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Patients with systemic lupus erythematosus (SLE) have accelerated atherogenesis. A recent study suggested that Chlamydia pneumoniae infection might also be a contributing factor in the development of atherogenesis in patients with SLE. The objective of this study was to investigate the possible association of C. pneumoniae infection with markers of atherosclerosis in adolescents with SLE compared with age-matched healthy controls. History and exam focused on cardiovascular risk factors were obtained from 20 patients with SLE and 20 age- and sex-matched controls. Laboratory studies included serum lipid profile and high-sensitivity C-reactive protein (hsCRP). Detection of C. pneumoniae in peripheral blood mononuclear cells (PBMCs) and in nasopharyngeal swab specimens was performed. Carotid Intima-Media Thickness (CIMT) was determined by sonography in all subjects. C. pneumoniae DNA was not detected in PBMCs of any of the patients or controls. Nasopharyngeal cultures were also negative for C. pneumoniae in all patients. CIMT was slightly higher in the SLE group (0.48 +/- 0.049) compared with controls (0.454 +/- 0.041, p = 0.29). There was no significant difference between the two groups in body mass index, blood pressure, hsCRP, and serum cholesterol (total, LDL and HDL). Serum triglycerides were higher in the lupus group (p = 0.03). Children and adolescents with SLE might have accelerated atherosclerosis; however, we did not observe an association with C. pneumoniae infection in this population.

We report a case of a 32-year-old man with hyper IgE syndrome (Job syndrome) who developed Fournier gangrene due to infectious multiple atheromas of the scrotal skin that progressed to the right groin and thigh. The patient required surgical debridement and subsequent skin grafting. This is a rare case of Fournier gangrene associated with hyper IgE syndrome (Job syndrome). When a patient without diabetes mellitus has repeated infections and atopic-like dermatitis, Job syndrome should be considered.

Background: Pathogens have been implicated in the pathogenesis of inflammatory atherosclerosis. Given the pleiotropic role of interleukin-6 in the regulation of cytokines, lipid homeostasis, vascular remodeling, and apoptosis we hypothesized that IL-6 plays an important role in development and progression to inflammatory atherosclerosis., Methods and Results: To explore the role of IL-6 in inflammation- and infection-associated atherosclerosis, 10-week-old ApoE(+/-)-IL-6(+/-) and ApoE(+/-)-IL-6(-/-) mice fed either high fat diet or regular chow diet were inoculated intravenously, once per week for 14 or 24 consecutive weeks with 50 microl live Porphyromonas gingivalis (P.g.) (10(7)CFU) or vehicle (normal saline). Animals were euthanized at 24 weeks of age (14 weeks injection) or 34 weeks of age (24 weeks injection). Histomorphometric analysis of atheromatous lesions, en face analysis over the aortic tree, immunohistochemistry for macrophages and smooth muscle cell, TUNEL staining for apoptotic cells, serum amyloid A (SAA) levels, serum lipids and glucose level, serum cytokines were obtained. ApoE(+/-)-IL-6(-/-) mice showed a significant increase in atheromatous lesions in proximal aorta and aortic tree compared to ApoE(+/-)-IL-6(+/-) mice for all conditions (chow diet and P.g.-inoculated, high fat diet and P.g.-inoculated, high fat diet and vehicle-inoculated) at 14 weeks and greater at 24 weeks. SAA levels from ApoE(+/-)-IL-6(-/-) mice were significantly higher than ApoE(+/-)-IL-6(+/-) mice. IL-6 deficiency led to profound changes in plaque composition evidenced by increased macrophage infiltration, apoptosis, lipid content and decreased smooth muscle cell mass reflecting an unstable plaque phenotype. Array analysis revealed increased levels of proinflammatory cytokines in ApoE(+/-)-IL-6(-/-) mice compared to ApoE(+/-)-IL-6(+/-) mice, irrespective of diet or inoculation., Conclusion: The genetic deficiency of IL-6 was found to enhance the formation of diet- and/or pathogen-associated atherosclerotic plaques and suggests that IL-6 may play an atheroprotective role.

Introduction: Porphyromonas gingivalis, a major periodontal pathogen, is gaining increasing attention for its possible association with cardiovascular diseases. Its fimbriae are classified into six genotypes (types I-V and Ib) based on the diversity of the fimA genes encoding the fimbrial subunits. In this study, fimA genotypic distribution was analyzed in P. gingivalis-infected cardiovascular specimens., Methods: A total of 112 heart valves and 80 atheromatous plaque specimens were collected from patients undergoing cardiovascular surgery, as well as 56 dental plaque specimens. Bacterial DNA was extracted from each, and polymerase chain reaction analysis was carried out with a P. gingivalis-specific set of primers. P. gingivalis-positive specimens were further analyzed to discriminate the fimA genotype using polymerase chain reaction with fimA type-specific primer sets., Results: P. gingivalis was detected in 10.4% of the cardiovascular specimens and 50.0% of the dental plaque samples. In the latter, type II was most frequently detected (35.7%), followed by types I (28.6%) and IV (21.4%), while types IV and II were detected with considerable frequencies of 45.0% and 30.0%, respectively, in the cardiovascular specimens. In contrast, the occurrence of type I was limited (5.0%) in the cardiovascular specimens., Conclusion: These results suggest that specific fimA genotypic clones, which are reportedly associated with periodontitis, are also frequently harbored in cardiovascular specimens, indicating the possible involvement of type II and IV clones in the initiation and progression of cardiovascular diseases.

Background and Objective: Previous studies have reported different periodontal bacteria in atherosclerotic lesions, but their involvement in plaque formation remains unclear. The aim of the present study was to investigate the presence of 20 periodontal bacteria in atherosclerotic samples and healthy blood vessels (used as controls) and to clarify their relationship in regard to clinical and bacteriological periodontal status., Material and Methods: The day before vascular surgery the patients had a thorough periodontal examination and bacteriological samples were taken from periodontally diseased sites. Atheromatous plaques, internal mammary arteries and saphenous veins were harvested during surgery. A DNA-DNA hybridization procedure was used to screen periodontal and vascular samples for the 20 selected bacterial species., Results: Periodontal samples from the severe periodontitis group were found to have a higher prevalence and biomass of bacterial species than the moderate periodontitis group. In vessel samples, the prevalence of the same 20 bacterial species analyzed together was similar in the two groups, except for saphenous veins., Conclusion: The presence of periodontal pathogens in atherosclerotic plaques and in apparently healthy vessels appeared to reflect a higher level of bacteremia rather than infection of endothelial cells.

Cardiovascular disease, resulting from atherosclerosis, is a leading cause of global morbidity and mortality. Genetic predisposition and classical environmental risk factors explain much of the attributable risk for cardiovascular events in populations, but other risk factors for the development and progression of atherosclerosis, which can be identified and modified, may be important therapeutic targets. Infectious agents, such as Chlamydia pneumoniae, have been proposed as contributory factors in the pathogenesis of atherosclerosis. In the present review, we consider the experimental evidence that has accumulated over the last 20 years evaluating the role of C. pneumoniae in atherosclerosis and suggest areas for future research in this field.

