in a substantial proportion of carotid plaques72 and by culturing the pathogen from a few specimens,73,74 whereas other studies did not detect viable bacteria.75 C pneumoniae can infect and was detected in EC, macrophages, and SMC.63 Interestingly, human macrophage/monocyte lineage cells infected with C pneumoniae degenerated into foam cells,76 an early hallmark of atherosclerotic plaque formation.8,9 C pneumoniae can induce proatherogenic and prothrombotic changes involving activation of the transcription factor NF-
B.77,78 Aspirin inhibited C pneumoniaeinduced NF-
B activation and chlamydial growth.79 C pneumoniaereactive T lymphocytes were detected in carotid plaques, and cross-reactivity between human and chlamydial heat shock protein-60 may also play a role in the atherosclerotic process.80 Chlamydial heat shock protein-60 induced the production of TNF-
and matrix-degrading metalloproteinases by plaque macrophages, mechanisms that may contribute to plaque rupture and thrombosis.64 Clinical data support that the presence of C pneumoniae in carotid stenoses increases local thrombogenicity and the risk of infarction,62,81 but not all results favor this hypothesis.65
Some8285 but not all86,87 seroepidemiological studies reported an association between past C pneumoniae infection and asymptomatic carotid atherosclerosis or increased intima-media thickness. A prospective study found an independent association between C pneumoniae seropositivity and (1) progression of the intima-media thickness and (2) ischemic events, effects that were particularly expressed in patients with increased CRP.88 In several case-control studies, elevated anti-chlamydial antibodies (mostly IgA) were associated with stroke,67,8992 whereas a population-based case-control study that assessed only IgG antibodies found no correlation.93 In 2 prospective studies, C pneumoniae seropositivity predicted the risk of future stroke or other ischemic events,88,94 whereas 2 other studies were negative, with 1 possibly influenced by a recent C pneumoniae epidemic95 and 1 measuring only IgG antibodies.96 Of note, endovascular presence and serological results were not correlated.61,62,67 In an increased proportion of stroke patients, C pneumoniae antigen was detected in circulating immune complexes.89,97 C pneumoniae DNA was found in circulating leukocytes in patients with carotid stenosis but not in control subjects, and C pneumoniae DNA was more common than seropositivity.98 It remains unclear whether C pneumoniae DNA correlates better with findings in plaques than serology. Seroepidemiological studies are limited by the high prevalence of antibodies in adults, by the failure to distinguish between subjects with prior infection and those with chronic infection, and by the discordance with findings in vessel walls.59 Furthermore, residual confounding, mainly by childhood and adult socioeconomic factors, may partly explain the associations found. In light of the more important tissue study results, the association between C pneumoniae and atherosclerosis is firmly established; however, causality is not yet proven, mainly because of a lack of interventional studies.7
Animal experiments and therapy studies may help to determine the nature of the relationship. To this end, intranasal inoculation of C pneumoniae initiated lesions similar to early atherosclerosis.99,100 In animals prone to develop atherosclerosis because of diet or genetic makeup, C pneumoniae could accelerate atherogenesis, an effect reversed by antibiotics.101,102 In a retrospective study, previous use of antibiotics with antichlamydial effectiveness reduced the incidence of myocardial infarction,103 but another study failed to find such association.104 Three small prospective studies reported a reduction of coronary events by antibiotic treatment,105107 but 1 did not.108 In 1 study, treatment for 1 month reduced cardiovascular events after 30 days but not after 6 months.106,109 However, a recent study with 3-month antibiotic treatment reported diminishing of cardiac events sustained up to 18 months, which could speak for a treatment duration effect.107 Antibiotics reduced the prevalence of C pneumoniae in carotid endarterectomy specimens studied by polymerase chain reaction.110 In contrast, C pneumoniae infection in circulating human monocytes was refractory to antibiotics.111 The infectious component of C pneumoniae, the metabolically inactive elementary body, is not affected by antibiotics.59 Therefore, eradication of C pneumoniae is demanding and may require extended therapy periods. Presently, antibiotics should not be advised for reduction of stroke risk outside of a scientific study.
Helicobacter pylori
Helicobacter pylori, a gram-negative spiral bacterium, is acquired mostly during childhood, generally persists during a lifetime, and can cause chronic gastritis, peptic ulcer disease, and gastric cancer. Seroepidemiological studies on H pylori and CHD yielded widely varying results, but the larger studies and those that adjusted for potential confounders were mostly negative or reported moderate effects in multivariate analyses.112 Regarding stroke, a small, nested, case-control study found an increased risk in univariate but not in multivariate analysis.113 In 4 other case-control studies, seropositivity was associated with the risk of atherothrombotic and/or microangiopathic stroke.93,114116 The studies used spouses as controls114 and adjusted for social class114,115 or school education93; however, confounding mainly by childhood socioeconomic factors that are important regarding H pylori infection was not sufficiently excluded by these studies. Furthermore, the studies were small and did not possess sufficient statistical power to exclude the play of chance in subgroup analyses. In a prospective study, seropositivity for H pylorias for C pneumoniae, cytomegalovirus (CMV), and herpes simplex virus (HSV)did not predict cardiovascular events in women.96 H pylori strains bearing the cytotoxin-associated gene-A (CagA) are particularly virulent and were associated with increased inflammation. Seroprevalence against CagA strains but not H pylori in general was increased in large-vessel stroke but not in cardioembolic stroke after adjustment for parental social class among other factors.117 An association between seropositivity against the CagA strain and increased intima-media thickness was rendered nonsignificant after controlling for cardiovascular risk factors.118 Antibodies against CagA cross-react with vascular wall antigens, and this may possibly represent a pathogenetic link between H pylori infection and atherosclerosis.119 Whereas H pylori had not been detected in atherosclerotic plaques in the past, recent studies showed its presence, eg, in carotid plaques and its association with upregulated adhesion receptors.120,121
Other Bacterial Infections
Symptoms of chronic bronchitis were an independent predictor of CHD in a large cohort study from Finland.122 In a case-control study, chronic bronchitis was also independently associated with stroke or transient ischemic attack123; however, this was not confirmed in a larger study (A.J. Grau, MD, PhD, et al, unpublished data). Periodontitis is among the most common human infections and results from a complex interplay between chronic bacterial infection and the inflammatory host response. Bacteria from periodontal pockets can enter the bloodstream, eg, during chewing or tooth brushing, leading to recurrent bacteremia.124 Periodontal pathogens were identified in carotid plaques.125,126 Several but not all studies reported periodontitis to be a risk factor for CHD.112,127 The association between periodontitis and stroke has been under less intensive investigation. Small case-control studies123,128 and a cross-sectional study129 indicated an association between stroke and periodontitis or poor dental status. In post hoc analyses of 2 cohort studies, periodontitis was an independent stroke risk factor,130,131 whereas self-reported periodontal disease was not.132 Adjustment for socioeconomic classes and other confounders was incomplete in these studies, and it cannot be excluded that such factors have biased the results.
Viruses
Viral pathogens and mainly herpes viruses have been discussed for decades to contribute to atherogenesis. They were shown to infect cells of vascular lineage, to induce proliferation of SMC, to render EC prothrombotic, and to induce adhesion receptors on EC.133,134 Antibodies against CMV, a herpes virus, were associated with future risk of carotid intima-media thickening in a population-based cohort study135 and with carotid atherosclerosis in a cross-sectional study.83 CMV and HSV-1 could be detected in carotid atheromas by some62 but not all authors.136 Antibody titers were not correlated with tissue findings.62 CMV seropositivity did not predict stroke or cardiovascular diseases,94 nor did HSV titers.137 In animal experiments, CMV infection led to an increased injury in the intima despite the absence of the virus in the vascular wall, suggesting a role for inflammatory and immune responses.138 Hepatitis A virus seropositivity was independently associated with CHD,139 but data on stroke are not yet available. Viruses, including varicella zoster virus and CMV, are also known to cause vasculitic stroke.140
Atherosclerotic plaques often harbor multiple pathogens, including CMV, HSV-1, and odontopathogenic agents, besides C pneumoniae.62,125 In agreement, seroepidemiological studies showed an association between the number of pathogens to which a subject had been exposed and (1) the extent of atherosclerosis, (2) future cardiovascular mortality, and (3) EC dysfunction.141,142 Similarly, chronic respiratory, urinary tract, dental, and other infections amplified the risk of developing carotid atherosclerosis.143 Therefore, multiple pathogens appear relevant, and the stroke risk may relate to the aggregate burden of microbial antigens. However, again, childhood and adult socioeconomic conditions were not sufficiently adjusted for in these studies, and important residual confounding cannot be excluded.
