Infection and coronary atherosclerosis: the role Chlamydia pneumonia]

The role of inflammatory reactions in the pathogenesis of atherosclerosis is widely accepted. Recently, an increasing body of evidence has linked infections to atherosclerosis. It is hypothesized that infections could interact with other risk factors of vascular disease, enhancing the endothelial damage and the production of atherosclerotic plaques. Several different infectious agents have been related to the atherosclerosis genesis: mainly herpesvirus, Helicobacter pylori and Chlamydia pneumoniae. Several lines of evidence strongly link C. pneumoniae to atherosclerosis. Consequently, several studies evaluating the effectiveness of antibiotic treatment in the reduction of cardiac ischemic events in patients with C. pneumoniae seropositivity have been performed. These studies support a causative role for C. pneumoniae. This article reviews the recent evidence linking infections to atherosclerosis, with emphasis on the role of C. pneumoniae on the atherosclerotic plaque.     

Interactive role of infection, inflammation and traditional risk factors in atherosclerosis and coronary artery disease

Although first suggested at the turn of the 20th century, there is a renewed interest in the infectious theory of atherosclerosis. Studies done in many laboratories around the world over the past several years have shown an association between markers of inflammation and coronary atherosclerosis with an exacerbation of the inflammatory process during acute myocardial ischemia, particularly in the early stages of reperfusion. It is also being recognized that the traditional risk factors, such as smoking, dyslipidemia, hypertension and diabetes mellitus, do not explain the presence of coronary atherosclerosis in a large proportion of patients. We believe that in certain genetically susceptible people, infection with very common organisms, such as Chlamydia pneumoniae or cytomegalovirus, may lead to a localized infection and a chronic inflammatory reaction. Persistence of infection may relate to the degree of inflammation and severity of atherosclerosis. Early trials with appropriate antibiotic agents in some patients with a recent history of acute myocardial infarction have led to very salutary results. If patients with an infectious basis of atherosclerosis can be identified, a therapy directed at eradication of the offending organism may be appropriate.     

Isolation of Chlamydia pneumoniae from the coronary artery of a patient with coronary atherosclerosis. The Chlamydia pneumoniae/Atherosclerosis Study Group

BACKGROUND: Atherosclerosis is pathologically similar to a chronic inflammatory response. Recent reports have suggested that Chlamydia pneumoniae may play a role in the pathogenesis of atherosclerosis. OBJECTIVE: To determine, by using various detection methods, whether C. pneumoniae is present in the coronary arteries of patients with coronary atherosclerosis. DESIGN: Multicenter investigation. SETTING: The Jewish Hospital Heart and Lung Institute in Louisville, Kentucky, and several laboratories. PATIENTS: 12 patients seeking heart transplantation. MEASUREMENTS: Culture for C. pneumoniae was done in HEp-2 cell monolayers. Other methods of detection included polymerase chain reaction (PCR) assay, immunocytochemistry, transmission electron microscopy, and in situ hybridization. RESULTS: Chlamydia pneumoniae was cultured from atherosclerotic plaques in one patient with severe coronary artery disease. The organism was found in the atheromas of this patient by PCR assay, immunocytochemistry, electron microscopy, and in situ hybridization. In addition, at least one testing method showed C. pneumoniae in coronary artery tissue in six of nine additional patients with coronary atherosclerosis. CONCLUSIONS: This study provides direct evidence of the presence of viable C. pneumoniae in atheromatous lesions. A chronic inflammatory response caused by a persistent infection of the coronary arteries may explain the link between C. pneumoniae and atherosclerosis.     

