Chlamydia pneumoniae and atherosclerosis

Chlamydia pneumoniae is the third species of the genus Chlamydia and has been known to cause respiratory tract infections. Since the association between the seropositivity of C. pneumoniae and ischemic heart diseases was reported in 1988, the association between C. pneumoniae and atherosclerosis has been noteworthy. Positive findings of the association between C. pneumoniae and atherosclerosis have been reported as the result of seroepidemiological surveys, histological studies to detect C. pneumoniae in human atherosclerotic tissues, and animal infection models. These data supported that C. pneumoniae infection occurs in human vascular walls and may accelerate the foam cell formation of macrophage and smooth muscle cells, and may play a causative role in atherosclerosis. Several large-scale studies of the antimicrobial prevention of secondary cardiac events are in progress. The genome projects for C. pneumoniae have recently been reported. A number of issues remain unclear, however, and further intensive research is necessary.     

Chlamydia pneumoniae-induced atherosclerosis in a rabbit model

In order to establish a causative relationship between Chlamydia pneumoniae and atherosclerosis, animal models have been proposed. In a rabbit model, arterial intimal thickening has been induced by direct intravascular and intranasal inoculation with C. pneumoniae. C. pneumoniae infection can induce significant acceleration of atherosclerosis in a mildly hyperlipidemic rabbit model but is prevented by treatment with azithromycin. Together these preliminary rabbit experiments suggest that C. pneumoniae may play a causative role in atherosclerosis. More animal studies are underway that are designed to address further mechanistic and therapeutic questions regarding the association between C. pneumoniae and atherosclerosis.     

Chlamydia pneumoniae infection is not an independent risk factor for arterial disease

Appreciation of atherosclerosis as an infectious disease has fostered interest in the role that Chlamydia pneumoniae may play in atheroma development. Although data from seroepidemiological and experimental studies have established an association between the pathogen and atherosclerosis, little is known about how the organism contributes to lesion development. Atherosclerosis is a complex disease process and the role of any pathogen must be considered in the context of other risk factors. Here we focus on the relationship between Chlamydia pneumoniae and conventional risk factors for atherosclerosis. There is evidence for a strong association between chronic infection with Chlamydia pneumoniae and smoking as well as high serum cholesterol. It is concluded from the present data that chronic infection with the pathogen is not an independent risk factor for atherosclerosis.     

Chlamydia pneumoniae and atherosclerosis

There is widespread consensus that atherosclerosis is an inflammatory disease. Between possible pathogenetic mechanisms, infective hypothesis has received increasing attention. Researches have recently focused their attention on the role of Chlamydia pneumoniae, a gram-negative intracellular organism, as infection by this bacterium has been demonstrated frequently associated with atherosclerosis. This review attempts to analyze and critically evaluate available data of the literature about the association between Chlamydia pneumoniae and atherosclerosis in order to provide updated elements of judgement concerning a possible future revolutionary scenario: the consideration of atherosclerosis as an infective disease, susceptible to prevention and treatment by means of antimicrobial therapy. More than twenty sero-epidemiological studies have found a two-fold or greater risk of cardiovascular events in subjects with serological evidence of Chlamydia pneumoniae infection. The organism has been identified in over 50% of atherosclerotic plaques examined by various histopathological techniques, while it has been only rarely found in normal artery tissues; moreover, viable Chlamydia pneumoniae has recently been isolated from coronary and carotid atherosclerotic plaques. Several experimental studies have shown that the biological properties of Chlamydia pneumoniae can explain its potential role in initiating and/or modulating plaque formation. The most relevant issue, i.e. the possibility of preventing or slowing progression of the disease with antimicrobial treatment, is still unsolved: only data from experimental studies on animals and four small intervention trials on humans are available, and their encouraging results require confirmation in larger prospective studies. In conclusion, while the association between Chlamydia pneumoniae and atherosclerosis seems to be established, it is still uncertain whether or not the organism plays a causal role in atherosclerosis and its complications. It is hoped that the results of wide scale clinical intervention trials with antibiotics for the secondary prevention of atherosclerotic diseases now in progress will clarify this problem.     