Mechanisms That Link Infection With Atherothrombosis
Intracellular pathogens, which can lead to a persistent life-long infection and/or elicit a long-term immune response, appear to be particularly important. Atherosclerosis is a discontinuously developing disease, and recurrent acute infections or intermittent reactivation of latent chronic infection may contribute to the intermittent exacerbations of atherosclerotic vessel disease. A multitude of mechanisms may link chronic infection and atherothrombotic events.144 The risk rendered by prior infection may be influenced by the individual inflammatory response mounted by the host, with the highest risk pertaining to those with a strong response.145 Pathogens can exert direct effects on atherogenesis by residing in the vascular wall, most likely after being delivered to the vessel wall by circulating monocytes (Figure). These include increased SMC proliferation and migration; inhibition of apoptosis with excessive accumulation of cells; increased cholesterol loading in macrophages and SMC; EC dysfunction with procoagulant effects and inhibited vasodilator function; increased expression of proinflammatory cytokines, chemokines, adhesion receptors, and reactive oxygen species; and contribution to plaque rupture by increased metalloproteinase activity.144 However, effects independent of microbial invasion to the vessel coexist. Chronic infection may indirectly influence the risk of atherosclerosis and thrombosis (Figure) by the following: (1) increased systemic inflammation, which in turn may damage vascular walls (eg, by cytokines and proteases) and lead to a procoagulant state146; (2) immune-mediated mechanisms, eg, molecular mimicry, possibly including a cross-reaction of antibodies between human and bacterial structures such as heat shock proteins84,147; (3) recurrent bacteremia (eg, periodontitis), which may induce platelet activation and a procoagulant state148; and (4) influence on risk factors, eg, alteration of serum lipids toward a more proatherogenic profile.144,149,150
Chronic Infection and Stroke Risk: Summary and Critical Evaluation
A meta-analysis of prospective studies on CHD and C pneumoniae, H pylori, and CMV seropositivity as well as dental disease concluded that there is no good evidence to support the existence of any strong epidemiological association.112 The evidence regarding stroke is even smaller when only large prospective studies are taken into account. When the criteria of Bradford Hill7 for causality (Table) are applied, the overall concept of chronic infection as a contributor to stroke appears biologically plausible in view of numerous experimental studies and does not appear to "conflict with generally known facts on the natural history and biology of the disease" (coherence).7 A dose-response relationship is more difficult to establish and was not shown for any single pathogen, but preliminary evidence suggests a graded response between the number of chronic infections and stroke risk.141143 However, seroepidemiological studies showed primarily associations of only moderate strength and yielded inconsistent results, and only a few prospective studies established the temporal sequence of infection occurring before stroke. There is certainly no specific link between any chronic infectious disease and stroke, but one-to-one relationships are generally infrequent in medicine.7 It appears much more likely that chronic infections are risk factors that act in cooperation with conventional risk factors and genetic predisposition (see below) and are neither necessary nor sufficient for disease generation. In such a concept, Kochs postulates for causality between microbial agent and disease that include a specific link cannot be satisfied. Furthermore, most seroepidemiological studies were case-control studies that are prone to selection bias and to a publication bias toward underreporting of negative results. Even prospective studies may be biased by residual confounding and were based on only 1 measurement; therefore, random measurement errors may be substantial. A source of confounding that has not been sufficiently observed is the role of childhood and adult socioeconomic factors. Cardiovascular morbidity is more common in lower social classes, in which several infectious diseases are also more prevalent because of poorer housing and nutrition. Social factors could confound the link between chronic infection and stroke; future studies thus need to control for these factors. Furthermore, chronic infections may partly explain the association between social class and vascular diseases.151
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However, the most important evidence for a role of chronic infection in atherogenesis, if not in stroke, stems from tissue analyses and not from seroepidemiological studies. In regard to tissue analyses and C pneumoniae, the criteria for causality are fulfilled to a higher degree, although causality is still not proven in the clinical setting (Table). The value of serological studies is also limited by a lack of good correlation between results from plaque analysis and serum titers. Other surrogate markers that may reflect vascular risk in association with chronic infection, such as antigen detection in leukocytes, are needed. In summary, although there is good evidence for an association between chronic infections and stroke, causality is unproven, and numerous reasons advocate caution in the interpretation of presently available data.
Systemic Inflammation and Stroke Risk
Inflammatory Markers and Stroke Risk
Systemic markers of inflammation have been shown to be risk markers of stroke. In epidemiological studies, the leukocyte count was associated with the risk of first-time myocardial infarction and ischemic stroke, an effect that was independent of smoking and other vascular risk factors in a recent meta-analysis.152155 The leukocyte count also predicts the risk of recurrent ischemic events, including stroke, in a high-risk population (A.J. Grau, MD, PhD, et al, unpublished data). Fibrinogen, an acute-phase reactant at the interface between inflammation and coagulation found to be an independent stroke risk factor,156 remains persistently elevated after stroke in association with an increased risk of recurrent vascular events.157 More recent prospective studies showed that baseline CRP levels predict the risk of stroke and more strongly that of myocardial infarction.158,159 The risk reduction afforded by aspirin was found to be largest in subjects with highest concentrations of CRP, suggesting that aspirin may exert its preventive effects partly by its anti-inflammatory mode of action.158 CRP was detected in atherosclerotic plaques and may contribute to atherogenesis and a procoagulant state.146,160 The predictive value of leukocyte counts (relative risk, 1.4; 95% CI, 1.3 to 1.5; upper versus lower tertile), fibrinogen (relative risk, 1.8; 95% CI, 1.6 to 2.0), and CRP (relative risk, 1.7; 95% CI, 1.4 to 2.1) was comparable according to a recent meta-analysis of CHD.155 In another study, CRP similarly predicted mortality of stroke and of noncardiovascular causes in elderly persons, suggesting CRP to be a nonspecific risk marker.161 CRP measured acutely after stroke was a predictor for future cardiovascular morbidity and mortality.162,163 Relative risk values were higher for secondary than for primary ischemic events in the aforementioned studies (eg, CRP on discharge: hazard ratio, 9.4; 95% CI, 4.3 to 19.1).163 Most recently, a study showed that the beneficial effect of ticlopidine over the effect of aspirin in secondary prevention was markedly reduced beyond a threshold of increasing CRP and fibrinogen values, indicating that the efficacy of antiplatelet therapy may be related to the level of inflammatory and thrombotic markers.164 A positive correlation between CRP levels and activation of the coagulation/fibrinolysis system and platelet function after stroke hints at a link between coagulation and inflammation.165 Statins lower CRP levels independent of lipid effects and reduce coronary events in subjects with below-median lipid levels but with above-median CRP levels.166 Statins may be a means for anti-inflammatory treatment strategies, but this option has been insufficiently evaluated, particularly in regard to stroke prevention.
In summary, prospective studies consistently showed an increasing risk of stroke along with increasing levels of systemic inflammatory parameters at baseline, although the overall strength of the association was mostly moderate (Table). However, studies usually relied on only 1 baseline value and may therefore underestimate "actual" associations due to so-called regression dilution effects.167 The link between inflammatory parameters and stroke is clearly nonspecific, and the source of such persistent low-grade inflammation is unknown. It may mirror ongoing atherosclerotic processes or reflect chronic infectious diseases or a particularly strong host response to ubiquitous stimuli (see below). At present, there is increasing evidence that inflammatory parameters, especially sensitive measurement of CRP, are useful risk markers in routine assessment of systemic cardiovascular risk in clinical practice. However, it is not yet established whether lowering of inflammatory indexes lowers stroke risk, and any causal role of these parameters in stroke pathophysiology is unproven.
Acute Infection and Stroke Risk
Acute infectious diseases had been linked to stroke in children and younger adults in the 19th century.168,169 In a case-control study, Syrjänen and coworkers170,171 showed that recent infection increased stroke risk in younger subjects. Similar and consistently strong associations have thereafter been shown by other groups (odds ratios, 3.4 to 14.5), indicating that infection during the preceding week is a risk factor for stroke (Table).172175 Both viral and bacterial infections were independent risk factors, and the risk by infection was particularly, but not exclusively, increased in younger age groups.172,173 Several different microbial agents were detected in patients with infection-associated stroke. Therefore, it is likely that the systemic inflammatory response in the host rather than the microbial invasion per se is responsible for this elevated stroke risk. Recent infection was found to be associated particularly with stroke due to cardioembolism and cervical artery dissection.173,176,177 However, all studies on stroke were retrospective case-control studies in which infection was ascertained after stroke. Studies that evaluated the risk of stroke after infections have not been performed thus far. Furthermore, study results may be biased by a low participation rate in control subjects with recent infection, although studies with different control groups (hospital controls, population controls, patients with previous stroke) and different risk of such bias showed similar results.
Several mechanisms have been indicated to link acute inflammation with a prothrombotic state and stroke. Macko et al178 found the level of circulating antithrombotic activated protein C (APC) to be decreased in stroke subjects, and those with an antecedent infection/inflammation had the lowest concentrations of APC. Stroke patients with recent infection/inflammation had elevated levels of C4b-binding protein, which binds the anticoagulant protein S, and a distinctively lower ratio of active tissue plasminogen activator to plasminogen activator inhibitor.178 Grau et al173,176 detected no differences among several factors regulating hemostasis and fibrinolysis between stroke patients with and without infection, whereas Ameriso et al179 found increased D-dimer levels in stroke patients with infections. Since systemic changes in hemostatic parameters have not been a consistent finding in these studies, it is possible that local procoagulant effects may dominate over robust systemic changes.
Septic states permit the entry of bacteria and LPS into the bloodstream, which has profound effects favoring thrombosis in vivo. As cited above, animal experiments indicated that vascular risk factors increased the risk of thrombosis and stroke on LPS stimulation, indicating a pathogenetic link between inflammatory stimuli, traditional risk factors, and stroke.36 TNF-
is released during septic states, resulting in procoagulant changes in vascular endothelium180 with increased expression of TF, which activates the extrinsic pathway of blood coagulation.181 TNF-
also reduces thrombomodulin, which is required for the anticoagulant effect of protein C, and increases PAI-1, which inhibits the fibrinolytic system.182 In septic patients, increased levels of systemic TNF-
have been correlated with antithrombin III and PAI-1.180 The aforementioned changes in hemostasis and fibrinolysis, eg, explain why the risk of ischemic stroke in patients with endocarditis is tremendously increased with high risk of recurrences.183
Multiple links between inflammation and coagulation may also explain the particular association between recent infection and stroke due to cardioembolism that was mainly caused by a frequent presence of atrial fibrillation in infection-associated stroke, whereas endocarditis was rare.173,176 In atrial fibrillation, coagulation is persistently activated,184 and, as shown recently, CRP is elevated, suggesting that inflammation may promote the persistence of atrial fibrillation.185 Not only septicemia but also milder infections are accompanied by a measurable activation of coagulation.186,187 Infection as an additional trigger factor could increase the prothrombotic state in atrial fibrillation and other sources of cardioembolism and finally lead to thrombosis and embolism. This underscores the concept that inflammatory mechanisms are important not only in stroke due to large-artery atherosclerosis.
Novel therapeutic strategies may arise. Vaccinations may offer a means to prevent infection-associated stroke. Influenza vaccination was found to be associated with reduced stroke risk188; however, it is unclear whether this reflected a specific effect or was due to residual confounding, mainly because of differences in health awareness. Induction of natural immune tolerance to endogenous inflammatory stimuli is also worth further studies in stroke prevention.12
In a critical appraisal, several case-control studies consistently showed strong associations between recent infection and ischemic stroke, and a framework of biochemical studies provides a background for the plausibility of the association. As with chronic infections, any association between acute infection and stroke appears nonspecific. A biological gradient7 in the association is difficult to establish because there is no clear measure for the severity of infection, but febrile infections and septicemia are associated with a higher risk than infections in general.172,183 Although infections very likely preceded stroke in these studies, the temporal sequence is insufficiently established, and there is a need for prospective studies of the risk of stroke after infections of any kind and more vigorously designed studies of potential preventive strategies (eg, vaccination) before a causal relationship is firmly established.