Vulnerable plaque: pathobiology and clinical implications

PURPOSE: To review the pathobiology and clinical implications of vulnerable coronary atherosclerotic plaques and to discuss the identification of vulnerable plaques and mechanisms of plaque stabilization. DATA SOURCES: English-language articles in the MEDLINE database that were published from 1966 to the present, identified by using the terms atherosclerotic plaque, myocardial revascularization, and plaque stabilization. Selected references cited in identified articles were reviewed. STUDY SELECTION: Experimental, clinical, and basic research studies related to coronary atherosclerotic plaques. DATA SYNTHESIS: Rupture at the site of a vulnerable atherosclerotic plaque is the most frequent cause of acute coronary syndromes. Typically, such plaque does not cause high-grade stenosis and has a large lipid core and a thin fibrous cap that is often infiltrated by inflammatory cells. Mechanical stresses contribute to plaque vulnerability, and certain triggers may cause plaque disruption directly. The most important consequence of plaque rupture is thrombosis. No method reliably identifies plaques prone to rupture. The reduction of coronary events by lipid-lowering agents despite only modest luminal changes suggests that these agents have a plaque-stabilizing effect. Surgical or percutaneous revascularization does not address the basic biology of coronary atherosclerosis and therefore may have little effect on plaque vulnerability. CONCLUSIONS: Improved understanding of the biology of atheromatous plaques has led to the concept of plaque vulnerability. Identification and stabilization of vulnerable plaques are important new directions in the treatment of coronary atherosclerosis. The relative benefits of aggressive medical therapy aimed at plaque stabilization should be compared with those of revascularization in the management of chronic coronary artery disease.     

Confirmed previous infection with Chlamydia pneumoniae (TWAR) and its presence in early coronary atherosclerosis

BACKGROUND: Chlamydia pneumoniae has been identified in coronary atheroma, but concomitant serum antibody titers have been inconsistently positive and unavailable before the detection of early or advanced atherosclerotic lesions. METHODS AND RESULTS: This retrospective investigation was performed on premortem serum specimens and autopsy tissue from 60 indigenous Alaska Natives at low risk for coronary heart disease, selected by the potential availability of their stored specimens. Serum specimens were drawn a mean of 8.8 years (range, 0.7 to 26.2 years) before death, which occurred at a mean age of 34.1 years (range, 15 to 57 years), primarily from noncardiovascular causes (97%). Coronary artery tissues were independently examined histologically and, for C pneumoniae organism and DNA, by immunocytochemistry (ICC) and polymerase chain reaction (PCR) with species-specific monoclonal antibody and primers. Microimmunofluorescence detected species-specific IgG, IgA, and IgM antibody in stored serum. C pneumoniae, frequently within macrophage foam cells, was identified in coronary fibrolipid atheroma (raised lesions, Stary types II through V) in 15 subjects (25%) and early flat lesions in 7 (11%) either by PCR (14, 23%) or ICC (20, 33%). The OR for C pneumoniae in raised atheroma after a level of IgG antibody > or =1:256 >8 years earlier was 6.1 (95% CI, 1.1 to 36.6) and for all coronary tissues after adjustment for multiple potential confounding variables, including tobacco exposure, was 9.4 (95% CI, 2.6 to 33.8). CONCLUSIONS: Serological evidence for C pneumoniae infection frequently precedes both the earliest and more advanced lesions of coronary atherosclerosis that harbor this intracellular pathogen, suggesting a chronic infection and developmental role in coronary heart disease.     

The past, present and future of arterial infection

Today, the pathology of large and medium-sized arteries is in most part considered as degenerative or inflammatory. The role of infection has been preponderant (syphilis) but has become quite modest now, restricted to infectious aneurysms. According to certain observations, infections may participate in initiating arterial inflammation, whether it be specific (Kawasaki's disease, Takayasu's arteritis, coronary artery disease of cardiac grafts) or less so ("plain" atherosclerosis). Suspected microbes (herpes viruses, Chlamydia pneumoniae, etc.) would damage the arterial wall either directly by infecting it, or indirectly by provoking an autoimmune reaction against some of its components (e.g. heat shock proteins). These hypotheses are worth serious consideration because, if established as correct, they would modify radically our etiologic, therapeutic and prophylactic conceptions of arterial diseases, including of course the main one, atherosclerosis.     