Chlamydophila pneumoniae has been implicated in atherosclerosis, but the role of this obligate intracellular pathogen in the development of the above pathology is still unclear. In particular, its presence and quantitative distribution within lesional areas has not yet been defined. We studied 18 carotid biopsies obtained from patients undergoing endoartherectomy. By laser microdissection (LCM), two different sites (intra-plaque and plaque-adjacent areas) were taken from each lesion, and the presence and quantity of the pathogen DNA were determined by real-time polymerase chain reaction (Real-time PCR). A total of 8 plaques, exclusively from patients with unstable angina, were positive in real-time PCR. The bacterial DNA was detected in both lesional areas of 3 plaques which contained the highest number of DNA copies (1,900 to 2,200 copy numbers), while C. pneumoniae DNA was detected only in the intra-plaque area of the other 5 positive (500 to 1,600 copy numbers). No C. pneumoniae DNA was found in the other 10 plaques of which 6 were from patients with unstable angina and 4 from stable angina patients. No DNA from Helicobacter pylori or Cytomegalovirus was found in any plaque. This is the first report where both the target lesion and an adjacent reference site were evaluated for the presence of C. pneumoniae DNA by the combination of LCM and Real-time PCR assays. The integration of these two methodologies offer an excellent tool for in situ studies and may help to elucidate the putative role of C. pneumoniae in atherosclerosis.

Background: The causes of accelerated atherosclerosis in end-stage renal disease (ESRD) patients are unknown, although recent studies have suggested that Chlamydia pneumoniae (Cp) infection and inflammation might be contributing factors. We aimed to evaluate the association of carotid atherosclerosis progression with Cp infection and inflammation in patients undergoing peritoneal dialysis (PD)., Methods: This is a prospective observational study. A total of 52 non-diabetic prevalent PD patients were included. The intima-media thickness of a common carotid artery (CCA-IMT) was measured at baseline and after 36 months by B-mode ultrasonography. Serum antibodies to Cp and inflammatory markers were obtained at the time of initial measurement of the CCA-IMT., Results: CCA-IMT progressors (deltaCCA-IMT > or = 0.015 mm/year) had a higher prevalence of seropositivity for Cp IgA antibody, a higher level of Cp IgA antibodies indices, log IL-(interleukin-)6, and intercellular adhesion molecule-1 (ICAM-1) compared to the non-progressors (deltaCCA-IMT < 0.015 mm/year). On multivariate analysis, Cp IgA index and log IL-6 were independent risk a factors for CCA-IMT progression. Also, Cp IgA index had independent positive correlation with the magnitude of annual deltaCCA-IMT. Cp IgA antibody seropositive patients showed significantly higher mean annual deltaCCA-IMT than seronegative patients. Moreover, patients with both positive Cp IgA antibodies and elevated IL-6 above the median level showed higher deltaCCA-IMT than those with either factor alone., Conclusions: Our data showed that Cp and inflammation were significant risk factors of CCA-IMT change in PD patients. This study strengthens evidence that Cp is involved in the pathogenesis of atherosclerosis and also suggests that the effect of Cp infection under high inflammatory status might be a risk factor for progression of atherosclerosis.

Patients with diabetes mellitus (DM) are at risk for Helicobacter pylori infection. This infection has been linked to atherosclerosis and its vascular complications. The aim of this study was to evaluate the: (1) prevalence of H pylori infection in patients with DM; (2) association between diabetic vascular complications and H pylori infection; and (3) influence of H pylori infection on atherosclerosis and inflammatory biomarkers. In this study, we evaluated 80 patients with DM for atherosclerosis; cardiac, cerebral, and peripheral vascular diseases; retinopathy; neuropathy; and nephropathy. We estimated the blood levels of glucose, glycosylated hemoglobin, complete blood cell count, erythrocytic sedimentation rate, lipid profile, tumor necrosis factor-alpha, interleukin (IL)-6, and anti-H pylori IgG antibodies. H pylori infection was detected in 85% of patients versus 76.7% for control subjects. Carotid artery intima-media thickness was significant in H pylori-infected patients. IL-6 and tumor necrosis factor-alpha were significantly associated with H pylori infection. In multivariate analysis, blood glucose, triglycerides, erythrocytic sedimentation rate, IL-6, and tumor necrosis factor-alpha increased the odds for atherothrombotic cause of cerebral ischemia in H pylori infection. We concluded that H pylori infection is common in DM and seems to be linked to the presence of atherosclerosis and ischemic cerebrovascular stroke. This effect could be mediated by increasing cytokine levels.

Background: Atherosclerosis is still the leading cause of death in the western world. Besides known risk factors studies demonstrating Chlamydophila pneumoniae (C. pneumoniae) to be implicated in the progression of the disease, little is known about C. pneumoniae infection dynamics. We investigated whether C. pneumoniae induce cell death of human aortic endothelial cells, a cell type involved in the initiation of atherosclerosis, and whether chlamydial spots derive from inclusions., Results: Lactate dehydrogenase release revealed host cell death to be dependent on the amounts of Chlamydia used for infection. The morphology of lysed human aortic endothelial cells showed DNA strand breaks simultaneously with cell membrane damage exclusively in cells carrying Chlamydia as spots. Further ultrastructural analysis revealed additional organelle dilation, leading to the definition as aponecrotic cell death of endothelial cells. Exclusive staining of the metabolic active pathogens by chlamydial heat shock protein 60 labelling and ceramide incorporation demonstrated that the bacteria responsible for the induction of aponecrosis had resided in former inclusions. Furthermore, a strong pro-inflammatory molecule, high mobility group box protein 1, was shown to be released from aponecrotic host cells., Conclusion: From the data it can be concluded that aponecrosis inducing C. pneumoniae stem from inclusions, since metabolically active bacterial spots are strongly associated with aponecrosis late in the infectious cycle in vascular endothelial cells and metabolic activity was exclusively located inside of inclusions in intact cells. Vice versa initial spot-like infection with metabolically inert bacteria does not have an effect on cell death induction. Hence, C. pneumoniae infection can contribute to atherosclerosis by initial endothelial damage.

Stimulation of Toll-like receptors, which serve to initiate inflammatory signaling in response to the detection of conserved microbial pathogen-associated molecular patterns (PAMPs), has been shown to play a central role in the development of atherosclerosis. In this review, the recent evidence supporting a role for both infection- and commensal-derived PAMPs in the pathogenesis of atherosclerosis will be discussed. Potential sources of PAMPs, their routes of delivery to the artery wall and the mechanisms by which PAMPs may affect vascular function independently of bacteremia or infection of the artery wall with viable organisms will be examined. Finally, the recent evidence that obesity and high-fat diets may each promote translocation of commensal-derived endotoxin from the gut into the circulation to induce inflammation, insulin resistance and atherosclerosis will be discussed.