Genetic Factors, Inflammation, and Stroke Risk
As noted above, the risk of atherosclerosis and ischemic events may depend not only on the infectious burden itself but also on the severity and the type of the immune response of the host.144 For example, susceptibility to CMV-related CHD was restricted to women with a humoral immune response and was not present in women with a cellular response.144 A hypothesis currently under investigation considers that a genetically determined strong response to inflammatory stimuli (eg, acute or chronic infection) may be associated with increased risk of stroke. The gene encoding for mannose-binding lectin codetermines individual susceptibility to certain infectious agents. Infection-susceptibility alleles were significantly associated with increased carotid plaque area and may influence interindividual differences in atherosclerotic risk.189 Polymorphisms of the P-selectin glycoprotein ligand-1 associated with lower capacity of neutrophils to bind activated platelets were linked to a reduced risk of cerebral ischemia.190 Polymorphisms in the genes of cathepsin G, a neutrophil-derived protease, and plasma platelet-activating factor (PAF) acetylhydrolase, leading to reduced inactivation of PAF, were associated with increased stroke risk.191,192 A common polymorphism in the promoter of the monocytic LPS receptor CD14 gene with potential association with higher receptor density was described as a risk factor for myocardial infarction.193,194 This polymorphism was not a risk factor for stroke in general,195197 but it was associated with atherothrombotic and lacunar stroke in a German197 but not in a Japanese population.195 Patients with a stroke at a young age (<50 years) showed a persistently increased release of interleukin-8 by leukocytes independent of coexisting risk factors.198 Interleukin-6 possesses both neuroprotective and neurotoxic properties; a polymorphism in the gene promoter associated with lower interleukin-6 plasma levels was recently linked to the risk of lacunar stroke.199 Most studies of inflammatory genes and stroke risk were small and require confirmation in larger studies that include analyses of etiologic stroke subgroups. However, genetic variability regulating the individual host response to immune challenges and stroke risk is an exciting field of research.
Tempering the Inflammation: The Lesson in Statins
Statins are a group of antihyperlipidemic compounds that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (eg, simvastatin, pravastatin, fluvastatin, cerivastatin) and that effectively decrease the blood level of LDL and triglycerides and raise HDL. Statins were found in several large-scale studies to substantially reduce cardiovascular morbidity (by approximately 30%) and mortality in mildly hyperlipemic or even normolipemic cohorts.200 Importantly, the risk of stroke was also significantly decreased by statins in several studies201 (reviewed in Hess et al202). It is now commonly believed that the beneficial effects of statins are not mediated solely by lipid lowering, but effects on systemic inflammatory parameters have also been observed in clinical studies.203 Through recent investigations of the effects of statins on both systemic parameters and local carotid plaque composition,204 we have begun to understand the clinical significance of the multifaceted inflammatory processes contributing to atherosclerosis and associated thrombotic events.
Pravastatin was reported to decrease the plasma concentration of CRP,205 a sensitive systemic marker of inflammation found to be independently associated with myocardial infarction and stroke.158,206 Statin therapy also reduced the concentrations of circulating soluble adhesion molecules P-selectin and ICAM-1 in hyperlipemic patients207 and reduced cytokine production.208 There is recent evidence that statins (lovastatin, simvastatin) inhibit the expression of MCP-1 by human EC and monocytes on stimulation by LPS or whole bacteria,209 which suggests that statins may inhibit the early stationing of inflammatory cells in vascular sites. In accordance, atorvastatin inhibited the expression of proinflammatory regulator NF-
B and the chemokines interferon-inducible protein 10 and MCP-1 in isolated SMC and mononuclear leukocytes.210 Lovastatin was reported to bind to the I domain of human leukocyte functionassociated antigen-1, thereby inhibiting leukocyte adhesion through interaction of leukocyte functionassociated antigen-1 and ICAM-1.211 Furthermore, statins inhibit the production and gene expression of cyclooxygenase-2, interleukin-1ß, and interleukin-6 in human EC.212 Targets of statin effects also include platelet-thrombus interaction, hemostasis, and nitric oxidedependent EC function.213,214 Recently, cerivastatin was shown to inhibit the production of MCP-1 and interleukin-8 by monocytes coincubated with C pneumoniae.215
Taken together, these data suggest that the substantial ameliorating effect of statins on the risk of cardiovascular insults and stroke is mediated largely through multifaceted anti-inflammatory systemic and local vascular effects in addition to lipid-lowering effects. Angiotensin-converting enzyme inhibitors also reduce vascular inflammation216 and may be another class of drugs that protect against vascular injury through anti-inflammatory mechanisms. Future studies may reveal additional aspects of the effects of different statins or angiotensin-converting enzyme inhibitors on the inflammatory pathogenesis of atherosclerosis that may help to target and tailor their use in a selected patient group chronically predisposed to unstable plaques.50
Conclusions
Starting from the continuous or occasional presence of inflammatory cells in the cerebral vasculature, stimuli that are currently not clearly defined lead to activation of the endothelium in either small cerebral microvessels or intracranial or extracranial arteries. Long-standing risk factors and chronic infectious diseases, possibly in conjunction with genetic predispositions, may lead to gradual activation of circulating mononuclear cells and their entry to subendothelial/perivascular locales and may aggravate proinflammatory and procoagulant EC effects. Responsiveness of the cerebrovascular tree to a systemic or local inflammatory challenge, eg, acute infection, is thus increased and may lead to local thrombosis. Infections with microbes such as C pneumoniae may actively prime this process in larger arteries and contribute to maturation of atherosclerotic plaques. Inflammatory cells are always present in these plaques and respond to further systemic stimuli by releasing proteases and procoagulant factors, which can trigger plaque rupture and thromboembolism. Measurement of sensitive indexes of plasma CRP may respond to an aggregate burden of microbial and nonmicrobial proinflammatory transformation of the vasculature and may be considered in routine clinical practice to identify individuals with elevated inflammatory risk for cardiovascular disease and stroke. It could also prove useful in monitoring treatment effects.
There is preliminary evidence for an association between chronic infections and atherosclerosis or stroke, but causality is not sufficiently established. The association between chronic infection and atherosclerotic diseases may be explained partly by residual confounding, eg, by childhood and adult socioeconomic conditions,151 which were insufficiently controlled for in several studies. On the basis of current knowledge, chronic infections appear to be risk factors that may act in cooperation with conventional risk factors and genetic predispositions and are neither necessary nor sufficient for disease development. In such a concept, Kochs postulates for causality, which require a specific link between microbial agent and disease, among others, cannot be satisfied. However, more general criteria for causality are still insufficiently fulfilled, and the role of chronic infection and inflammation in stroke pathogenesis is still incompletely defined. Future studies need to address whether inhibition of inflammation or long-standing antimicrobial therapies will reduce the risk of ischemic stroke to offer effective adjuncts to platelet inhibitors, anticoagulants, and statin therapies already in clinical use.
| Acknowledgments |
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Received October 22, 2002; revision received March 12, 2003; accepted March 19, 2003.
| References |
|---|
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|
|---|
2. Kelly-Hayes M, Wolf PA, Kase CS, Brand FN, McGuirk JM, dAgostino RB. Temporal patterns of stroke onset: the Framingham Study. Stroke. 1995; 26: 13431347.
3. Jakovljevic D, Salomaa V, Sivenius J, Tamminen M, Sarti C, Salmi K, Kaarsalo E, Narva V, Immonen-Räihä P, Torppa J, Tuomilehto J. Seasonal variation in the occurrence of stroke in a Finnish adult population: the FINMONICA Stroke Register. Stroke. 1996; 27: 17741779.
4. Bonita R, Beaglehole R. Does treatment of hypertension explain the decline in mortality from stroke? BMJ. 1986; 292: 191192.
5. Klag MJ, Whelton PK, Seidler AJ. Decline in US stroke mortality: demographic trends and antihypertensive treatment. Stroke. 1989; 20: 1421.
6. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115126.
7. Bradford Hill A. The environment and disease: association or causation. Proc R Soc Med. 1965; 58: 295300.[Medline] [Order article via Infotrieve]
8. Stary HC, Chandler AB, Glagov S, Fuster V, Glagov S, Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation. 1994; 89: 24622478.
9. Napoli C, DArmiento FP, Mancini FP, Postiglione A, Witztum JL, Palumbo G, Palinski W. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia: intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest. 1997; 100: 26802690.[Medline] [Order article via Infotrieve]
10. Endres M, Laufs U, Merz H, Kaps M. Focal expression of intercellular adhesion molecule-1 in the human carotid bifurcation. Stroke. 1997; 28: 7782.
11. Perry VH, Anthony DC, Bolton SJ, Brown HC. The blood-brain barrier and the inflammatory response. Mol Med Today. 1997; 3: 337341.
12. Takeda H, Spatz M, Ruetzler C, McCarron R, Becker K, Hallenbeck JM. Induction of mucosal tolerance to E-selectin prevents ischemic and hemorrhagic stroke in spontaneously hypertensive genetically stroke-prone rats. Stroke. 2002; 33: 21562164.
13. Andjelkovic AV, Spencer DD, Pachter JS. Visualization of chemokine binding sites on human brain microvessels. J Cell Biol. 1999; 145: 403412.
14. Stern DM, Kaiser E, Nawroth PP. Regulation of the coagulation system by vascular endothelial cells. Haemostasis. 1988; 18: 202214.[Medline] [Order article via Infotrieve]
15. Fassbender K, Bertsch T, Mielke O, Mühlhauser F, Hennerici M. Adhesion molecules in cerebrovascular diseases: evidence for an inflammatory endothelial activation in cerebral large- and small-vessel disease. Stroke. 1999; 30: 16471650.