Cytomegalovirus prophylaxis and treatment following bone marrow transplantation

OBJECTIVE: To provide an overview of the role of cytomegalovirus (CMV) in the bone marrow transplant (BMT) population and update the current methods of prevention and treatment of CMV infection and disease, with emphasis on CMV interstitial pneumonia (CMV-IP). DATA SOURCES: The current medical literature, including abstracts presented at recent national and international meetings, is reviewed. References were identified by searching the MEDLINE database from January 1988 through June 1994. The reference lists of the published studies and reviews obtained from the initial literature search were reviewed as well. STUDY SELECTION: Data regarding the epidemiology of CMV, the risk factor associated with CMV infection and disease, as well as data on the prevention and the treatment of CMV infection and disease in the BMT population are cited. Specific attention was focused on randomized, placebo-controlled studies pertaining to the prevention of CMV infection and disease in CMV-immunoglobulin G positive recipients undergoing allogeneic BMT. Information from nonrandomized, placebo-controlled studies was included in the absence of stronger data. DATA EXTRACTION: Information contributing to CMV in the BMT population was reviewed. Data supporting and disputing specific preventive and treatment modalities are presented. DATA SYNTHESIS: The incidence of CMV seropositivity in the general population is high and while BMT becomes a widely accepted treatment modality, CMV reactivation and subsequent disease, especially CMV-IP, becomes a significant prognostic factor of morbidity and mortality. Even though antiviral agents such as ganciclovir and foscarnet can inhibit the viral replication in vivo, they have not been able to treat CMV-IP effectively. It has been suggested that CMV-IP is an immunopathologic process that can cause irreversible damage, hence, the low efficacy of antiviral therapy and the associated high mortality. Immunomodulating agents such as intravenous immune globulin and cytomegalovirus hyperimmune globulin can increase the efficacy of antivirals in the treatment of CMV-IP. This further supports the postulated immunopathologic process of this disease. The lack of understanding of the pathophysiology of the disease compromised the efforts of treatment and led to the development of preventive interventions with antiviral and immunomodulatory regimens that resulted in a significantly lower incidence of infection and disease. As a result of current data, the Eastern Cooperative Oncology Group has published guidelines for the prevention and treatment of CMV infection and disease. CONCLUSIONS: The prognosis of CMV disease in the BMT recipients has improved as a result of a wide variety of modifications in the management of BMT recipients. These include an increased understanding of the risk factors associated with CMV infection, routine screening for CMV replication and excretion, and more effective prophylactic regimens. Still, more than half of the patients who develop pneumonia will die, indicating that more studies are needed to increase the understanding of the pathophysiology and refine the preventive and therapeutic regimens against CMV.     

The differential effects of prostaglandin E1 and nitroglycerin on regional cerebral oxygenation in anesthetized patients

OBJECTIVES: We sought to study the possible presence of Chlamydia pneumoniae in aortic valve stenosis (AVS). BACKGROUND: Inflammation and immune mechanisms are considered important for the pathogenesis of nonrheumatic AVS. All chlamydial species are able to cause heart infections, and seroepidemiologic studies have indicated an association between chronic C. pneumoniae infection and coronary artery disease. Furthermore, the organism has been demonstrated in atherosclerotic lesions. METHODS: Aortic valve specimens with varying degrees of macroscopic disease were obtained from 35 subjects--17 consecutive patients undergoing aortic valve replacement for treatment of nonrheumatic AVS and 18 age-matched subjects at autopsy. The possible presence of C. pneumoniae in aortic valves was studied by immunohistochemical analysis, polymerase chain reaction or transmission electron microscopy, or a combination of these. RESULTS: Positive immunohistochemical staining with C. pneumoniae specific antibody was found in 9 (53%) of 17 patients with advanced aortic valve disease requiring surgical treatment (group A), 8 (80%) of 10 cadavers with clearly macroscopic aortic valve pathology (group B) and 1 (12%) of 8 grossly normal cadaver control subjects (group C). Statistical significance with regard to the presence of C. pneumoniae was found when combined diseased subjects (groups A and B: total 17 of 27 subjects) were compared with group C (p = 0.018). However, when group A was compared with group C, there was only marginal statistical significance (p = 0.088). Finally, there was a strong statistical significance (p = 0.015) when groups B and C were compared. Chlamydia pneumoniae DNA was also found in three stenotic valves, and in two of the three tested valve specimens chlamydia-like particles were seen by electron microscopy. CONCLUSIONS: Chlamydia pneumoniae is frequently present in nonrheumatic AVS. Similarly, the high number of C. pneumoniae infections detected in the early lesions of "degenerative" AVS suggest that this pathogen may play an etiologic role in the development of this disease. The validity of this relation requires additional study.     