Already at the beginning of the 20th century, a potential role for microbes in vascular diseases was suggested. However, until the late '70 of that century, not much attention has been paid to this infection hypothesis. Then, predominantly based on the pioneering work of Fabricant et al., evidence for a contributing or even initiating role for microbes in atherosclerosis, as well as other vascular diseases, was accumulating. Also, the seminal paper by Saikku and co-workers, demonstrating serological evidence of an association of Chlamydia pneumoniae, an obligate intracellular respiratory gram-negative bacterium, with chronic coronary heart disease and acute myocardial infarction, significantly boosted the research on the infection hypothesis. Since then, numerous papers have been published demonstrating associations between a large variety of pathogens and atherosclerotic disease. Furthermore, many molecular mechanisms have been suggested by which microbes may affect atherogenesis. Nevertheless, in recent large randomised prospective trials, evaluating the efficacy of antibiotic treatment for the secondary prevention of coronary events, no reduction in the rate of cardiovascular events was observed, thereby seriously challenging the validity of the infection hypothesis. Nevertheless, the large body of supporting evidence, which has accumulate over the past decades, should not be ignored and maybe we should look at the hypothesis, and in particular the mechanisms by which microbes affect the disease, from a different angle.

Microorganisms which belong to Chlamydophila sp and Chlamydia sp genus are intracellular pathogens with characteristic life cycle. In humans the most common infections are caused by Chlamydophila pneumoniae i Chlamydia trachomatis.These pathogens are mainly responsible for infections of upper respiratory tract, infections of urinary tract and conjunctivitis. They are also considered to take part in patophysiology of Atherosclerosis, nervous system diseases and exacerbation of chronic respiratory tract diseases.

Microorganisms infection was thought to be associated with atherosclerosis (AS), but the results of trials investigating antibiotic therapy in patients with coronary artery disease were controversial. Recently, a series of studies explored the relationship between gut flora and obesity, which showed that western-style diet (high fat) could induce imbalanced ratio of the Firmicutes versus the Bacteroidetes in the gut of germ-free mice and human beings, and gut flora could promote obesity through several novel pathways, such as inhibition of fasting-induced adipocyte factor. Meanwhile, data from some studies confirm that some link exists between the abdominal obesity and satiety centers (hindbrain and hypothalamus) with neurotransmitters and hormones. All of the above showed some connection between western-style diet, gut flora, visceral fat, and satiety centers, but until now, no study has shown us the exact mechanism about it. It is proposed that the vicious cycle composed of gut flora and visceral fat may initiate and promote AS. Attempts to confirm this hypothesis may lead to new directions in the study of the pathogenesis of AS and the development of novel strategies for the treatment of AS.

Our aim was to detect markers of Chlamydia pneumoniae (CPN) and human cytomegalovirus (HCMV) infection in patients with peripheral vascular occlusive disease and to follow markers of inflammation, endothelial dysfunction and lipid metabolism alteration in patients with active infection. CPN genome was detected in 9 (47.4 %) patients by at least one PCR method. Serological markers of acute CPN infection were found in 5 (26.3 %) subjects; each of them showed also positivity in at least one of the PCR methods. HCMV DNA were detected in 2 (10.5 %) patients; HCMV-specific antibodies were detected in 14 (73.7 %) subjects, however only in IgG subclass. Subjects with HCMV PCR positivity thus showed no serological markers of active HCMV infection. Laboratory findings of acute CPN infection were associated with increased plasma levels of Lp(a), triacylglycerols, atherogenic index of plasma and E-selectin (p < 0.05). No significant differences were found in the other markers, including plasma levels of total cholesterol, ferritin, homocysteine, oxidized LDL, IL-6, IL-8, IL-18, TNF-alpha, soluble forms of VCAM-1 and ICAM-1, von Willebrand factor, C-reactive protein, and plasma nitrites & nitrates. Frequent presence of chlamydial DNA in atheromatous plaques from patients with peripheral vascular disease was confirmed. HCMV DNA was detected only sporadically and with positivity in anamnestic anti-HCMV antibodies (IgG) only, indicating a rare presence of latent virus rather than active replication. Patients with laboratory markers of acute CPN infection exhibited more pronounced alterations in lipid metabolism and endothelial dysfunction.

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.

Background: The aim of this study was to investigate the presence of various atypical pneumonia agents (Chlamydia pneumoniae, cytomegalovirus, Mycoplasma pneumoniae), which are considered to have a role in the ethiopathogenesis of atherosclerosis, in aortic biopsies without macroscopically visible plaque and in internal thoracic artery biopsies., Material and Methods: Thirty-three patients (group 1), who had undergone coronary bypass operation and 10 non-atherosclerotic patients (group 2), were included in the study. Seventy-six tissue biopsies were taken. Biopsies from the patients in group 1 a were obtained from the atheroma plaque-free aortic tissue and 33 biopsies (group Ib) were obtained from their internal thoracic arteries. Following DNA extraction, nested PCR was used to detect Chlamydia pneumoniae DNA, and real time PCR was used to detect cytomegalovirus and Mycoplasma pneumoniae DNA. Blood parameters (lipid profile, CRP, fibrinogen) of the patients and operation characteristics were recorded., Results: Chlamydia pneumoniae DNA was detected in 5 of 33 biopsy samples from coronary bypass patients, whereas none of the control patients (group 1b and group 2) were positive for this agent (P = 0.001). Neither CMV nor Mycoplasma pneumoniae was detected in IMA and aortic biopsies of both bypass and control patients. Elevated total cholesterol levels (P = 0.02) and positive CRP (P = 0.001) was found in C. pneumoniae positive patients. Prevalence of acute coronary syndrome was significantly higher in C. pneumoniae detected patients compared (P = 0.00 1)., Conclusions: Detection of C. pneumoniae DNA in the atheroma free aortic biopsies might indicate that this micro-organism intervened in the progression of atheroma plaque. There was a strong relationship between the detection of this micro-organism in the aortic wall and acute coronary syndrome. The absence of DNA of the corresponding micro-organisms in the IMA wall may show its resistance to infective agents and in turn to atherosclerosis, which is a result of the prevailing endothelial functions of this artery.

Background: Chlamydia pneumoniae has been repeatedly associated with atherosclerotic cardiovascular diseases. We investigated the pattern of distribution of C. pneumoniae among patients with carotid atherosclerotic disease evaluating chlamydial load in carotid plaque, peripheral blood mononuclear cells (PBMC) and lymph node from same patient., Methods and Results: Thirty carotid plaques, 30 PBMC and 30 lymph nodes were examined by real-time PCR assay. C. pneumoniae DNA was detected, in carotid plaques, PBMC and lymph nodes in 11 patients; in carotid plaques and PBMC in five patients; in PBMC and lymph nodes in four patients; in lymph nodes in two patients; and in PBMC only in one patient. C. pneumoniae DNA in PBMC significantly coincided with the presence of the respective DNA in carotid plaque (p=0.0001) and lymph node (p=0.02). A higher chlamydial load was detected in PBMC than in lymph nodes and carotid plaques. More than 90% of patients with carotid plaques, PBMC and lymph nodes positive to C. pneumoniae were symptomatic, smokers, hypertensives, dyslipidemics and showed carotid plaques with rupture on the surface, hemorrhage and thrombosis., Conclusion: The measurement of chlamydial load in PBMC may be helpful in the future to assess the state of C. pneumoniae infection and the risk of developing sequelae.