16. Rohde LE, Hennekens CH, Ridker PM. Cross-sectional study of soluble intercellular adhesion molecule-1 and cardiovascular risk factors in apparently healthy men. Arterioscler Thromb Vasc Biol. 1999; 19: 15951599.
17. Hackman A, Abe Y, Insull W Jr, Pownall H, Smith L, Dunn K, Gotto AM Jr, Ballantyne CM. Levels of soluble adhesion molecules in patients with dyslipidemia. Circulation. 1996; 93: 13341338.
18. Ferri C, Desideri G, Valenti M, Bellini C, Pasin M, Santucci A, De Mattia G. Early upregulation of endothelial adhesion molecules in obese hypertensive men. Hypertension. 1999; 34: 568573.
19. Kawamura T, Umemura T, Kanai A, Uno T, Matsumae H, Sano T, Sakamoto N, Sakakibara T, Nakamura J, Hotta N. The incidence and characteristics of silent cerebral infarction in elderly diabetic patients: association with serum-soluble adhesion molecules. Diabetologia. 1998; 41: 911917.[CrossRef][Medline] [Order article via Infotrieve]
20. Bruunsgaard H, Skinhøj P, Pedersen AN, Schroll M, Pedersen BK. Ageing, tumour necrosis factor-
(TNF-
) and atherosclerosis. Clin Exp Immunol. 2000; 121: 255260.[CrossRef][Medline]
[Order article via Infotrieve]
21. Lechleitner M, Koch T, Herold M, Dzien A, Hoppichler F. Tumour necrosis factor-
plasma level in patients with type I diabetes mellitus and its association with glycaemic control and cardiovascular risk factors. J Intern Med. 2000; 248: 6776.[CrossRef][Medline]
[Order article via Infotrieve]
22. Wong D, Prameya R, Dorovini-Zis K. In vitro adhesion and migration of T lymphocytes across monolayers of human brain microvessel endothelial cells: regulation by ICAM-1, VCAM-1, E-selectin and PECAM-1. J Neuropathol Exp Neurol. 1999; 58: 138152.[Medline] [Order article via Infotrieve]
23. Rajamani K, Fisher M, Fisher M. Atherosclerosis: pathogenesis and pathophysiology. In: Ginsberg MD, Bogousslavsky J, eds. Cerebrovascular Disease: Pathophysiology, Diagnosis, and Management. Malden, Mass: Blackwell Science; 1998: 308318.
24. Lefer DJ, Granger DN. Monocyte rolling in early atherogenesis: vital role in lesion development. Circ Res. 1999; 84: 13531355.
25. Wilson SH, Caplice NM, Simari RD, Holmes DR Jr, Carlson PJ, Lerman A. Activated nuclear factor
B is present in the coronary vasculature of experimental hypercholesterolemia. Atherosclerosis. 2000; 148: 2330.[CrossRef][Medline]
[Order article via Infotrieve]
26. Blann AD, Tse W, Maxwell SJ, Waite MA. Increased levels of the soluble adhesion molecule E-selectin in essential hypertension. J Hypertens. 1994; 12: 925928.[Medline] [Order article via Infotrieve]
27. DeSouza CA, Dengel DR, Macko RF, Cox K, Seals DR. Elevated levels of circulating cell adhesion molecules in uncomplicated essential hypertension. Am J Hypertens. 1997; 10: 13351341.[Medline] [Order article via Infotrieve]
28. Buemi M, Allegra A, Aloisi C, Corica F, Alonci A, Ruello A, Montalto G, Frisina N. Cold pressor test raises serum concentrations of ICAM-1, VCAM-1, and E-selectin in normotensive and hypertensive patients. Hypertension. 1997; 30: 845847.
29. Porreca E, Di Febbo C, Mincione G, Reale M, Baccante G, Guglielmi MD, Cuccurullo F, Colletta G. Increased transforming growth factor-beta production and gene expression by peripheral blood monocytes of hypertensive patients. Hypertension. 1997; 30: 134139.
30. Dorffel Y, Latsch C, Stuhlmüller B, Schreiber S, Scholze S, Burmeister GR, Scholze J. Preactivated peripheral blood monocytes in patients with essential hypertension. Hypertension. 1999; 34: 113117.
31. Woodman RJ, Watts GF, Puddey IB, Burke V, Mori TA, Hodgson JM, Beilin LJ. Leukocyte count and vascular function in type 2 diabetic subjects with treated hypertension. Atherosclerosis. 2002; 163: 175181.[CrossRef][Medline] [Order article via Infotrieve]
32. Holschermann H, Terhalle HM, Zakel U, MausU, Parviz B, Tillmans H, Haberbosch W. Monocyte tissue factor expression is enhanced in women who smoke and use oral contraceptives. Thromb Haemost. 1999; 82: 16141620.[Medline] [Order article via Infotrieve]
33. Bergmann S, Siekmeier R, Mix CD, Jaross W. Even moderate cigarette smoking influences the pattern of circulating monocytes and the concentration of sICAM-1. Respir Physiol. 1998; 114: 269275.[CrossRef][Medline] [Order article via Infotrieve]
34. Grau AJ, Buggle F, Becher H, Werle E, Hacke W. The association of leukocyte count, fibrinogen and C-reactive protein with vascular risk factors and ischemic vascular diseases. Thromb Haemost. 1996; 82: 245255.
35. Mendall MA, Patel P, Ballam L, Strachan D, Northfield TC. C reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study. BMJ. 1996; 312: 10611065.
36. Hallenbeck JM, Dutka AJ, Kochanek PM, Siren A, Pezeshkpour GH, Feuerstein G. Stroke risk factors prepare rat brainstem tissues for modified local Shwartzman reaction. Stroke. 1988; 19: 863869.
37. Hallenbeck JM, Dutka AJ, Vogel SN, Heldman E, Doron DA, Feuerstein G. Lipopolysaccharide-induced production of tumor necrosis factor activity in rats with and without risk factors for stroke. Brain Res. 1991; 541: 115120.[CrossRef][Medline] [Order article via Infotrieve]
38. Siren AL, Liu Y, Feuerstein G, Hallenbeck JM. Increased release of tumor necrosis factor-
into cerebrospinal fluid and peripheral circulation of aged rats. Stroke. 1993; 24: 880886.
39. Virchow R. Der atheromatöse Prozess der Arterien. Wien Med Wochenschr. 1856; 6: 825.
40. Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis. 1986; 6: 131138.
41. van der Wal AC, Das PK, Bentz van de Berg D, van der Loos CM, Becker AE. Atherosclerotic lesions in humans: in situ immunophenotypic analysis suggesting an immune mediated response. Lab Invest. 1989; 61: 166170.[Medline] [Order article via Infotrieve]
42. Kaartinen M, van der Wal AC, van der Loos CM, Piek JJ, Koch KT, Becker AE, Kovanen PT. Mast cell infiltration in acute coronary syndromes: implications for plaque rupture. J Am Coll Cardiol. 1998; 32: 606612.
43. Johnson JL, Jackson CL, Angelini GD, George SJ. Activation of matrix-degrading metalloproteinases by mast cell proteases in atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 1998; 18: 707715.
44. Lehtonen-Smeds EMP, Lindsberg PJ, Soinne L, Saimanen E, Salonen O, Lassila R, Järvinen AA, Sarna S, Kaste M, Kovanen PT. High mast cell density in atherosclerotic plaques from endarterectomized carotid arteries is associated with an atherogenic serum lipid profile and cerebrovascular events: results from the Helsinki Carotid Endarterectomy Study. Stroke. 2002; 33: 376.
45. Ylä-Herttuala S, Palinski W, Rosenfeld ME, Parthasarathy S, Carew TE, Butler S, Witztum JL, Steinberg D. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989; 84: 10861095.[Medline] [Order article via Infotrieve]
46. Rajavashisth TB, Andalibi A, Territo MC, Berliner JA, Navab M, Fogelman AM, Lusis AJ. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature. 1990; 344: 254257.[CrossRef][Medline] [Order article via Infotrieve]
47. Leonard EJ, Yoshimura T. Human monocyte chemoattractant protein-1 (MCP-1). Immunol Today. 1990; 11: 97101.[CrossRef][Medline] [Order article via Infotrieve]
48. Berliner JA, Territo MC, Sevanian A, Ramin S, Kim JA, Bamshad B, Esterson M, Fogelman AM. Minimally modified low density lipoprotein stimulates monocyte endothelial interactions. J Clin Invest. 1990; 85: 12601266.[Medline] [Order article via Infotrieve]
49. Navab M, Imes SS, Hama SY, Hough GP, Ross LA, Bork RW, Valente AJ, Berliner JA, Drinkwater DC, Laks HL. Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 and is abolished by high density lipoprotein. J Clin Invest. 1991; 88: 20392046.[Medline] [Order article via Infotrieve]
50. Rothwell PM, Villagra R, Gibson R, Donders RC, Warlow CP. Evidence of a chronic systemic cause of instability of atherosclerotic plaques. Lancet. 2000; 355: 1924.[CrossRef][Medline] [Order article via Infotrieve]
51. van der Wal AC, Becker AE, van der Loos CM, Tigger AJ, Das PK. Fibrous and lipid-rich atherosclerotic plaques are part of interchangeable morphologies related to inflammation: a concept. Coron Artery Dis. 1994; 5: 463469.[Medline] [Order article via Infotrieve]
52. OHolleran LW, Kennelly MM, McClurken M, Johnson JM. Natural history of asymptomatic carotid plaque: a five year follow-up study. Am J Surg. 1987; 154: 659662.[CrossRef][Medline] [Order article via Infotrieve]
53. Avril G, Batt M, Guidoin R, Marois M, Hassen-Khodja R, Daune B, Galiardi JM, Le-Bas P. Carotid endarterectomy plaques: correlations of clinical and anatomic findings. Ann Vasc Surg. 1991; 5: 5054.[CrossRef][Medline] [Order article via Infotrieve]
54. Hatsukami TS, Ferguson MS, Beach KW, Gordon D, Detmer P, Burns D, Alpers C, Strandness DE Jr. Carotid plaque morphology and clinical events. Stroke. 1997; 28: 95100.