Chlamydia pneumoniae and atherosclerosis

OBJECTIVE: To review the literature for evidence that chronic infection with Chlamydia pneumoniae is associated with atherosclerosis and acute coronary syndromes. DATA SOURCES: MEDLINE and Institute of Science and Information bibliographic databases were searched at the end of September 1998. Indexing terms used were chlamydi*, heart, coronary, and atherosclerosis. Serological and pathological studies published as papers in any language since 1988 or abstracts since 1997 were selected. DATA EXTRACTION: It was assumed that chronic C pneumoniae infection is characterised by the presence of both specific IgG and IgA, and serological studies were examined for associations that fulfilled these criteria. Pathological studies were also reviewed for evidence that the presence of C pneumoniae in diseased vessels is associated with the severity and extent of atherosclerosis. DATA SYNTHESIS: The majority of serological studies have shown an association between C pneumoniae and atherosclerosis. However, the number of cases in studies that have reported a positive association when using strict criteria for chronic infection is similar to the number of cases in studies which found no association. Nevertheless, the organism is widely found in atherosclerotic vessels, although it may not be at all diseased sites and is not confined to the most severe lesions. Rabbit models and preliminary antibiotic trials suggest that the organism might exacerbate atherosclerosis. CONCLUSION: More evidence is required before C pneumoniae can be accepted as playing a role in atherosclerosis. Although use of antibiotics in routine practice is not justified, large scale trials in progress will help to elucidate the role of C pneumoniae.     

Role of Chlamydia pneumoniae in the pathogenesis of coronary disease

Several studies have demonstrated an association Chlamydia pneumoniae with coronary artery disease, suggesting that infection with C. pneumoniae increases the risk for coronary artery disease by factor 2 or more. Since atherosclerosis is considered to be a chronic inflammatory process, these data would fit into the response-to-injury hypothesis of atherosclerosis rather than representing a completely novel concept. Several pathomechanisms as increased cytokine synthesis, proliferative and proaggregatory effects could transmit the effects of chronic C. pneumoniae infection. Animal models and first clinical trials using antibiotic therapy seem to support an etiological role of C. pneumoniae in coronary artery disease. In this paper the current knowledge of the role of C. pneumoniae in coronary artery disease is reviewed and possible pathomechanisms are discussed.     

Atherosclerosis and infection due to Chlamydia pneumoniae or cytomegalovirus: weighing the evidence.

A link between infectious agents and atherosclerosis has been postulated for decades. This review describes the epidemiological and biological evidence linking cytomegalovirus and Chlamydia pneumoniae to atherosclerotic disease. Case-control studies and histologic evidence from atheromatous specimens support an association between atherosclerosis and infection with these two microorganisms, and small interventional trials appear to confirm the link with C. pneumoniae, but these findings require confirmation in larger studies. A lack of clinically relevant animal models has hampered investigations regarding biological mechanisms, particularly for C. pneumoniae.     

Antibiotics effects in a rabbit model of Chlamydia pneumoniae-induced atherosclerosis

The association of Chlamydia pneumoniae infection with the complications of atherosclerosis, cardiovascular disease, and stroke are well established. C. pneumoniae infection of New Zealand White rabbit respiratory tract can result in early changes of atherosclerosis of the aorta that are not produced by sham infection or by Mycoplasma pneumoniae (which result in similar lung pathology). Early institution of antimicrobials with antichlamydial activity (azithromycin, clarithromycin, moxifloxacin, and doxycycline) within 5 days of infection can largely prevent the aortic lesions (75%-85% efficacy). Early treatment is also effective in suppressing the IgG antibody response to C. pneumoniae. However, delayed treatment (6 weeks after infection) with azithromycin was ineffective in aborting vascular changes but clarithromycin was partially effective (62.5% reduction). These studies support but do not prove that C. pneumoniae can cause atherosclerosis. Antibiotics are potentially useful in this model, but the optimum dose and duration of therapy or use of combination of agents remain to be determined.     

Chlamydia pneumoniae in atherosclerosis

Chlamydia pneumoniae is currently the infectious agent most often associated with the inflammation found in atherosclerosis. The seroepidemiological association and the actual presence of pathogen in lesions has been confirmed in numerous studies, in which technical difficulties seem to be the only limitation. Besides animal experiments and intervention trials, we need information of possible pathogenic mechanisms. Recently, several studies have suggested mechanisms by which C. pneumoniae infection could participate in the development of atherosclerosis.     