Rifalazil is a benzoxazinorifamycin which inhibits bacterial DNA-dependent RNA polymerase. The benzoxazine ring endows benzoxazinorifamycins with unique physical and chemical characteristics which favor the use of rifalazil and derivatives in treating diseases caused by the obligate intracellular pathogens of the genus chlamydia. Minimal inhibitory concentrations of benzoxazinorifamycins against chlamydia are in the pg/mL range. These compounds have potential as monotherapeutic agents to treat chlamydia-associated disease because they retain activity against chlamydia strains resistant to currently approved rifamycins such as rifampin. A pivotal clinical trial with rifalazil has been initiated for the treatment of peripheral arterial disease. The rationale for this innovative use of rifalazil, including the association of C. pneumoniae in atherosclerotic plaque formation, as well as rifalazil's potency and efficacy against chlamydia in both preclinical and clinical studies, is discussed. Other benzoxazino derivatives may have utility as stand-alone topical antibacterials or combination antibacterials to treat serious Gram-positive infections. None of the benzoxazinorifamycins examined to date induce the cytochrome P450 3A4 enzyme. This is in contrast to currently approved rifamycins which are strong inducers of P450 enzymes, resulting in drug-drug interactions that limit the clinical utility of this drug class.

Background: In recent years, many researchers have focused their attention on the ability of periodontal pathogens to colonize atheromatous plaques. Nevertheless, a clear correlation between the detection rates of periodontopathic bacterial DNA in atheromas and in subgingival plaque samples has not been established. The aim of our study was to assess the presence of five periodontal pathogens (Actinobacillus actinomycetemcomitans, Prevotella intermedia, Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia [formerly Tannerella forsythensis]) in periodontal pockets and in carotid atheromas recovered from the same patients., Methods: Thirty-three patients with advanced chronic periodontitis scheduled for endarterectomy were enrolled in the study. DNA was extracted from subgingival plaque samples and carotid atheromas. Universal bacteria primers for general detection of bacteria and species-specific primers for detection of periodontal pathogens were used to amplify part of the 16S rRNA gene by polymerase chain reaction., Results: All subgingival plaque samples were positive for at least one target microorganism. The prevalence of T. forsythia, P. gingivalis, T. denticola, P. intermedia, and A. actinomycetemcomitans were 69.7%, 63.6%, 54.5%, 45.4%, and 33.3%, respectively. Bacterial DNA was detected in 31 out of 33 endarterectomy specimens. However, none of the samples tested positive for DNA from periodontal pathogens., Conclusion: The presence of periodontal bacteria in atheromatous plaques was not confirmed by this investigation; thus, no correlation could be drawn between periodontitis bacteria and microorganisms involved in the atherosclerotic lesions.

Infection with bacteria such as Chlamydia pneumonia, Helicobacter pylori or Porphyromonas gingivalis may be triggering the secretion of inflammatory cytokines that leads to atherogenesis. The mechanisms by which the innate immune recognition of these pathogens could lead to atherosclerosis remain unclear. In this study, using human vascular endothelial cells or HEK-293 cells engineered to express pattern-recognition receptors (PRRs), we set out to determine Toll-like receptors (TLRs) and functionally associated PRRs involved in the innate recognition of and response to lipopolysaccharide (LPS) from H. pylori or P. gingivalis. Using siRNA interference or recombinant expression of cooperating PRRs, we show that H. pylori and P. gingivalis LPS-induced cell activation is mediated through TLR2. Human vascular endothelial cell activation was found to be lipid raft-dependent and to require the formation of heterotypic receptor complexes comprising of TLR2, TLR1, CD36 and CD11b/CD18. In addition, we report that LPS from these bacterial strains are able to antagonize TLR4. This antagonistic activity of H. pylori or P. gingivalis LPS, as well as their TLR2 activation capability may be associated with their ability to contribute to atherosclerosis.

The present paper reviews relationship between chronic periodontitis and cardiovascular diseases. Original papers on this subject, published in English in the period between 2001 and the first semester 2006, were located in the MEDLINE/PubMed database. Additional studies were obtained by searching reference lists of previously published papers. Periodontal infection provides a chronic reservoir of inflammatory mediators and cytokines, lipopolysaccharide, which contribute to the formation of atheroma. Moreover, periodontal pathogens can penetrate the epithelial barrier of the periodontal tissues and reach the blood stream, carrying out a local atherogenic activity. Some studies indicated that periodontal treatment could result in reduction of cardiovascular events. If these results are confirmed in further intervention studies, the prevention and the treatment of periodontitis should be considered as factors able to avoid or reduced the onset and/or evolution of cardiovascular diseases.

Objective: To investigate the possible link between symptomatic carotid atherosclerotic plaque and Chlamydia pneumoniae., Background: Recently, several studies have demonstrated that there may be a possible link between Chlamydia pneumonia and carotid atherosclerosis, however the real role of Chlamydia pneumoniae is not completely understood., Method: This is a prospective study with a total of 52 patients analyzed. All patients had been submitted to endarterectomy, and had suffered thrombotic ischemic stroke or transient ischemic attack up to 60 days prior to the surgery. Every patient presented carotid stenosis over 70%. The plaque was removed during the surgery and the laboratory exams were immediately done. Evaluation of Chlamydia pneumoniae DNA was done using polymerase chain reaction (PCR)., Results: The PCR analyses of all 52 patients were negative for Chlamydia pneumoniae., Conclusion: These initial results do not show a relationship between Chlamydia pneumoniae and symptomatic carotid atherosclerotic plaque.

Background: Chronic infections, such as periodontitis, have been associated with an increased risk for atherosclerosis and coronary artery disease. The aim of this study was to investigate biopsy samples of coronary and internal mammary arteries for the presence of putative pathogenic bacteria (Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Prevotella intermedia, and Tannerella forsythensis), Chlamydia pneumoniae, and human cytomegalovirus (CMV)., Methods: Patients with a diagnosis of coronary artery disease were included in the study. Fifteen coronary arteries with atherosclerosis and 15 internal mammary arteries without clinically assessable atherosclerotic degeneration were investigated. Both groups of specimens were obtained during coronary artery bypass grafting surgery. In all cases, the coronary and mammary artery specimens were taken from the same patient. The detection of periodontal pathogens, C. pneumoniae, and CMV was done by polymerase chain reaction analysis., Results: Bacterial DNA was found in nine of 15 (60%) coronary artery biopsy samples: P. gingivalis in eight (53.33%), A. actinomycetemcomitans in four (26.67%), P. intermedia in five (33.33%), and T. forsythensis in two (13.33%) samples; CMV was detected in 10 (66.67%) samples, and C. pneumoniae was detected in five (33.33%) samples. Some of the samples contained more than one type of bacteria. Periodontal pathogens were not detected in internal mammary artery biopsies, whereas CMV was present in seven (46.67%) samples and C. pneumoniae was present in six (40%) samples., Conclusion: The absence of putative pathogenic bacteria in internal mammary arteries, which are known to be affected rarely by atherosclerotic changes, and their presence in a high percentage of atherosclerotic coronary arteries support the concept that periodontal organisms are associated with the development and progression of atherosclerosis.