55. Nuotio K, Lindsberg PJ, Carpén O, Soinne L, Sarna S, Saimanen E, Salonen O, Lassila R, Järvinen A, Kovanen P, Kaste M. Adhesion molecule expression in symptomatic and asymptomatic carotid stenosis: results from the Helsinki Carotid Endarterectomy Study. Neurology. 2003; 60: 18901899.
56. Sohma Y, Sasano H, Shiga R, Saeki R, Suzuki T, Nagura H, Nose M, Yamamoto T. Accumulation of plasma cells in atherosclerotic lesions of Watanabe heritable rabbits. Proc Natl Acad Sci U S A. 1995; 92: 49374941.
57. Hajjar DP. Viral pathogenesis of atherosclerosis: Warner Lambert/Parke-Davis Award lecture. Am J Pathol. 1991; 139: 1195211.[Abstract]
58. Saikku P, Leinonen M, Mattila K, Ekman M-R, Nieminen MS, Mäkelä PH, Huttunen JK, Valtonen V. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet. 1988; 2: 983985.[Medline] [Order article via Infotrieve]
59. Grayston JT. Background and current knowledge of Chlamydia pneumoniae and atherosclerosis. J Infect Dis. 2000; 181: S402S410.[CrossRef][Medline] [Order article via Infotrieve]
60. Grayston JT, Kuo CC, Coulson AS, Campbell LA, Lawrence RD, Lee MJ, Strandness ED, Wang SP. Chlamydia pneumoniae (TWAR) in atherosclerosis of the carotid artery. Circulation. 1995; 92: 33973400.
61. Maass M, Krause E, Engel PM, Kruger S. Endovascular presence of Chlamydia pneumoniae in patients with hemodynamically effective carotid artery stenosis. Angiology. 1997; 48: 699706.[Medline] [Order article via Infotrieve]
62. Chiu B, Viira E, Tucker W, Fong IW. Chlamydia pneumoniae, cytomegalovirus, and herpes simplex virus and atherosclerosis of the carotid artery. Circulation. 1997; 96: 21442148.
63. Yamashita K, Ouchi K, Shirai M, Gondo T, Nakazawa T, Ito H. Distribution of Chlamydia pneumoniae infection in the atherosclerotic carotid artery. Stroke. 1998; 29: 773778.
64. Kol A, Sukhova GK, Lichtman AH, Libby P. Chlamydial heat shock protein 60 localizes in human atheroma and regulates macrophage tumor necrosis factor-alpha and matrix metalloproteinase expression. Circulation. 1998; 98: 300307.
65. Gibbs RG, Sian M, Mitchell AW, Greenhalgh RM, Davies AH, Carey N. Chlamydia pneumoniae does not influence atherosclerotic plaque behavior in patients with established carotid stenosis. Stroke. 2000; 31: 29302935.
66. Ouchi K, Fujii B, Kudo S, Shirai M, Yamashita K, Gondo T, Ishihara T, Ito H, Nakazawa T. Chlamydia pneumoniae in atherosclerotic and nonatherosclerotic tissue. J Infect Dis. 2000; 181 (suppl 3): S441S443.[Medline] [Order article via Infotrieve]
67. LaBiche R, Koziol D, Quinn TC, Gaydos C, Azhar S, Ketron G, Sood S, DeGraba TJ. Presence of Chlamydia pneumoniae in human symptomatic and asymptomatic carotid atherosclerotic plaque. Stroke. 2001; 32: 855860.
68. Dobrilovic N, Vadlamani L, Meyer M, Wright CB. Chlamydia pneumoniae in atherosclerotic carotid artery plaques: high prevalence among heavy smokers. Am Surg. 2001; 67: 589593.[Medline] [Order article via Infotrieve]
69. Ong GM, Coyle PV, Barros DSa AA, McCluggage WG, Duprex WP, ONeil HJ, Wyatt DE, Bamford KB, OLouglin B, McCaughey C. Non-detection of Chlamydia species in carotid atheroma using gene primers by nested PCR in a population with a high prevalence of Chlamydia pneumoniae antibody. BMC Infect Dis. 2001; 1: 12.[CrossRef][Medline] [Order article via Infotrieve]
70. Paterson DL, Hall J, Rasmussen SJ, Timms P. Failure to detect Chlamydia pneumoniae in atherosclerotic plaques of Australian patients. Pathology. 1998; 30: 169172.[CrossRef][Medline] [Order article via Infotrieve]
71. Virok D, Kis Z, Karai L, Intzedy L, Burian K, Szabo A, Ivanyi B, Gonczol E. Chlamydia pneumoniae in atherosclerotic middle cerebral artery. Stroke. 2001; 32: 19731976.
72. Johnston SC, Messina LM, Browner WS, Lawton MT, Morris C, Dean D. C-reactive protein levels and viable Chlamydia pneumoniae in carotid artery atherosclerosis. Stroke. 2001; 32: 27482752.
73. Jackson LA, Campbell LA, Kuo CC, Rodriguez DI, Lee A, Grayston JT. Isolation of Chlamydia pneumoniae from a carotid endarterectomy specimen. J Infect Dis. 1997; 176: 292295.[Medline] [Order article via Infotrieve]
74. Apfalter P, Loidl M, Nadrchal R, Makristathis A, Rotter M, Bergmann M, Polterauer P, Hirshl AM. Isolation and continuous growth of Chlamydia pneumoniae from arterectomy specimens. Eur J Clin Microbiol Infect Dis. 2000; 19: 305308.[CrossRef][Medline] [Order article via Infotrieve]
75. Valassina M, Miglorini L, Sansoni A, Sani G, Corsaro D, Cusi MG, Valensin PE, Cellesi C. Search for Chlamydia pneumoniae genes and their expression in atherosclerotic plaques of carotid arteries. J Med Microbiol. 2001; 50: 228232.
76. Kalayoglu MV, Byrne GI. Induction of macrophage foam cell formation by Chlamydia pneumoniae. J Infect Dis. 1998; 177: 725729.[Medline] [Order article via Infotrieve]
77. Godzik KL, OBrien ER, Wang SK, Kuo CC. In vitro susceptibility of human vascular wall cells to infection with Chlamydia pneumoniae. J Clin Microbiol. 1995; 33: 24112414.[Abstract]
78. Dechend R, Maass M, Gieffers J, Dietz R, Scheidereit C, Leutz A, Gulba DC. Chlamydia pneumoniae infection of vascular smooth muscle and endothelial cells activates NF-
B and induces tissue factor and PAI-1 expression: a potential link to accelerated arteriosclerosis. Circulation. 1999; 100: 13691373.
79. Tiran A, Gruber HJ, Graier WF, Wagner AH, van Leeuwen EBM, Tiran B. Aspirin inhibits Chlamydia pneumoniae-induced nuclear factor-
B activation, cytokine expression, and bacterial development in human endothelial cells. Arterioscler Thromb Vasc Biol. 2002; 22: 10751080.
80. Mosorin M, Surcel HM, Laurila A, Lehtinen M, Karttunen R, Juvonen J, Paavonen J, Marrison RP, Saikku P, Juvonen T. Detection of Chlamydia pneumoniaereactive T lymphocytes in human atherosclerotic plaques of carotid artery. Arterioscler Thromb Vasc Biol. 2000; 20: 10611067.
81. Vainas T, Kurvers AJM, Mess WH, de Graaf R, Ezzahiri R, Tordoir JHM, Schurink GWH, Bruggeman CA, Kitslaar PJ. Chlamydia pneumoniae serology is associated with thrombosis-related but not with plaque-related microembolization during carotid endarterectomy. Stroke. 2002; 33: 12491254.
82. Melnick SL, Shahar E, Folsom AR, Grayston JT, Sorlie PD, Wang SP, Szklo M. Past infection by Chlamydia pneumoniae strain TWAR and asymptomatic carotid atherosclerosis. Am J Med. 1993; 95: 499504.[CrossRef][Medline] [Order article via Infotrieve]
83. Espinola-Klein C, Rupprecht HJ, Blankenberg S, Bickel C, Kopp H, Rippin G, Hafner G, Pfeifer U, Meyer J. Are morphological or functional changes in the carotid artery wall associated with Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, or herpes simplex virus infection? Stroke. 2000; 31: 21272133.
84. Mayr M, Kiechl S, Willeit J, Wick G, Xu Q. Infections, immunity, and atherosclerosis: associations of antibodies to Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus with immune reactions to heat-shock protein 60 and carotid or femoral atherosclerosis. Circulation. 2000; 102: 833839.
85. Schmidt C, Hulthe J, Wikstrand J, Gnarpe H, Gnarpe J, Agewall S, Fagerberg B. Chlamydia pneumoniae seropositivity is associated with carotid artery intima-media thickness. Stroke. 2000; 31: 15261531.
86. Markus HS, Sitzer M, Carrington D, Mendall MA, Steinmetz H. Chlamydia pneumoniae infection and early asymptomatic carotid atherosclerosis. Circulation. 1999; 100: 832837.
87. Coles KA, Plant AJ, Riley TV, Smith DW, McQuillan BM, Thompson PL. Lack of association between seropositivity to Chlamydia pneumoniae and carotid atherosclerosis. Am J Cardiol. 1999; 84: 825828.[CrossRef][Medline] [Order article via Infotrieve]
88. Sander D, Winbeck K, Klingelhöfer J, Etgen T, Conrad B. Enhanced progression of early carotid atherosclerosis is related to Chlamydia pneumoniae (Taiwan acute respiratory) seropositivity. Circulation. 2001; 103: 13901395.
89. Wimmer ML, Sandmann-Strupp R, Saikku P, Haberl RL. Association of chlamydial infection with cerebrovascular disease. Stroke. 1996; 27: 22072210.
90. Cook PJ, Honeybourne D, Lip GYH, Beevers DG, Wise R, Davies P. Chlamydia pneumoniae antibody titers are significantly associated with acute stroke and transient cerebral ischemia: the West Birmingham Stroke Project. Stroke. 1998; 29: 404410.
91. Elkind MS, Lin IF, Grayston JT, Sacco RL. Chlamydia pneumoniae and the risk of first ischemic stroke: the Northern Manhattan Stroke Study. Stroke. 2000; 31: 15211525.