Chlamydia pneumoniae-based atherosclerosis: a smoking gun

Chronic and acute infectious diseases have been implicated in modifying the risk of atherosclerosis independently or in collaboration with conventional risk factors. During the past two decades, the discussion on microbial agents and atherosclerosis has mainly been centred on Chlamydia pneumoniae.The strongest evidence linking Chlamydia pneumoniae and atherosclerotic disease comes from in vitro experimental studies. In this review, we summarize and critically evaluate the available data of human diagnostic and therapeutic studies on the association of Chlamydia pneumoniae with atherosclerosis.Taking into account the human in vivo data, there is currently insufficient proof linking Chlamydia pneumoniae to atherosclerosis.At present, there are no indications for antibiotic treatment targeted at Chlamydia pneumoniae in the management of atherosclerosis.     

高敏C反应蛋白和肺炎衣原体感染与颈动脉粥样硬化及缺血性脑卒中的相关性研究

目的探讨高敏C反应蛋白水平、肺炎衣原体抗体与颈动脉粥样硬化及缺血性脑卒中TOAST亚型的关系。方法缺血性脑卒中组135例,对照组135例,测定2组的高敏C反应蛋白水平、肺炎衣原体IgG抗体、颈动脉内膜中层厚度及颈动脉粥样硬化程度。结果(1)高敏C反应蛋白水平升高与颈动脉内膜中层厚度及颈动脉粥样硬化程度相关,OR值分别为3.44和6.82;高敏C反应蛋白水平升高与大动脉粥样硬化性脑卒中危险性升高相关,OR值为10.11。(2)肺炎衣原体抗体的阳性率与颈动脉内膜中层厚度及颈动脉粥样硬化程度相关,OR值分别为1.76和4.89。结论高敏C反应蛋白水平和慢性肺炎衣原体感染与颈动脉粥样硬化密切相关,同时高敏C反应蛋白水平升高,可增加发生大动脉粥样硬化性脑卒中的风险。     

Chlamydia Pneumoniae Infection is Not an Independent Risk Factor for Arterial Disease

Appreciation of atherosclerosis as an infectious disease has fostered interest in the role that Chlamydia pneumoniae may play in atheroma development. Although data from seroepidemiological and experimental studies have established an association between the pathogen and atherosclerosis, little is known about how the organism contributes to lesion development. Atherosclerosis is a complex disease process and the role of any pathogen must be considered in the context of other risk factors. Here we focus on the relationship between Chlamydia pneumoniae and conventional risk factors for atherosclerosis. There is evidence for a strong association between chronic infection with Chlamydia pneumoniae and smoking as well as high serum cholesterol. It is concluded from the present data that chronic infection with the pathogen is not an independent risk factor for atherosclerosis. Zusammenfassung Eine Vielzahl epidemiologischer Studien zeigte eine Assoziation zwischen Serumantikörpern gegen Chlamydia pneumoniae und atherosklerotischen Erkrankungen. Bisher ist jedoch unklar, welche biologische Rolle die Bakterien bei der Entstehung der Atherosklerose spielen. Die vorliegende Arbeit beschäftigt sich hauptsächlich mit der Frage, in welcher Beziehung die klassischen Risikofaktoren mit den Chlamydien stehen. Mehrere Autoren haben bei Patienten mit koronarer Herzerkrankung eine Assoziation zwischen Zigarettenrauchen bzw. hohen Cholesterinkonzentrationen und positiven Chlamydienantikörpern gefunden. Diese Ergebnisse zusammen mit experimentellen Daten lassen vermuten, daß Chlamydieninfektionen sowohl statistisch wie auch biologisch keinen unabhängigen Risikofaktor für kardiovaskuläre Erkrankungen darstellen.     

The evolving relationship between Chlamydia pneumoniae and atherosclerosis

A body of evidence supports an association between Chlamydia pneumoniae and atherosclerosis. Recent prospective, seroepidemiologic studies have refined estimations of relative risk. Advances in diagnostic testing with the polymerase chain reaction have created a potential opportunity to screen for infected individuals. New insights into the pathogenesis of infection with C. pneumoniae have been reported, many of which are relevant to the development of atherosclerotic plaque. Clinical trials have now been initiated and should provide guidance as to the utility of antibiotics in the treatment or prevention of coronary artery disease.     