Is infection with Chlamydia pneumoniae a causative agent in atherosclerosis?

There is mounting evidence to suggest that Chlamydia pneumoniae might play a role in atherosclerosis. Serological studies and detection of the microorganism in atheromatous lesions were the first indications of an association between C. pneumoniae and the disease. Studies suggest that anti-chlamydial chemotherapy has a favorable effect on cardiovascular disease in humans. Moreover, infection of animals with C. pneumoniae induces inflammatory changes in the aorta that are suggestive of atherosclerosis and accelerates the progression of existing atherosclerotic lesions. If the pathogenic role of C. pneumoniae in atherosclerosis is defined more conclusively by future studies, the development of preventive or therapeutic measures against infection might provide an effective strategy to reduce the risk of atherosclerosis.     

Infectious causes of chronic inflammatory diseases and cancer

Powerful diagnostic technology, plus the realization that organisms of otherwise unimpressive virulence can produce slowly progressive chronic disease with a wide spectrum of clinical manifestations and disease outcomes, has resulted in the discovery of new infectious agents and new concepts of infectious diseases. The demonstration that final outcome of infection is as much determined by the genetic background of the patient as by the genetic makeup of the infecting agent is indicating that a number of chronic diseases of unknown etiology are caused by one or more infectious agents. One well-known example is the discovery that stomach ulcers are due to Helicobacter pylori. Mycoplasmas may cause chronic lung disease in newborns and chronic asthma in adults, and Chlamydia pneumoniae, a recently identified common cause of acute respiratory infection, has been associated with atherosclerosis. A number of infectious agents that cause or contribute to neoplastic diseases in humans have been documented in the past 6 years. The association and causal role of infectious agents in chronic inflammatory diseases and cancer have major implications for public health, treatment, and prevention.     

Laminin-like proteins are differentially regulated during cerebellar development and stimulate granule cell neurite outgrowth in vitro

OBJECTIVE: To review data supporting the hypothesis that syndrome X plays a major role in the pathogenesis of coronary artery disease (CAD), and the effects of lifestyle factors and pharmacologic interventions on insulin, other metabolic parameters, and outcomes. DATA SOURCES: MEDLINE (January 1966-August 1997) and Current Contents database searches identified applicable English-language experimental trials, epidemiologic studies, reviews, and editorials. STUDY SELECTION AND DATA EXTRACTION: Studies that were included addressed the role of insulin resistance and hyperinsulinemia in the pathogenesis of CAD or the effects of lifestyle factors and pharmacologic interventions on metabolic parameters and outcomes. DATA SYNTHESIS: The main characteristics of syndrome X are hyperinsulinemia and insulin resistance. These result in secondary syndrome X features, including hyperglycemia, increased very-low-density lipoprotein concentrations, decreased high-density lipoprotein cholesterol, and hypertension. Insulin resistance is worsened by obesity, and insulin has been shown to contribute to the development of hypertension. Other studies demonstrate that smoking adversely affects glucose and insulin concentrations. Animal studies have linked hyperinsulinemia and atherogenesis. These animal data have been confirmed by several large prospective and population studies that have identified associations between hyperinsulinemia and CAD. CONCLUSIONS: Strong evidence links insulin resistance and hyperinsulinemia to CAD. Lifestyle modifications play an important role in decreasing cardiovascular risk, and clinicians should strongly encourage such changes. Clinicians must also carefully consider the effects of antihypertensive, antihyperglycemic, and antidyslipidemic agents on patients' metabolic profiles when choosing appropriate therapeutic regimens. However, outcome data on many potentially beneficial agents, including calcium antagonists, alpha 1-adrenergic antagonists, angiotensin-converting enzyme inhibitors, metformin, acarbose, and troglitazone, are not yet available.     