92. Madre JG, Garcia JL, Gonzalez RC, Montero JM, Paniagua EB, Escribano JR, Martinez JD, Cenjor RF. Association between seropositivity to Chlamydia pneumoniae and acute ischaemic stroke. Eur J Neurol. 2002; 9: 303306.[CrossRef][Medline] [Order article via Infotrieve]
93. Heuschmann PU, Neureiter D, Gesslein M, Craiovan B, Maass M, Faller G, Beck G, Neundörfer B, Kolominsky-Rabas PL. Association between infection with Helicobacter pylori and Chlamydia pneumoniae and risk of ischemic stroke subtypes: results from a population-based case-control study. Stroke. 2001; 32: 22532258.
94. Fagerberg B, Gnarpe J, Gnarpe H, Agewall S, Wikstrand J. Chlamydia pneumoniae but not cytomegalovirus antibodies are associated with future risk of stroke and cardiovascular disease: a prospective study in middle-aged to elderly men with treated hypertension. Stroke. 1999; 30: 299305.
95. Glader CA, Stegmayr B, Boman J, Stenlund H, Weinehall L, Hallmans G, Dahlen GH. Chlamydia pneumoniae antibodies and high lipoprotein(a) levels do not predict ischemic cerebral infarctions: results from a nested case control study in Northern Sweden. Stroke. 1999; 30: 20132018.
96. Ridker PM, Hennekens CH, Buring JE, Kundsin R, Shih J. 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: 573577.
97. Tarnacka B, Gromadzka G, Czlonkowska A. Increased circulating immune complexes in acute stroke: the triggering role of Chlamydia pneumoniae and cytomegalovirus. Stroke. 2002; 33: 936940.
98. Freidank HM, Lux A, Dern P, Meyer-König U, Els T. Chlamydia pneumoniae DNA in peripheral venous blood samples from patients with carotid artery stenosis. Eur J Microbiol Infect Dis. 2002; 21: 6062.
99. Fong IW, Chiu B, Viira E, Fong MW, Jang D, Mahony J. Rabbit model for Chlamydia pneumoniae infection. J Clin Microbiol. 1997; 35: 4852.[Abstract]
100. Laitinen K, Laurila A, Pyhälä L, Leinonen M, Saikku P. Chlamydia pneumoniae infection induces inflammatory changes in the aorta of rabbits. Infect Immun. 1997; 65: 48324835.[Abstract]
101. Muhlestein JB, Anderson JL, Hammond EH, Zhao L, Trehan S, Schwobe EP, Carlquist JF. Infection with Chlamydia pneumoniae accelerates the development of atherosclerosis and treatment with azithromycin prevents it in a rabbit model. Circulation. 1998; 97: 633636.
102. Moazed TC, Campbell LA, Rosenfeld ME, Grayston JT, Kuo CC. Chlamydia pneumoniae infection accelerates the progression of atherosclerosis in apolipoprotein (Apo E)-deficient mice. J Infect Dis. 1999; 180: 238241.[CrossRef][Medline] [Order article via Infotrieve]
103. Meier CR, Derby LE, Jick SS, Vasilakis C, Jick H. Antibiotics and risk of subsequent first-time acute myocardial infarction. JAMA. 1999; 281: 427431.
104. Jackson LA, Smith NL, Heckbert SR, Grayston JT, Siscovick DS, Psaty BM. Lack of association between first myocardial infarction and past use of erythromycin, tetracycline, or doxycycline. Emerg Infect Dis. 1999; 5: 281284.[Medline] [Order article via Infotrieve]
105. Gupta S, Leatham EW, Carrington D, Mendall MA, Kaski JC, Camm J. Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction. Circulation. 1997; 96: 404407.
106. Gurfinkel E, Bozovich G, Daroca A, Beck E, Mautner B. Randomised trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS pilot study. Lancet. 1997; 350: 404407.[CrossRef][Medline] [Order article via Infotrieve]
107. Sinisalo J, Mattila K, Valtonen V, Anttonen O, Juvonen J, Melin J, Vuorinen-Markkola H, Nieminen MS, for the Clarithromycin in Acute Coronary Syndrome Patients in Finland (CLARIFY) Study Group. Effect of 3 months of antimicrobial treatment with clarithromycin in acute non-Q-wave coronary syndrome. Circulation. 2002; 105: 15551560.
108. Anderson JL, Muhlestein JB, Carlquist J, Allen A, Trehan S, Nielson C, Hall S, Brady J, Egger M, Horne B, Lim T. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for Chlamydia pneumoniae infection: the Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infarction With Chlamydia (ACADEMIC) study. Circulation. 1999; 99: 15401547.
109. Gurfinkel E, Bozovich G, Beck E, Testa E, Livellara B, Mautner B. Treatment with the antibiotic roxithromycin in patients with acute non-Q-wave coronary syndromes: the final report of the ROXIS study. Eur Heart J. 1999; 20: 121127.
110. Melissano G, Blasi F, Esposito G, Tarsia P, Dordoni L, Arosio C, Tshomba Y, Fagetti L, Allegra L, Chiesa R. Chlamydia pneumoniae eradication from carotid plaques: results of an open, randomized study. Eur J Vasc Endovasc Surg. 1999; 18: 355359.[CrossRef][Medline] [Order article via Infotrieve]
111. Gieffers J, Fullgraf H, Jahn J, Klinger M, Dalhoff K, Katus HA, Solbach W, Maass M. Chlamydia pneumoniae infection in circulating human monocytes is refractory to antibiotic treatment. Circulation. 2001; 103: 351356.
112. Danesh J. Coronary heart disease, Helicobacter pylori, dental disease, Chlamydia pneumoniae, and cytomegalovirus: meta-analyses of prospective studies Am Heart J. 1999; 138: S434S437.[CrossRef][Medline] [Order article via Infotrieve]
113. Whincup PH, Mendall MA, Perry IJ, Strachan DP, Walker M. Prospective relations between Helicobacter pylori infection, coronary heart disease and stroke in middle aged men. Heart. 1996; 75: 568572.
114. Markus HS, Mendall MA. Helicobacter pylori infection: a risk factor for ischaemic cerebrovascular disease and carotid atheroma. J Neurol Neurosurg Psychiatry. 1998; 64: 104107.
115. Grau AJ, Buggle F, Lichy C, Brandt T, Becher H, Rudi J. Helicobacter pylori infection as an independent risk factor for cerebral ischemia of atherothrombotic origin. J Neurol Sci. 2001; 186: 15.[CrossRef][Medline] [Order article via Infotrieve]
116. Ponzetto A, Marchet A, Pellicano R, Lovera N, Chianale G, Nobili M, Rizzetto M, Cerrato P. Association of Helicobacter pylori infection with ischemic stroke of non-cardiac origin: the BAT.MA.N. Project study. Hepatogastroenterology. 2002; 49: 631634.[Medline] [Order article via Infotrieve]
117. Pietroiusti A, Diomedi M, Silvestrini M, Cupini LM, Luzzi I, Gomez-Miguel MJ, Bergamaschi A, Magrini A, Carrabs T, Vellini M, Galante A. Cytotoxin-associated gene-A-positive Helicobacter pylori strains are associated with atherosclerotic stroke. Circulation. 2002; 106: 580584.
118. Markus HS, Risley P, Mendall MA, Steinmetz H, Sitzer M. Helicobacter pylori infection, the cytotoxin gene A strain, and carotid artery intima-media thickness. J Cardiovasc Risk. 2002; 9: 16.[CrossRef][Medline] [Order article via Infotrieve]
119. Franceschi F, Sepulveda AR, Gasbarrini A, Pola P, Silveri NG, Dasbarrini G, Graham DY, Genta RM. Cross-reactivity of anti-CAGa antibodies with vascular wall antigens: possible pathogenic link between Helicobacter pylori infection and atherosclerosis. Circulation. 2002; 106: 430434.
120. Farsak B, Yildirir A, Akyon Y, Pinar A, Oc M, Boke E, Kes S, Tokgozoglu L. Detection of Chlamydia pneumoniae and Helicobacter pylori DNA in human atherosclerotic plaques by PCR. J Clin Microbiol. 2000; 38: 44084411.
121. Ameriso SF, Fridman EA, Leiguarda RC, Sevlever GE. Detection of Helicobacter pylori in human carotid atherosclerotic plaques. Stroke. 2001; 32: 385391.
122. Jousilahti P, Vartiainen E, Tuomilehto J, Puska P. Symptoms of chronic bronchitis and the risk of coronary disease. Lancet. 1996; 348: 567572.[CrossRef][Medline] [Order article via Infotrieve]
123. Grau AJ, Buggle F, Ziegler C, Schwarz W, Meuser J, Tasman AJ, Buhler A, Benesch C, Becher H, Hacke W. Association between acute cerebrovascular ischemia and chronic and recurrent infection. Stroke. 1997; 28: 17241729.
124. Lockhart PB. The risk for endocarditis in dental practice. Periodontology. 2000; 23: 12735.[CrossRef][Medline] [Order article via Infotrieve]
125. Chiu B. Multiple infections in carotid atherosclerotic plaques. Am Heart J. 1999; 138: S534S546.[CrossRef][Medline] [Order article via Infotrieve]
126. Haraszthy VI, Zambon JJ, Trevisan M, Zeid M, Genco RJ. Identification of periodontal pathogens in atheromatous plaques. J Periodontol. 2000; 71: 15541560.[CrossRef][Medline] [Order article via Infotrieve]
127. Armitage GC. Periodontal infections and cardiovascular disease: how strong is the association? Oral Dis. 2000; 6: 335350.[Medline] [Order article via Infotrieve]
128. Syrjänen J, Peltola J, Valtonen V, Iivanainen M, Kaste M, Huttunen JK. Dental infections in association with cerebral infarction in young and middle-aged men. J Intern Med. 1989; 225: 179184.[Medline] [Order article via Infotrieve]
129. Lösche WJ, Schork A, Terpenning MS, Chen YM, Kerr C, Dominguez BL. The relationship between dental disease and cerebral vascular accident in elderly United States veterans. Ann Periodontol. 1998; 3: 161174.[Medline] [Order article via Infotrieve]
130. Beck J, Garcia R, Heiss G, Vokonas PS, Offenbacher S. Periodontal disease and cardiovascular disease. J Periodontol. 1996; 67: 11231137.[Medline] [Order article via Infotrieve]
131. Wu T, Trevisan M, Genco RJ, Dorn JP, Falkner KL, Sempos CT. Periodontal disease and risk of cerebrovascular disease: the First National Health and Nutrition Examination Survey and its follow-up study. Arch Intern Med. 2000; 160: 27492755.