The involvement of oral bacteria in the pathogenesis of cardiovascular disease has been studied, with Streptococcus mutans, a pathogen of dental caries, detected in cardiovascular lesions at a high frequency. However, no information is available regarding the properties of S. mutans detected in those lesions. Heart valve specimens were collected from 52 patients and atheromatous plaque specimens from 50 patients, all of whom underwent cardiovascular operations, and dental plaque specimens were taken from 41 of those subjects prior to surgery. Furthermore, saliva samples were taken from 73 sets of healthy mothers (n=73) and their healthy children (n=78). Bacterial DNA was extracted from all specimens, then analysed by PCR with S. mutans-specific and serotype-specific primer sets. The detection rates of S. mutans in the heart valve and atheromatous plaque specimens were 63 and 64 %, respectively. Non-c serotypes were identified with a significantly higher frequency in both cardiovascular and dental plaque samples from the subjects who underwent surgery as compared to serotype c, which was detected in 70-75 % of the samples from the healthy subjects. The serotype distribution in cardiovascular patients was significantly different from that in healthy subjects, suggesting that S. mutans serotype may be related to cardiovascular disease.

Actinobacillus actinomycetemcomitans, an important pathogen in periodontitis, has also been detected in cardiovascular tissues. Sixty heart valves were collected during valve replacement surgery from 60 patients (one from each), 10 were from patients with infective endocarditis (IE group) and 50 were from patients with other valvular diseases (non-IE group). In addition, 46 samples of aneurysmal tissue were taken from 46 patients with a thoracic or abdominal aneurysm (Aneurysm group, one from each). Dental plaque samples were taken from 54 of the patients, 31 in the IE and non-IE groups and 23 in the aneurysm group. First, the distribution of A. actinomycetemcomitans in all specimens was analysed using a polymerase chain reaction method, which resulted in a positive reaction in 33 (31.1%) of the cardiovascular specimens and 25 (46.3%) of the dental plaque samples. Next, using serotype-specific sets of primers, the serotype distribution of A. actinomycetemcomitans in the cardiovascular specimens and dental plaque samples was found to be significantly different compared to dental plaque samples from Japanese subjects reported previously.

Background: Periodontal disease is a chronic inflammatory infectious disease that may act as a focus of infection. Preeclampsia is a pregnancy-specific hypertensive disorder that often leads to maternal morbidity and mortality. Acute atherosis, the placental lesion of preeclampsia, shares many histopathological features with atherosclerosis. Recently, chronic infection was linked to the initiation of atherosclerosis. Oral pathogens have been detected in atherosclerotic plaques, where they may play a role in the development and progression of atherosclerosis. The purpose of the present study was to explore the possibility that periopathogenic bacteria may translocate into the placental tissues of women with preeclampsia., Methods: Samples were taken from 16 placentas obtained from cesarean sections of women with preeclampsia and from 14 age-matched healthy pregnant women. Polymerase chain reaction was used to detect Actinobacillus actinomycetemcomitans, Fusobacterium nucleatum ssp., Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythensis, and Treponema denticola., Results: Eight of the 16 (50%) placenta specimens were positive for one or more periopathogenic bacteria in the preeclampsia group, compared to only two of the 14 samples (14.3%) from controls. Bacterial counts were statistically significantly higher in the preeclampsia group for all of the periopathogenic bacteria examined (P

Aim: In the last years the relationship between periodontitis and cardiovascular diseases has been a subject of increasing research. The identification of periodontopathic bacteria in atheromas can contribute to our knowledge of such an association. The aim of our study was to assess the concomitant presence of 5 periodontal pathogens (Actinobacillus actinomycetemcomitans, Prevotella intermedia, Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia) in periodontal pockets and in carotid atheromas recovered from the same individuals., Methods: Twenty-one patients with chronic periodontitis scheduled for endarterectomy for carotid stenosis were enrolled in the study. Subgingival plaque samples and carotid atheromas were examined using the polymerase chain reaction and reverse hybridization techniques by means of specific probes for periodontal bacteria. Human beta-globin amplification was used as internal polymerase chain reaction efficiency control., Results: Three patients were excluded because the endarterectomy specimens were negative to DNA amplification. All subgingival plaque samples were positive for at least one target micro-organism. The prevalence of Tannerella forsythia, Porphyromonas gingivalis, Prevotella intermedia, Treponema denticola, and Actinobacillus actinomycetemcomitans was 72.22%, 61.11%, 55.56%, 50%, and 33.33%, respectively. No periodontal bacteria DNA was detected in any endarterectomy specimen., Conclusions: The presence of periodontal bacteria in atheromatous plaques was not confirmed by this investigation and, thus, no correlation between periodontitis bacteria and micro-organisms involved in the atherosclerotic lesions could be drawn.

Atherosclerosis is no longer considered a disorder of lipid accumulation, but a disease process characterized by the dynamic interaction between endothelial dysfunction, subendothelial inflammation and the 'wound healing response' of the vascular smooth muscle cells. Prospective epidemiological studies have unequivocally demonstrated increased vascular risk in individuals with elevated levels of (i) cytokines such as interleukin-6 and tumour necrosis factor-alpha, (ii) cell adhesion molecules such as intercellular adhesion molecule-1 and P-selectin, and (iii) acute-phase proteins such as C-reactive protein, fibrinogen and serum amyloid A. Furthermore, evidence from clinical trials have demonstrated that risk reduction achieved with anti-inflammatory agents such as statins is significantly greater in patients with evidence of inflammation. A number of risk factors for atherogenesis, including infectious agents, have been shown to exert their influence via inflammatory mechanisms. However, despite compelling experimental evidence, clinical studies looking at the role of infection in atherogenesis have lacked consistency. The clinical product of this dynamic process is variable and unpredictable between individuals, even those with apparently similar risk profiles.

Atherosclerosis is a chronic inflammation and the cause of most cardiovascular diseases. It is the main cause of death in the Western world today, even though growing incidence of atherosclerosis-related diseases has been recently observed in developing countries, too. In many patients with atherosclerosis, however, traditional risk factors for atherosclerosis are not identifiable. This has renewed the interest, in recent years, in the links between atherosclerosis and environmental exposures, including infectious agents. Infection was identified as as risk factor for atherosclerosis in the first half of the 20th century. Experimental and clinical studies have shown that infection can stimulate atherogenic processes and that there are significant interactions between infection and traditional risk factors. Yet there are questions concerning etiology, pathogenesis and appropriate interventions which remain unanswered. The following article provides an overview of the role of the infectious agents in atherosclerosis and discusses possible intervention strategies.