Chlamydial virulence determinants in atherogenesis: the role of chlamydial lipopolysaccharide and heat shock protein 60 in macrophage-lipoprotein interactions

Data from a spectrum of epidemiologic, pathologic, and animal model studies show that Chlamydia pneumoniae infection is associated with coronary artery disease, but it is not clear how the organism may initiate or promote atherosclerosis. It is postulated that C. pneumoniae triggers key atherogenic events through specific virulence determinants. C. pneumoniae induces mononuclear phagocyte foam cell formation by chlamydial lipopolysaccharide (cLPS) and low-density lipoprotein oxidation by chlamydial hsp60 (chsp60). Thus, different chlamydial components may promote distinct events implicated in the development of atherosclerosis. Data implicating cLPS and chsp60 in the pathogenesis of atherosclerosis are discussed and novel approaches are presented for attempting to elucidate how these putative virulence determinants signal mononuclear phagocytes to modulate lipoprotein influx and modification.     

Epidemiologic association of Chlamydia pneumoniae and atherosclerosis: the initial serologic observation and more

About 70% of persons with acute myocardial infarction (AMI) show a seroresponse to a chlamydial lipopolysaccharide (LPS) epitope. Elevated titers against Chlamydia pneumoniae in sera from such patients point to an exacerbation in a chronic infection as does a change in the nature of immune complexes containing chlamydial LPS. The presence of antibodies to C. pneumoniae proteins in immune complexes suggests an intimate association of the pathogen with the vascular system. In the first prospective study, elevated antibody titers or immune complexes containing chlamydial LPS were an independent significant risk factor (odds ratio, 相似文献   

Chlamydia pneumoniae infection is not involved in carotid artery stenosis

Recent studies have suggested the existence of a close relationship between Chlamydia pneumoniae infection and atherosclerosis. However, it has been speculated that C. pneumoniae infection is not associated with early atherosclerosis but with advanced atherosclerosis. In the present study, we test this hypothesis. In 524 consecutive patients who underwent cerebral angiography were recruited for the study. From the films obtained during angiography, percent stenosis of neck internal carotid artery was calculated according to the method of the North American Symptomatic Carotid Endarterectomy Trial (NASCET). Serum C. pneumoniae IgG and IgA antibodies were measured by a commercial ELISA enzyme immunoassay kit. Cerebrovascular risk factors such as age, gender, hypertension, diabetes mellitus, hyperlipidemis and smoking were assessed by interview. Old age above 60 years and diabetes mellitus were found to be independent risk factors for carotid artery stenosis in this study after adjustment for cerebrovascular risk factors. When we defined carotid artery stenosis as the presence of greater than 30% stenosis of one artery, there was no association after adjustment for other risk factors between C. pneumoniae IgG and IgA seropositivity and the presence of carotid artery stenosis for any cut-off value of seropositivity. When we defined carotid artery stenosis as the presence of greater than 70%, there was also no association between C. pneumoniae IgG and IgA seropositivity and the presence of carotid artery stenosis for any cut-off value of seropositivity. These results suggest that C. pneumoniae infection is not associated with carotid artery atherosclerosis.     

Repetitive measurements of Chlamydia pneumoniae DNA in peripheral blood mononuclear cells in healthy control subjects and dialysis patients: a prospective study

Infection with Chlamydia pneumoniae has been suggested to play a role in the development and maintenance of atherosclerosis. However, the course of C. pneumoniae infection is not clarified. Thus, both the persistence of C. pneumoniae DNA in blood and the tendency to recurrence have not been studied. We determined the prevalence of C. pneumoniae DNA in the white cells of the peripheral blood in 98 dialysis patients and in 52 healthy subjects. Blood samples were collected approximately 6 times from each subject during a period of 1 y with an interval of approximately 2 months and analysed with a polymerase chain reaction. C. pneumoniae DNA was detectable in 47 out of 150 subjects at least once during a y. Reinfection was a rare phenomenon and the presence of C. pneumoniae DNA in blood was of less than 2 months' duration in almost all patients. There was a significant association between the presence of C. pneumoniae DNA during 1 y and the presence of atherosclerosis in the legs of dialysis patients (OR=3.50, p=0.03). Additionally, a significant association was found between the presence of C. pneumoniae DNA and an abnormal electrocardiogram (ECG) (OR=3.16, p=0.01). These findings may support the hypothesis of an association between infection with C. pneumoniae and the presence or development of atherosclerosis.     