Cytomegalovirus encephalitis

PURPOSE: To review the pathologic and clinical features of and establish the frequency of cytomegalovirus encephalitis in adults and to review the methods available for diagnosis and treatment. DATA SOURCE: MEDLINE search of all English-language articles from January 1965 to August 1995. STUDY SELECTION: Articles dealing with cytomegalovirus infection of the brain in adults. We also reviewed all unselected autopsies of these populations to establish the frequency of cytomegalovirus encephalitis in recipients of organ transplants and in patients infected with the human immunodeficiency virus (HIV). DATA EXTRACTION: Epidemiologic and pathologic characteristics, clinical manifestations, diagnostic methods, pathogenetic mechanisms, and use of anticytomegalovirus treatments. DATA SYNTHESIS: Of 676 patients receiving a diagnosis of cytomegalovirus encephalitis, 574 (85%) were infected with HIV, 81 (12%) had other causes of immunosuppression, and 21 (3%) were otherwise healthy. Cytomegalovirus encephalitis was confirmed during autopsy in 12% of HIV-infected patients and 2% of transplant recipients. The most common lesion was microglial nodule encephalitis, but the clinical findings corresponding to this pathologic entity are not well defined. In contrast, the pathologic entity of cytomegalovirus ventriculoencephalitis, found almost exclusively in patients with advanced HIV infection, has distinct clinical features that allow recognition even in patients with HIV encephalopathy. Polymerase chain reaction has been shown to be useful for diagnosis of cytomegalovirus encephalitis. CONCLUSIONS: Cytomegalovirus encephalitis is an important opportunistic infection in HIV-infected patients but is rarely recognized in other groups. Cytomegalovirus ventriculoencephalitis has emerged as a unique entity in patients with advanced HIV infection. Recent developments in diagnostic techniques allow early recognition and may make more aggressive approaches to therapy possible.     

Prevalence of Helicobacter pylori infection in children from urban and rural West Virginia

BACKGROUND AND PURPOSE: Chlamydia pneumoniae infection has recently become noteworthy in relation to atherosclerosis. We investigated by immunohistochemistry the distribution of C pneumoniae infection in the atherosclerotic carotid artery. METHODS: Twenty carotid atherosclerotic lesions that were resected during carotid endarterectomy were investigated. Parallel sections were stained immunohistochemically with monoclonal antibodies for a C pneumoniae-specific antigen, macrophages, and smooth muscle cells. RESULTS: Immunoreactivity for the C pneumoniae-specific antigen was observed in 11 of 20 specimens (55%), and intense immunoreactivity was observed in 7 of 20 (35%). C pneumoniae infection was observed in endothelial cells, macrophages and in smooth muscle cells that had migrated into the atheromatous plaque, as well as in smooth muscle cells and small arteries in the media underlying the atheromatous plaques. C pneumoniae infection was most prominently observed in smooth muscle cells. The severity of the infection as demonstrated by immunohistochemistry was not significantly related to general risk factors for atherosclerosis. CONCLUSIONS: C pneumoniae widely infects endothelial cells, macrophages, and smooth muscle cells in the atherosclerotic carotid artery. The results of the present study can help us to understand how C pneumoniae infection contributes to the progression of carotid atherosclerosis.     

Serological response to Chlamydia pneumoniae in adults with coronary arterial fatty streaks and fibrolipid plaques

The antigen-specific serological response to Chlamydia pneumoniae was studied in 45 adults with coronary artery atherosclerosis and compared with that in 40 adults with acute respiratory infection. C. pneumoniae antigen and DNA were detected in lesions more frequently in patients with low immunoglobulin G titers against C. pneumoniae than in those with high immunoglobulin G titers. Reactivities with the 42-kDa (46%) and 52-kDa (31%) proteins were observed more frequently in sera from seropositive individuals with atherosclerosis than in sera from patients with acute respiratory infection. Antibodies against the C. pneumoniae-specific 42- and/or 52-kDa protein may be a marker for chronic C. pneumoniae infection.     

Association of chronic infection of Chlamydia pneumoniae and coronary heart disease in the Japanese

The association of Chlamydia pneumoniae with atherosclerosis of coronary and carotid arteries and the aorta has been demonstrated by seroepidemiology and by detection of the organism in atheromata. We investigated the frequency of C. pneumoniae seropositivity in patients with acute myocardial infarction (AMI). C. pneumoniae-specific antibodies were measured by the microimmunofluorescence test in 160 AMI patients and 160 control subjects matched for age and gender. The odds ratios (ORs) were 2.2 (95% confidence interval (CI), 1.2 to 3.9) for immunoglobulin (Ig)G and 2.7 (95% CI, 1.7 to 4.3) for IgA. After adjustment for other cardiovascular risk factors of age, gender, hypertension, diabetes, cigarette smoking and serum cholesterol, the ORs were essentially unchanged. This study confirmed that the observations of an association between antibody against C. pneumoniae and coronary heart disease in Western nations is also present in Japan. Our results are comparable to the previous seroepidemiological studies reporting ORs of 2.0 or greater.     