132. Howell TH, Ridker PM, Ajani UA, Hennekens CH, Christen WG. Periodontal disease and risk of subsequent cardiovascular disease in U. S. male physicians. J Am Coll Cardiol. 2001; 37: 445450.
133. Benditt EP, Barrett T, McDougall JK. Viruses in the etiology of atherosclerosis. Proc Natl Acad Sci U S A. 1983; 80: 63866389.
134. Nicholson AC, Hajjar DP. Herpesviruses and thrombosis: activation of coagulation on the endothelium. Clin Chim Acta. 1999; 286: 2329.[CrossRef][Medline] [Order article via Infotrieve]
135. Nieto FJ, Adam E, Sorlie P, Farzadegan H, Melnick JL, Comstock GW, Szklo M. Cohort study of cytomegalovirus infection as a risk factor for carotid intimal-medial thickening, a measure of subclinical atherosclerosis. Circulation. 1996; 94: 922927.
136. Saetta A, Fanourakis G, Agapitos E, Davaris PS. Atherosclerosis of the carotid artery: absence of evidence for CMV involvement in atheroma formation. Cardiovasc Pathol. 2000; 9: 181183.[CrossRef][Medline] [Order article via Infotrieve]
137. Ridker PM, Hennekens CH, Stampfer MJ, Wang F. Prospective study of herpes simplex virus, cytomegalovirus, and the risk of future myocardial infarction and stroke. Circulation. 1998; 98: 27962799.
138. Zhou YF, Shou M, Guetta E, Guzman R, Unger EF, Yu ZX, Zhang J, Finkel T, Epstein SE. Cytomegalovirus infection in rats increases the neointimal response to vascular injury without consistent evidence of direct infection of the vascular wall. Circulation. 1999; 100: 15691575.
139. Zhu J, Quyyumi AA, Norman JE, Costello R, Csako G, Epstein SE. The possible role of hepatitis A virus in the pathogenesis of atherosclerosis. J Infect Dis. 2000; 182: 15831587.[CrossRef][Medline] [Order article via Infotrieve]
140. Del Brutto OH. Infections and stroke. In: Ginsberg MD, Bogousslavsky J, eds. Cerebrovascular Disease: Pathophysiology, Diagnosis, and Management. Vol II. Malden, Mass: Blackwell Science; 1998: 16391640.
141. Espinola-Klein C, Rupprecht HJ, Blankenberg S, Bickel C, Kopp H, Rippin G, Victor A, Hafner G, Schlumberger W, Meyer J. Impact of infectious burden on extent and long-term prognosis of atherosclerosis. Circulation. 2002; 105: 1521.
142. Prasad A, Zhu J, Halcox JP, Waclawiw MA, Epstein SE, Quyyumi AA. Predisposition to atherosclerosis by infections: role of endothelial dysfunction. Circulation. 2002; 106: 164166.
143. Kiechl S, Egger G, Mayr M, Wiedermann CJ, Bonora E, Oberhollenzer F, Muggeo M, Xu Q, Wick G, Poewe W, Willeit J. Chronic infections and the risk of carotid atherosclerosis: prospective results from a large population study. Circulation. 2001; 103: 10641070.
144. Epstein SE, Zhou YF, Zhu J. Infection and atherosclerosis: emerging mechanistic paradigms. Circulation. 1999; 100: e20e28.[Medline] [Order article via Infotrieve]
145. Zhu J, Quyyumi AA, Norman JE, Csako G, Epstein SE. Cytomegalovirus in the pathogenesis of atherosclerosis: the role of inflammation, as reflected by elevated C-reactive protein levels. J Am Coll Cardiol. 1999; 34: 17381743.
146. Cermak J, Key NS, Bach RR, Balla J, Jacob HS, Vercellotti GM. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood. 1993; 82: 513520.
147. Xu Q, Schett G, Perschinka H, Mayr M, Egger G, Oberhollenzer F, Willeit J, Kiechl S, Wick G. Serum soluble heat shock protein 60 is elevated in subjects with atherosclerosis in a general population. Circulation. 2000; 102: 1420.
148. Lourbakos A, Yuan YP, Jenkins AL, Travis J, Andrade-Gordon P, Santulli R, Potempa J, Pike RN. Activation of protease-activated receptors by gingipains from Porphyromonas gingivalis leads to platelet aggregation: a new trait of microbial pathogenicity. Blood. 2001; 97: 37903797.
149. Laurila A, Bloigu A, Näyhä S, Hassi J, Leinonen M, Saikku P. Chronic Chlamydia pneumoniae infection is associated with a serum lipid profile known to be a risk factor for atherosclerosis. Arterioscler Thromb Vasc Biol. 1997; 17: 29102913.
150. Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet. 1997; 350: 430436.[CrossRef][Medline] [Order article via Infotrieve]
151. Wannamethee SG, Whincup PH, Shaper G, Walker M. Influence of fathers social class on cardiovascular disease in middle-aged men. Lancet. 1996; 348: 12591263.[CrossRef][Medline] [Order article via Infotrieve]
152. Prentice RL, Szatrowski TP, Kato H, Mason MW. Leukocyte counts and cerebrovascular disease. J Chron Dis. 1982; 35: 703714.[CrossRef][Medline] [Order article via Infotrieve]
153. Ernst E, Hammerschmidt DE, Bagge U, Matrai A, Dormandy JA. Leukocytes and the risk of ischemic diseases. JAMA. 1987; 257: 23182324.
154. Gillum RF, Ingram DD, Makuc DM. White blood cell count and stroke incidence and death: the NHANES I epidemiologic follow-up study. Am J Epidemiol. 1994; 139: 894902.
155. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA. 1998; 279: 14771482.
156. Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med. 1984; 311: 501505.[Abstract]
157. Beamer NB, Coull BM, Clark WM, Briley DP, Wynn M, Sexton G. Persistent inflammatory response in stroke survivors. Neurology. 1998; 50: 17221728.
158. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and risks of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336: 973979.
159. Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, DAgostino RB, Franzblau C, Wilson PW. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham Study. Stroke. 2001; 32: 25752579.
160. Torzewski J, Torzewski M, Bowyer DE, Frohlick M, Koenig W, Waltenberger J, Fitzsimmons C, Hombach V. C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler Thromb Vasc Biol. 1998; 18: 13861392.
161. Gussekloo J, Schaap MC, Frolich M, Blauw GJ, Westendorp RG. C-reactive protein is a strong but nonspecific risk factor of fatal stroke in elderly persons. Arterioscler Thromb Vasc Biol. 2000; 20: 10471051.
162. Muir KW, Weir CJ, Alwan W, Squire IB, Lees KR. C-reactive protein and outcome after ischemic stroke. Stroke. 1999; 30: 981985.
163. Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke. 2001; 32: 917924.
164. Di Napoli M, Papa F. Inflammation, hemostatic markers, and antithrombotic agents in relation to long-term risk of new cardiovascular events in first-ever ischemic stroke patients. Stroke. 2002; 33: 17631771.
165. Tohgi H, Konno S, Takahashi S, Koizumi D, Kondo R, Takahashi H. Activated coagulation/fibrinolysis system and platelet function in acute thrombotic stroke patients with increased C-reactive protein levels. Thromb Res. 2000; 100: 373379.[CrossRef][Medline] [Order article via Infotrieve]
166. Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, Gotto AM Jr. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001; 344: 19591965.
167. Clarke R, Shipley M, Lewington S, Youngman L, Collins R, Marmot M, Peto R. Underestimation of risk associations due to regression dilution in longterm follow-up of prospective studies. Am J Epidemiol. 1999; 150: 341353.
168. Marie P. Hémiplégie cérébrale infantile et maladies infectieuses. Le Progrès Médical. 1885; 13: 167169.
169. Freud S. Die infantile Cerebrallähmung. In: Nothnagel H, ed. Specielle Pathologie 9, Teil 3 (I. Hälfte). Wien, Austria: Holder; 1897: 1327.
170. Syrjänen J, Valtonen VV, Iivanainen M, Kaste M, Huttunen JK. Preceding infection as an important risk factor for ischaemic brain infarction in young and middle aged subjects. BMJ. 1988; 296: 11561160.[Medline] [Order article via Infotrieve]
171. Syrjänen J, Valtonen VV, Iivanainen M, Hovi T, Malkamäki M, Mäkelä PH. Association between cerebral infarction and increased serum bacterial antibody levels in young adults. Acta Neurol Scand. 1986; 73: 273278.[Medline] [Order article via Infotrieve]
172. Grau AJ, Buggle F, Heindl S, Steichen-Wiehn C, Banerjee T, Maiwald M, Rohlfs M, Suhr H, Fiehn W, Becher H. Recent infection as a risk factor for cerebrovascular ischemia. Stroke. 1995; 26: 373379.
173. Grau AJ, Buggle F, Becher H, Zimmermann E, Spiel M, Fent T, Maiwald M, Werle E, Zorn M, Hengel H, Hacke W. Recent bacterial and viral infection is a risk factor for cerebrovascular ischemia: clinical and biochemical studies. Neurology. 1998; 50: 196203.
174. Bova IY, Bornstein NM, Korczyn AD. Acute infection as a risk factor for ischemic stroke. Stroke. 1996; 27: 22042206.
175. Macko RF, Ameriso SF, Barndt R, Clough W, Weiner JM, Fisher M. Precipitants of brain infarction: roles of preceding infection/inflammation and recent psychological stress. Stroke. 1996; 27: 19992004.
176. Grau AJ, Buggle F, Steichen-Wiehn C, Heindl S, Banerjee T, Seitz R, Winter R, Forsting M, Werle E, Bode C. Clinical and biochemical analysis in infection-associated stroke. Stroke. 1995; 26: 15201526.