Chlamydia pneumoniae DNA in peripheral blood mononuclear cells in healthy control subjects and patients with diabetes mellitus, acute coronary syndrome, stroke, and arterial hypertension

Infection with Chlamydia pneumoniae has been suggested to play a role in the development and maintenance of atherosclerosis based on differences in the prevalence of antibodies against Chlamydia pneumoniae in patients with and without atherosclerotic lesions. We evaluated the prevalence of Chlamydia pneumoniae DNA in the white cells of the peripheral blood in 194 patients with diabetes mellitus, 50 patients with acute coronary syndrome, 102 hypertensive patients, 193 patients having suffered a stroke and in 368 healthy subjects with a nested polymerase chain reaction (nPCR). Overall the prevalence of Chlamydia pneumoniae DNA in peripheral blood cells was: diabetes mellitus (11.9%), stroke (10.4%), hypertension (6.9%), acute coronary syndrome (4.0%) and healthy subjects (7.9%). The prevalence of Chlamydia pneumoniae DNA in the patients was not significantly different from prevalence in the healthy subjects. However, a significant association was found between high levels of triglycerides and presence of C. pneumoniae DNA (OR = 3.27, p < 0.04). The prevalence of C. pneumoniae DNA was not associated with age, gender, smoking, BMI, HDL, CRP, plasma creatinine and symptoms or signs of ischaemic heart disease. The association between high levels of triglycerides and C. pneumoniae DNA suggests that infection by C. pneumoniae affects lipid metabolism.     

Association of CD14 promoter gene polymorphism and Chlamydia pneumoniae infection

Recent studies have suggested that Chlamydia pneumoniae infection is an important factor in the development of atherosclerosis. The C(-260)-->T polymorphism in the CD14 promoter gene has been reported to regulate the density of CD14 expression on monocytes for the activation of monocytes to secrete inflammatory cytokines by lipopolysaccharide. We investigated this genetic marker and its association with C. pneumoniae infection. Among 315 healthy subjects, the distribution of the C(-260)-->T polymorphism in the CD14 promoter gene was 14.9% for the CC genotype, 54.3% for the CT genotype, and 30.8% for the TT genotype. Among subjects with the 3 CD14 genotypes, 59.5%, 64.9%, and 78.3%, respectively, were seropositive for C. pneumoniae. With multiple logistic regression analysis, the odds ratio of C. pneumoniae infection was 2.08 for CD14 TT genotype (95% confidence interval, 1.18-3.69; P=.016). A significant association between the CD14 TT genotype and C. pneumoniae infection was found.     

Chlamydia pneumoniae does not increase atherosclerosis in the aortic root of apolipoprotein E-deficient mice

In epidemiological studies, an association between cardiovascular disease and Chlamydia pneumoniae (C pneumoniae) infection has been observed. Although C pneumoniae has been shown to be present in atherosclerotic lesions, a causal relationship between C pneumoniae infection and atherosclerosis has not been demonstrated. To study this question, we used 2 strains of apolipoprotein (apo) E-deficient mice. Eight-week-old mice on an FVB background that were maintained on either a low- or a high-fat diet were infected 3 times at 1-week intervals with C pneumoniae, and atherosclerotic lesions were measured in the aortic root at 10 weeks after the primary infection. In each of the diet groups, no difference in the extent of atherosclerosis could be observed between the C pneumoniae-infected and control animals. In further studies, 2 strains of apoE-deficient mice (FVB or C57BL/6J background) were infected 4 times at 3- to 4-week intervals, and the extent of atherosclerosis was analyzed 18 weeks later. The mice were kept on either a low- or a high-fat diet. The high-fat diet increased atherosclerosis, and a difference in atherosclerosis susceptibility between the mouse strains was observed. However, C pneumoniae infection did not influence lesion size in either mouse strain. On the other hand, C pneumoniae could not be demonstrated by polymerase chain reaction in any of the atherosclerotic lesions of the infected animals studied. A small decrease in serum cholesterol and triglyceride levels 3 days after the primary infection occurred, but after that no differences in serum lipid levels compared with those in noninfected animals were evident. In the myocardium of C pneumoniae-infected mice, no inflammatory signs could be observed. We conclude that under the experimental conditions used, C pneumoniae infection does not accelerate atherogenic changes in the aortic root of apoE-deficient mice.