Objectives: Atherosclerotic vascular disease is the most frequent complication seen in haemodialysis (HD) patients. Evidence suggests that inflammation may play a role in the pathogenesis and progression of atherosclerosis. Our aim was to evaluate the causative role of inflammation in atherosclerosis among HD patients., Methods: Intima-media thickness (IMT) in carotid arteries was determined in 54 HD patients and 52 controls. Plasma levels of lipids, glucose, albumin and several acute phase proteins, and immunoglobulin G titres against chlamydia and cytomegalovirus were measured in all subjects., Results: Mean carotid IMT was significantly greater in HD patients than in controls (0.75 mm vs 0.56 mm, P < 0.005). While plasma levels of C-reactive protein (CRP), serum amyloid A (SAA), lipoprotein (a) Lp(a), fibrinogen and ferritin were higher in HD patients, albumin levels were lower. In HD patients, carotid IMT was correlated positively with CRP (R = 0.29, P = 0.019), SAA (R = 0.69, P < 0.001), Lp(a) (R = 0.42, P = 0.001), fibrinogen (R = 0.57, P < 0.001) and chlamydia pneumonia immunoglobulin G titres (R = 0.50, P < 0.001), and negatively with albumin levels (R = -0.33, P = 0.02); there was no relationship between carotid IMT and hypertension, plasma lipid levels and cytomegalovirus. In multivariate regression analysis, these variables still showed a significant relationship with IMT (R(2) = 0.694 and P < 0.001)., Conclusion: We conclude that atherosclerotic changes are more common in HD patients than in controls, and that inflammatory processes may play a role in the pathogenesis of atherosclerosis.

The activation of the immunologic system plays an immportant role in the initiation of atherogenesis, as shown in numerous studies. However the role of infectious agents in this process still remains controversial. The aim of this study was to investigate the involvement of heat shock protein as a link between infection and peripheral arterial disease. 31 patients suffering from lower limb ischemia were enrolled in the study. Patients were divided into 2 groups. Group I - patients with peripheral arterial disease, group II patients with diabetic macroangiopathy. The control group consisted of 11 healthy volunteers. Blood samples were taken from each participant in order to determine serum concentrations of anti Chlamydia pneumoniae, CMV and HSP 60/65 antibodies. Statistic analysis showed anti-C. pneumoniae IgG (p< 0.025) and anti-CMV IgG (p<0.0157) antibodies were significantly more frequent in both study groups in comparison with healthy controls. Antibodie levels were also found significantly higher than in controls. Mean concentration of anti-C. pneumoniae IgG in the study group was 69.67574 vs. 18.59722 [AU/ml] in the control group (p<0.01). Analogical anti CMV IgG levels in the study group were 337.6516 vs 121.3778 [AU/ml] in controls (p<0.025). Similar changes in antibody concentration were noticed for the C. pneumoniae IgA index. 0.835258 vs. 0.176333 (p< 0.005). Antibodies against HSP 60/65 were present in significantly higher titre (p<0.005). No significant differences in antibody levels were detected beteween groups I and II. The positive correlation between anti-C. pneumoniae Ig A (r=0.3910; p<0.03) and anti HSP 60/65 antibodies titre, as well as anti-C. pneumoniae Ig G (r= 0.7151; p<0.00009) and anti HSP 60/65 speaks for the heat shock protein involvement in atherosclerotic plaque development.

Accumulation of inflammatory cells identifies atherosclerotic plaque at risk for rupture. Typically, activated immune cells occupy the rupture-prone areas of the atherosclerotic lesion. These cells are an appealing therapeutic target for novel strategies of plaque stabilization. Biologic consequences of plaque inflammation ultimately depend not only on the cellular players populating the lesion but also on triggers of immune activation originating from within the plaque or arriving from the circulation, and immune effector mechanisms that mediate cellular damage and plaque destabilization. Recent studies have provided insights into particular immune mechanisms in the atherosclerotic plaque that contribute to plaque vulnerability. This knowledge provides the basis for potential immunomodulatory therapies in cardiovascular disease. These therapeutic approaches can be classified as (1) immunomodulatory effects of existing therapies, (2) therapies targeting inflammatory triggers, and (3) agents inhibiting specific immune mechanisms.

Background: It has been postulated that systemic infection with pathogens such as Porphyromonas gingivalis (Pg) elevates the inflammatory response and increases susceptibility to atherosclerosis. We hypothesized that Doxycycline would be beneficial in diet- and/or Pg-induced atherosclerosis given its role in various cell functions and matrix remodeling., Methods and Results: ApoE+/- mice were inoculated weekly with Pg and treated with either Doxycycline or saline; animals were fed either a high-fat or chow diet. Animals were euthanized at 14 or 24 weeks and histomorphometric analysis of atheromatous lesions in proximal aorta, levels of SAA and serum cytokine profiling were performed. Histomorphometric analysis demonstrated that in non-infected mice fed a high fat diet, Doxycycline treatment resulted in a reduction of mean lesions from 10.5%+/-.49 to 1.09%+/-0.102 (p<0.05) at 14 weeks and a reduction from 21.5%+/-6.49 to 8.26%+/-0.162 (p=0.106) at 24 weeks. Chow-fed Pg mice treated with Doxyclycline also resulted in a reduction from 0.62%+/-0.128 to 0.0%+/-0.0 (p<0.05) at 14 weeks and a reduction from 0.92%+/-0.23 to 0.0%+/-0.0 (p<0.05) at 24 weeks. Administration of Doxycycline to mice fed a high fat diet and Pg-inoculated resulted in a reduction of mean percentage of atheromatous lesions from 16.46%+/-1.69 to 1.141%+/-0.23 (p<0.05) at 14 weeks and a reduction from 25.27%+/-1.734 to 0.428%+/-0.033 (p<0.05) at 24 weeks. At this timepoint, SAA levels in Pg-infected animals were reduced by five-fold and three-fold in Doxycycline-treated chow and high fat-diet groups, respectively. Cytokine antibody arrays revealed a marked reduction in the levels of pro-inflammatory cytokines in Doxycycline-treated groups whether Pg-infected or fed a high fat diet while anti-inflammatory cytokines were not affected. Consistent with the role of Doxycycline on matrix proteases, at 24 weeks MMP-9 Serum levels were markedly reduced by 60% (p<0.05) and 30% (p<0.05) with Doxycycline treatment in Pg-infected high fat and chow diet groups, respectively., Conclusions: Doxycycline decreases pro-inflammatory cytokines and results in reduction of atherosclerosis in ApoE+/-Pg-inoculated and/or high fat diet fed mice.

Atherosclerosis is a major global cause of morbidity and mortality, and diabetes patients are at increased risk of coronary heart disease development. Advanced glycation of proteins occurs in the body due to raised concentrations of reducing sugars and reactive oxygen species, and is a causal factor behind complications of diabetes. Glycated proteins, through alteration of protein structure and function, and from ligation with their receptors, lead to widespread vascular damage. The alpha-oxoaldehyde, methylglyoxal (MG) is the most reactive glycation precursor, and is increased in the blood of diabetes patients. There is debate about the triggering events leading to atherosclerosis, but the inflammatory action of glycated proteins, including those with MG adducts, through their receptor, RAGE, is a major candidate for initiating plaque formation. In addition glycation may cause cross-links on proteins of the extracellular matrix, stiffening arteries and 'trapping' other macromolecules. MG is also likely to form adducts on many other proteins, enzymes, lipids, DNA or RNA, changing their structure, and may disrupt enzyme activity, hormone regulation and immune function. In the latter context, MG disrupts function of the potent antigen presenting cells, dendritic cells. This effect may be a double edged sword: Poor control of infections may contribute to persistent inflammation, whilst inhibition of immune activation by dendritic cells may inhibit plaque progression. This review aims to present these ideas as a novel slant on the role of the glycation process in atherosclerosis.