177. Grau AJ, Brandt T, Buggle F, Orberk E, Mytilineos J, Werle E, Conradt C, Krause M, Winter R, Hacke W. Association of cervical artetry dissection with recent infection. Arch Neurol. 1999; 56: 851856.
178. Macko RF, Ameriso SF, Gruber A, Griffin JH, Fernandez JA, Barndt R, Quismorio FP Jr, Weiner JM, Fisher M. Impairments of the protein C system and fibrinolysis in infection-associated stroke. Stroke. 1996; 27: 20052011.
179. Ameriso SF, Wong VLY, Quismorio FP Jr, Fisher M. Immunohematologic characteristics of infection-associated cerebral infarction. Stroke. 1991; 22: 10041009.
180. Martinez MA, Pena JM, Fernandez A, Jimenez M, Juarez S, Madero R, Vazquez JJ. Time course and prognostic significance of hemostatic changes in sepsis: relation to tumor necrosis factor-
. Crit Care Med. 1999; 27: 13031308.[CrossRef][Medline]
[Order article via Infotrieve]
181. Conway EM, Bach R, Rosenberg RD, Konigsberg WH. Tumor necrosis factor enhances expression of tissue factor mRNA in endothelial cells. Thromb Res. 1989; 53: 231241.[CrossRef][Medline] [Order article via Infotrieve]
182. Moore KL, Esmon CT, Esmon NL. Tumor necrosis factor leads to the internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture. Blood. 1989; 73: 159165.
183. Hart RG, Foster JW, Luther MF, Kanter MC. Stroke in infective endocarditis. Stroke. 1990; 21: 695700.
184. Gustafsson C, Blombäck M, Britton M, Hamsten A, Svensson J. Coagulation factors and the increased risk of stroke in nonvalvular atrial fibrillation. Stroke. 1990; 21: 4751.
185. Chung MK, Martin DO, Sprecher D, Wazni O, Kanderian A, Carnes CA, Bauer JA, Tchou PJ, Niebauer MJ, Natale A, van Wagoner DR. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation. 2001; 104: 28862891.
186. Richardson SGN, Matthews KB, Cruickshank JK, Geddes AM, Stuart J. Coagulation activation and hyperviscosity in infection. Br J Haematol. 1979; 42: 469480.[Medline] [Order article via Infotrieve]
187. Ogata K, Yagawa K, Hayashi S, Ogino H, Miyagawa Y, Masayuki M, Ichinose Y, Koga T. Thrombosis-inducing activity in plasma of patients with acute respiratory tract infection disappears after treatment. Respiration. 1991; 58: 176180.[Medline] [Order article via Infotrieve]
188. Lavallee P, Perchaud V, Gautier-Bertrand M, Grabli D, Amarenco P. Association between influenza vaccination and reduced risk of brain infarction. Stroke. 2002; 33: 513518.
189. Hegele RA, Ban MR, Anderson CM, Spence JD. Infection-susceptibility alleles of mannose-binding lectin are associated with increased carotid plaque area. J Invest Med. 2000; 48: 198202.[Medline] [Order article via Infotrieve]
190. Lozano ML, Gonzalez-Conejero R, Corral J, Rivera J, Iniesta JA, Martinez C, Vicente V. Polymorphisms of P-selectin glycoprotein ligand-1 are associated with neutrophil-platelet adhesion and with ischaemic cerebrovascular disease. Br J Haematol. 2001; 115: 969976.[CrossRef][Medline] [Order article via Infotrieve]
191. Herrmann SM, Funke-Kaiser H, Schmidt-Petersen K, Nicaud V, Gautier-Bertrand M, Evans A, Kee F, Arveiler D, Morrison C, Orzechowski HD, et al. Characterization of polymorphic structure of cathepsin G gene: role in cardiovascular and cerebrovascular diseases. Arterioscler Thromb Vasc Biol. 2001; 21: 15381543.
192. Hiramoto M, Yoshida H, Imaizumi T, Yoshimizu N, Satoh K. A mutation in plasma platelet-activating factor acetyhydrolase (Val279
Phe) is a genetic risk factor. Stroke. 1997; 28: 24172420.
193. Unkelbach K, Gardemann A, Kostrzewa M, Philipp M, Tillmanns H, Haberbosch WA. New promoter polymorphism in the gene of lipopolysaccharide receptor CD14 is associated with expired myocardial infarction in patients with low atherosclerotic risk profile. Arterioscler Thromb Vasc Biol. 1999; 19: 932938.
194. Hubacek JA, Pitha J, Skodova Z, Stanek V, Poledne R. C(-260)
T polymorphism in the promotor of the CD14 monocyte receptor gene as a risk factor for myocardial infarction. Circulation. 1999; 99: 32183220.
195. Ito D, Murata M, Tanashi N, Sato H, Sonoda A, Saito I, Watanabe K, Fukuuchi Y. Polymorphism in the promotor of lipopolysaccharide receptor CD14 and ischemic cerebrovascular disease. Stroke. 2000; 31: 26612664.
196. Zee RY, Bates D, Ridker PM. A prospective evaluation of the CD14 and CD18 gene polymorphisms and risk of stroke. Stroke. 2002; 33: 892895.
197. Lichy C, Meiser H, Grond-Ginsbach C, Buggle F, Dörfer C, Grau A. Lipopolysaccharide receptor CD14 polymorphism and risk of stroke in a South-German population. J Neurol. 2002; 249: 821823.[CrossRef][Medline] [Order article via Infotrieve]
198. Grau AJ, Aulmann M, Lichy C, Meiser H, Buggle F, Brandt T, Grond-Ginsbach C. Increased cytokine release by leucocytes in survivors of stroke at young age. Eur J Clin Invest. 2001; 31: 9991006.[CrossRef][Medline] [Order article via Infotrieve]
199. Revilla M, Obach V, Cervera A, Dávalos A, Castillo J, Chamorro A. A-174G/C polymorphism of the interleukin-6 gene in patients with lacunar infarction. Neurosci Lett. 2002; 324: 2932.[CrossRef][Medline] [Order article via Infotrieve]
200. Velasco JA. After 4S, CARE and LIPIDis evidence-based medicine being practised? Atherosclerosis. 1999; 147 (suppl 1): S39S44.[Medline] [Order article via Infotrieve]
201. Plehn JF, Davis BR, Sacks FM, Rouleau JL, Pfeffer MA, Bernstein V, Cuddy TE, Moyé LA, Piller LB, Rutherford J, et al, for the CARE Investigators. Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. Circulation. 1999; 99: 216223.
202. Hess DC, Demchuk AM, Brass LM, Yatsu FM. HMG-CoA reductase inhibitors (statins): a promising approach to stroke prevention. Neurology. 2000; 54: 790796.
203. Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, Flaker GC, Braunwald E, for the CARE Investigators. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation. 1998; 98: 839844.
204. Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJP, Stalenhoef AFH. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet. 2001; 357: 577581.[CrossRef][Medline] [Order article via Infotrieve]
205. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E, for the CARE Investigators. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation. 1999; 100: 230235.
206. Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation. 1998; 98: 731733.
207. Romano M, Mezzetti A, Marulli, Ciabattoni G, Febo F, Di Ienno S, Roccaforte S, Vignieri S, Nubile G, Milani M, Davi G. Fluvastatin reduces soluble P-selectin and ICAM-1 levels in hypercholesterolemic patients: role of nitric oxide. J Invest Med. 2000; 48: 183189.[Medline] [Order article via Infotrieve]
208. Rosenson RS, Tangney CC, Casey LC. Inhibition of proinflammatory cytokine production by pravastatin. Lancet. 1999; 353: 983984.[Medline] [Order article via Infotrieve]
209. Romano M, Diomede L, Sironi M, Massimiliano L, Sottocorno M, Polentarutti N, Guglielmotti A, Albani D, Bruno A, Fruscella P, et al. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab Invest. 2000; 80: 10951100.[Medline] [Order article via Infotrieve]
210. Ortego M, Bustos C, Hernandez-Presa MA, Tunon J, Diaz C, Hernandez G, Egido J. Atorvastatin reduces NF-
B acivation and chemokine expression in vascular smooth muscle cells and mononuclear cells. Atherosclerosis. 1999; 147: 253261.[CrossRef][Medline]
[Order article via Infotrieve]
211. Kallen J, Welzenbach K, Ramage P, Geyl D, Kriwacki R, Legge G, Cottens S, Weitz-Schmidt G, Hommel U. Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain. J Mol Biol. 1999; 292: 19.[CrossRef][Medline] [Order article via Infotrieve]
212. Inoue I, Goto S, Mizotani, Awata T, Mastunaga T, Kawai S, Nakajima T, Hokari S, Komoda T, Katayama S. Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect: reduction of m-RNA levels for interleukin-1ß, interleukin-6, cyclooxygenase-2, and p22phox by regulation of peroxisome proliferator-activated receptor a (PPARa) in primary endothelial cells. Life Sci. 2000; 67: 863876.[CrossRef][Medline] [Order article via Infotrieve]
213. Dupuis J, Tardif J-C, Cernacek P, Théroux P. Cholesterol reduction rapidly improves endothelial function after acute coronary sundromes: the RECIFE (Reduction of Cholesterol in Ischemia and Function of the Endothelium) trial. Circulation. 1999; 99: 32273233.
214. Weissberg P. Mechanisms modifying atherosclerotic disease: from lipids to vascular biology. Atherosclerosis. 1999; 147 (suppl 1): S3S10.[CrossRef][Medline] [Order article via Infotrieve]
215. Kothe H, Dalhoff K, Rupp J, Müller A, Kreutzer J, Maass M, Katus HA. Hydroxylmethylglutaryl coenzyme A reductase inhibitors modify the inflammatory response of human macrophages and endothelial cells infected with Chlamydia pneumoniae. Circulation. 2000; 101: 17601763.
216. Hernandez-Presa MA, Bustos C, Ortego M, Tunon J, Ortega L, Egido J. ACE inhibitor quinapril reduces the arterial expression of NF-kappaB-dependent proinflammatory factors but not of collagen I in a rabbit model of atherosclerosis. Am J Pathol. 1998; 153: 18251837.
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