Specificity of detection of Chlamydia pneumoniae in cardiovascular atheroma: evaluation of the innocent bystander hypothesis

Chlamydia pneumoniae has been detected in atherosclerotic plaque, raising the question of whether this detection is specific to atheromatous tissue. To evaluate this question, we tested cardiovascular and non-cardiovascular tissue samples from 38 autopsy cases by polymerase chain reaction and immunocytochemistry. We also tested 33 granuloma biopsy specimens, as the organism has been detected in macrophages. C. pneumoniae was detected in coronary artery tissue from 13 (34%), lung from 5 (13%), liver from 4 (10%), and spleen from 2 (5%) of the 38 autopsy cases (P < 0.05 for comparison of proportion of positive coronary arteries with that of each of the other types of tissue). Of the 21 cases with at least one positive tissue sample, 11 had only a positive cardiovascular tissue (coronary artery, venous bypass graft, or myocardium), 7 had both cardiovascular and non-cardiovascular positive tissues, and 3 had only a non-cardiovascular positive tissue. C. pneumoniae was thus detected relatively infrequently in non-cardiovascular tissues, and its detection in these tissues was usually in association with its detection in cardiovascular tissue from the same patient. The organism was also infrequently detected in granulomatous tissue (3/33 specimens). These findings demonstrate that C. pneumoniae is more frequently found in atherosclerotic than normal tissue and support the hypothesis that C. pneumoniae has a role in the pathogenesis of atherosclerosis.     

The systemic inflammatory response to cardiopulmonary bypass and the brain

The acquired immune deficiency syndrome (AIDS) is a lethal multisystem disease. Its ocular manifestations have received relatively little attention in the literature. Between 73% and 100% of AIDS patients develop ocular lesions. The commonest lesions seen are retinal--either infectious or noninfectious retinopathy. Involvement of the conjunctiva with Kaposi's sarcoma, infected tears and infected cornea as well as the vitreous are less common. Infections with cytomegalovirus and varicella zoster virus are common causes of visual loss and can be treated with antiviral agents such as ganciclovir and foscarnet. This greatly increases the quality of life in these patients by preventing visual loss.     

Insulin resistance implications for type II diabetes mellitus and coronary heart disease

PURPOSE: To review information on the implications of insulin resistance for type II diabetes mellitus (non-insulin-dependent diabetes mellitus) and coronary heart disease, and to derive guidance from this information for the management of these conditions. DATA SOURCES: A MEDLINE search of English-language articles published between 1985 and July 1996, and review of the bibliographies of articles obtained through the MEDLINE search and textbooks. STUDY SELECTION: Primary research articles, reviews and perspectives on the epidemiology of diabetes and cardiovascular diseases and on intervention outcomes in these diseases. DATA EXTRACTION: Study design and quality were assessed, with particular attention to methods, study population size and other characteristics. Conclusions of review articles and perspectives were analyzed critically. DATA SYNTHESIS: Type II diabetes is associated with a two- to fourfold excess of coronary heart disease, compared to nondiabetic populations. In most studies, glycemia and duration of clinical diabetes were found to be only weak risk factors for coronary heart disease. Conventional coronary heart disease risk factors such as dyslipidemia and hypertension have been associated with coronary heart disease in type II diabetes subjects. Hyperinsulinemia and insulin resistance have been predictive of the development of type II diabetes and, in some studies, of coronary heart disease. CONCLUSION: Strategies to prevent the development of coronary heart disease in diabetic and possibly prediabetic subjects should emphasize a multifactorial approach, including: a) improved glycemic control; b) aggressive treatment of risk factors for coronary heart disease, including insulin resistance; c) primary prevention of NIDDM; and d) use of glucose lowering agents that improve insulin sensitivity and cardiovascular risk factors.