Since the discovery of Helicobacter pylori, several studies have investigated the hypothetical role of this bacterium in various extragastric diseases, e.g. ischemic heart disease, idiopathic thrombocytopenic purpura, iron-deficiency anaemia, and other disorders. The majority of these studies are epidemiological or eradication trials, but there are also case reports and in-vitro studies. Idiopathic thromobocytopenic purpura is the disease that shows the strongest link with H. pylori infection. There is also evidence of a role of CagA-positive H. pylori infection in iron-deficiency anaemia and ischemic heart disease. The association between H. pylori infection and other extragastric diseases remains controversial, being mostly supported by 'case reports', small pilot studies, or just in-vitro data. Further studies are needed to identify whether there is any pathological implication for H. pylori infection in these diseases.

Toll-like receptors (TLRs) are a group of pathogen-associated molecular pattern receptors, which play an important role in innate immune signaling in response to microbial infection. It has been demonstrated that TLRs are differentially up regulated in response to microbial infection and chronic inflammatory diseases such as atherosclerosis. Furthermore hyperlipidemic mice deficient in TLR2, TLR4, and MyD88 signaling exhibit diminished inflammatory responses and decreased atherosclerosis. Accumulating evidence has implicated specific infectious agents including the periodontal disease pathogen Porphyromonas gingivalis in the progression of atherosclerosis. Evidence in humans suggesting that periodontal infection predisposes to atherosclerosis is derived from studies demonstrating that the periodontal pathogen P. gingivalis resides in the wall of atherosclerotic vessels and seroepidemiological studies demonstrating an association between pathogen-specific IgG antibodies and atherosclerosis. We have established that the inflammatory signaling pathways that P. gingivalis utilizes is dependent on the cell type and this specificity clearly influences innate immune signaling in the context of local and distant chronic inflammation induced by this pathogen. We have demonstrated that P. gingivalis requires TLR2 to induce oral inflammatory bone lose in mice. Furthermore, we have demonstrated that P. gingivalis infection accelerates atherosclerosis in hyperlipidemic mice with an associated increase in expression of TLR2 and TLR4 in atherosclerotic lesions. Our recent work with P. gingivalis has demonstrated the effectiveness of specific intervention strategies (immunization) in the prevention of pathogen-accelerated atherosclerosis. Improved understanding of the mechanisms driving infection, and chronic inflammation during atherosclerosis may ultimately provide new targets for therapy.

Background: That infections with certain pathogens, by initiating an inflammatory response, may contribute to the development of atherosclerosis is suggested by clinical and experimental evidence., Aim: To analyse atherosclerotic plaques of the carotid artery, samples of apparently healthy greater saphenous veins and circulating leucocytes from the same individual patients for the presence of Helicobacter pylori and Mycoplasma pneumoniae., Methods: Samples from 36 patients undergoing carotid endarterectomy for symptomatic carotid artery stenosis were analysed by polymerase chain reaction for the presence of DNA specific for H. pylori and M. pneumoniae. IgG antibody titres against H. pylori and M pneumoniae and plasma levels of soluble E-selectin, soluble intercellular adhesion molecule-1 and soluble vascular cell adhesion molecule-1 were determined., Results: M. pneumoniae-specific DNA was detected in the atherosclerotic plaques of 13 of 36 (36.1%) patients, in the saphenous veins of 9 of 36 (25%) patients and in the leucocytes of 27 of 36 (75%) patients. No salient association was observed between the presence of M. pneumoniae-specific DNA in leucocytes and atherosclerotic plaques or veins. A marked correlation between the presence of M. pneumoniae in the respective specimens and the studied inflammatory markers or the presence of anti-M. pneumoniae antibodies was not observed. H. pylori-specific DNA could not be detected in the specimens tested., Conclusions: The absence of H. pylori and the random distribution of M. pneumoniae in tissue samples obtained from patients with symptomatic carotid artery stenosis do not support a role for these pathogens in the development of atherosclerosis due to a direct interaction of the bacteria with the vasculature.

The high incidence of cardiovascular diseases resulting from atherosclerosis, especially in individuals lacking classic risk factors, has spawned interest in the possibility of unrecognized risk factors, such as chronic bacterial infection. Longstanding low-grade infections, such as periodontal disease, have the potential to affect distant sites in the body by inducing host cells to release inflammatory mediators into the bloodstream. Inflammatory mediators are released by macrophages upon interaction with activated T-helper cells or upon direct recognition of bacterial antigens, and by nonimmune cells upon recognition of antigen through Toll-like receptors. One key mediator, interleukin-1 (IL-1) is released in response to bacterial infection and is known to have specific proatherogenic properties. Increased levels of IL-1 enhance vascular adhesion, vascular permeability, macrophage activation, endothelial and smooth muscle cell proliferation, and protease-induced plaque rupture - all key steps in the progression of atherogenesis. In a recent study, we demonstrated a profound reduction in the progression of atherosclerosis in IL-1 knockout mice. IL-1 holds potential as a target for future antiatherosclerotic therapies, although given its ubiquity in the body, this would not come without unwanted side effects, such as immunosuppression., (Copyright 2006 Prous Science. All rights reserved.)

The involvement of oral bacteria in the pathogenesis of cardiovascular diseases has been the focus of attention in many studies, and several periodontal pathogens have been detected in diseased cardiovascular lesions, suggesting relationships between oral microorganisms and cardiovascular diseases. However, no information is available regarding the involvement of cariogenic pathogens such as Streptococcus mutans. The presence of oral streptococcal species and periodontitis-related bacteria in 35 heart valve and 27 atheromatous plaque clinical specimens, as well as 32 dental plaque specimens from the same subjects, was analyzed using a PCR method. Furthermore, broad-range PCR with DNA sequencing analysis was employed to identify the bacterial species in those samples. Streptococcus mutans was frequently detected in the heart valve (69%) and atheromatous plaque (74%) specimens, while other bacterial species, including those related to periodontitis, were detected with much lower frequencies. The bacterial composition in cardiovascular tissues was found to be markedly distinct from that in dental plaque, with only a limited number of species, including S. mutans, in the cardiovascular regions shown to have possibly originated from the oral cavity. Semiquantitative assay results revealed that S. mutans was detected in significant quantities in the heart valve (40%) and atheromatous plaque (48%) specimens, whereas the quantities of all other tested bacterial species, including several related to periodontitis, were negligible in the cardiovascular samples. These results indicate that S. mutans is a possible causative agent of cardiovascular disease.

A polymerase chain reaction (PCR) method for the detection of the glmM gene, selected as Helicobacter pylori target sequence, was improved. While performing pathogenicity island cagA gene detection to discriminate pathogenic strains in atherosclerotic carotid samples, several cagA-positive but glmM-negative samples were found. Polymorphisms present in the region amplified in the nested PCR reaction could explain this result; primers were therefore designed to perform a seminested reaction; this modification optimized sensitivity while maintaining specificity. A real-time PCR for Helicobacter DNA detection was also setup. The combination of all 4 PCR reactions detected 83% of H. pylori DNA-positive samples in atherosclerotic carotid tissue, 64% of which were cagA gene positive.

Atherosclerosis is guided by chronicle inflammation process. In the last decades of the 20th century, studies considering infection another possible risk factor of atherosclerosis development were written. Helicobacter pylori, Porphyromas gingivalis, some viruses but most frequently Chlamydia pneumonie are infection agens mentioned in these studies. Some of them emphasize also combined infections caused by more pathogenic factors having influence on vascular inflammation. Serological, epidemiological, histological and imunological studies show the pathogenic influence of acute or chronic infections. Many studies selected makrolid antibiotics as treatment in patients with ischaemic heart disease. However, existing experience with antibiotics did not bring clear results. These studies have mentioned the fact antibiotics have not been indicated as treatment in patients with acute or chronic vascular system infliction by atherosclerosis. Since the experimental and clinical research of influence of inflammations on the development of atherosclerosis moved forward a lot, no exact evidence of this complicated pathogenic mechanism was given. It will obviously take some time to confirm whether the relation between infections and artherosclerosis is causal, i.e. initiating the pathogenic process, accelerating it or keeping it alive.

Advanced complicated atherosclerotic lesions have been related to many factors, including inflammation, infectious agents, and growth factors. Mycoplasma pneumoniae (MP) and Chlamydia pneumoniae (CP), inflammation, and growth factors have been associated with severe atherosclerotic lesions in necropsy material in recent work at our lab. The present study intends to clarify the pathogenesis of atherosclerosis, analyzing which of these elements (macrophages, MP, CP, lymphocytes, and growth factors) are associated with initial development of atherosclerotic lesions, discriminating elements related to stabilization of the plaque versus those related to subendothelial active accumulation of macrophages in living patients. Surgical ascending aorta fragments presenting mild atherosclerotic lesions from 30 coronary atherosclerotic patients were immunohistochemically quantified regarding CP, MP, T cells (CD4, CD8), B cells (CD20), macrophages (CD68), and growth factors [platelet-derived growth factor A (PDGF-A), PDGF-B, transforming growth factor-beta (TGF-beta), granulocyte-macrophage colony-stimulating factor (GM-CSF)]. Cases were grouped according to the presence or not of active accumulation of macrophages at the subendothelium that indicates atheroma in development: group I (GI) fragments with <4 CD68+ cells/x400 field, in normal distribution (mean 1.8 +/- 1) representing stable atherosclerotic mild lesion, and GII fragments presenting >or=4 CD68+ cells/x400 field, in a non-normal distribution, mean (8.9 +/- 4.8, atheromas in progress), which was followed by increased number of lymphocytes. The median number in GI was significantly lower than that in GII: CD4 T (2.5 vs. 7.7), CD8 T (1.0 vs. 5.5), and CD20 B (1.5 vs. 5.5) cells/x400 field, p < 0.001. Percentage area positive for CP antigens was significantly lower in GI than in GII: 1.0 vs. 9.2, p < 0.001. There was a higher percentage area occupied by MP than CP in both GI and GII (7.8 vs. 13.8). There was no difference regarding mean number of growth factor-positive cells/x400 field: PDGF-A, 1.4 vs. 3.9; PDGF-B, 3.4 vs. 5.7; TGF-beta, 0.9 vs. 2.2; and GM-CSF, 2.0 vs. 2.2. Considering all cases, a positive correlation was seen between inflammatory cells and CP+ cells (r > 0.5 and p < 0.01). Growth factors did not correlate with inflammatory cells, CP, or MP and were usually seen in smooth muscle cell and fibrotic areas. Study of initial atherosclerotic lesions showed that MP is present in both kinds of lesion: stable and active subendothelial accumulation of macrophages. Stabilization was related to proportional increase of both infectious agents, which were also related to increased amount of PDGF-A and PDGF-B. Active macrophage accumulation lesions were related to higher elevation in CP concentration at subendothelial regions, in association with B cells, but not of MP and growth factors. MP and CP, inflammation, and growth factors, which were already described in severe atherosclerotic lesions in necropsy material, are also present in mild lesions in living patients, strongly favoring a pathogenetic role for these bacteria in the pathogenesis of atherosclerosis. Predominance of CP in relation to MP may favor progression of the plaque, which is associated with increased B-cell proliferation. PDGF-A and PDGF-B are associated with plaque stability, at least in arterial segments not prone for development of complicated lesions.

Background: Inflammation is a significant component of atherosclerosis lesions. Bacteria, including periodontopathogens, have been demonstrated in atherosclerotic plaques and cross-reactivity of the immune response to bacterial GroEL with human heat shock protein 60 has been suggested as a link between infections and atherosclerosis., Methods: In this study, the nature of the inflammatory infiltrate and the presence of human heat shock protein 60 and GroEL were examined in 31 carotid endarterectomy specimens. Additionally, monoclonal antibodies were used to detect the presence of six bacteria, including those implicated in periodontal disease., Results: The inflammatory cell infiltrate of the lesions was dominated by CD14(+) macrophages and CD4(+) T cells. Most cells of the infiltrate as well as the endothelium were HLA-DR(+), indicating activation; however, there was an absence of CD25 expression, demonstrating that the activated T cells were not proliferating. Few CD1a(+) and CD83(+) cells were noted. Human heat shock protein 60 expression was evident on endothelial cells and cells with the appearance of smooth muscle cells and lymphocytes. GroEL and bacteria were detected within intimal cells. Chlamydia pneumoniae, Porphyromonas gingivalis, Fusobacterium nucleatum, Tannerella forsythia, Prevotella intermedia, and Actinobacillus actinomycetemcomitans were found in 21%, 52%, 34%, 34%, 41%, and 17% of arteries, respectively., Conclusion: These results give evidence for a specific immune response associated with atherosclerosis. Whether bacteria initiate the observed inflammation in atherosclerotic lesions is not clear; however, the present study shows that maintenance of inflammation may be enhanced by the presence of periodontopathic bacteria.

The role of periodontal infections as a putative risk factor for atherosclerotic vascular disease (ASVD) has been reported in the literature over the past decade. This review provides insights into biologically plausible pathways that can potentially mediate such an association, and discusses recent findings from epidemiological studies and intervention trials. Accumulating epidemiological evidence suggests that clinical, microbiological and serological markers of periodontal infection are associated with subclinical and manifest ASVD. Early evidence from intervention studies suggests that the control of periodontal infections may result in improved levels of markers of systemic inflammation and measures of endothelial dysfunction. The extent to which the control of periodontal infections results in lower incidence of ASVD events is logistically difficult to assess and has not been addressed in any study so far.