Chlamydia pneumoniae and vascular disease: An update
2006; Elsevier BV; Volume: 43; Issue: 6 Linguagem: Inglês
10.1016/j.jvs.2006.02.050
ISSN1097-6809
AutoresFiras F. Mussa, Hong Chai, Xinwen Wang, Qing Yao, Alan B. Lumsden, Changyi Chen,
Tópico(s)Inflammatory mediators and NSAID effects
ResumoExposure to Chlamydia pneumoniae is extremely common, and its incidence increases with age. C pneumoniae infection is strongly associated with coronary artery disease, as well as with atherosclerosis of the carotid artery, aorta, and peripheral arteries. This association has been shown in seroepidemiologic studies and by direct detection of the organism in atherosclerotic lesions by immunohistochemistry, polymerase chain reaction, electron microscopy, and tissue culture. Animal models of atherosclerosis have been used to study the role of C pneumoniae in the initiation and progression of atherosclerotic disease. The association of this organism with cardiovascular complications has inspired many human trials of antibiotics for the secondary prevention of atherosclerosis. C pneumoniae can infect several types of cells, including circulating macrophages, arterial smooth muscle cells, and vascular endothelial cells, causing the secretion of proinflammatory cytokines and procoagulants by endothelial cells and foam cell formation by infected macrophages. This report reviews the role of C pneumoniae in atherogenesis in light of recent, large antibiotic treatment trials, animal studies, and in vitro studies. The role of Chlamydia heat shock protein as a potential mediator of this harmful effect is also reviewed. Exposure to Chlamydia pneumoniae is extremely common, and its incidence increases with age. C pneumoniae infection is strongly associated with coronary artery disease, as well as with atherosclerosis of the carotid artery, aorta, and peripheral arteries. This association has been shown in seroepidemiologic studies and by direct detection of the organism in atherosclerotic lesions by immunohistochemistry, polymerase chain reaction, electron microscopy, and tissue culture. Animal models of atherosclerosis have been used to study the role of C pneumoniae in the initiation and progression of atherosclerotic disease. The association of this organism with cardiovascular complications has inspired many human trials of antibiotics for the secondary prevention of atherosclerosis. C pneumoniae can infect several types of cells, including circulating macrophages, arterial smooth muscle cells, and vascular endothelial cells, causing the secretion of proinflammatory cytokines and procoagulants by endothelial cells and foam cell formation by infected macrophages. This report reviews the role of C pneumoniae in atherogenesis in light of recent, large antibiotic treatment trials, animal studies, and in vitro studies. The role of Chlamydia heat shock protein as a potential mediator of this harmful effect is also reviewed. The notion that atherosclerosis is linked to a chronic inflammatory state is not new.1Ross R. Atherosclerosis—an inflammatory disease.N Engl J Med. 1999; 340: 115-126Crossref PubMed Scopus (18416) Google Scholar This state may result from chronic infection that can initiate or promote atherogenesis. Recent seroepidemiologic studies suggest that Chlamydia pneumoniae infection predicts the development of vascular disease, just as smoking, hypertension, and elevated low-density lipoprotein (LDL) cholesterol do.2Grayston J.T. Background and current knowledge of Chlamydia pneumoniae and atherosclerosis.J Infect Dis. 2000; 181: S402-S410Crossref PubMed Scopus (262) Google Scholar C pneumoniae is an obligatory intracellular Gram-negative bacterium that was first isolated as a respiratory pathogen two decades ago.3Grayston J.T. Kuo C.C. Wang S.P. Altman J. A new Chlamydia psittaci strain, TWAR, isolated in acute respiratory tract infections.N Engl J Med. 1986; 315: 161-168Crossref PubMed Scopus (547) Google Scholar This organism has also been isolated from the coronary arteries of patients with acute coronary syndrome,4Saikku P. Leinonen M. Mattila K. Ekman M.R. Nieminen M.S. Makela P.H. et al.Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction.Lancet. 1988; 2: 983-986Abstract PubMed Scopus (1394) Google Scholar as well as from carotid arteries,5Sessa R. Di Pietro M. Schiavoni G. Santino I. Benedetti-Valentini F. Perna R. et al.Chlamydia pneumoniae DNA in patients with symptomatic carotid atherosclerotic disease.J Vasc Surg. 2003; 37: 1027-1031Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 6Grayston J.T. Kuo C.C. Coulson A.S. Campbell L.A. Lawrence R.D. Lee M.J. et al.Chlamydia pneumoniae (TWAR) in atherosclerosis of the carotid artery.Circulation. 1995; 92: 3397-3400Crossref PubMed Scopus (312) Google Scholar the aorta,7Kuo C.C. Gown A.M. Benditt E.P. Grayston J.T. Detection of Chlamydia pneumoniae in aortic lesions of atherosclerosis by immunocytochemical stain.Arterioscler Thromb. 1993; 13: 1501-1504Crossref PubMed Scopus (303) Google Scholar and peripheral arteries.8Kuo C.C. Coulson A.S. Campbell L.A. Cappuccio A.L. Lawrence R.D. Wang S.P. et al.Detection of Chlamydia pneumoniae in atherosclerotic plaques in the walls of arteries of lower extremities from patients undergoing bypass operation for arterial obstruction.J Vasc Surg. 1997; 26: 29-31Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar On the cellular level, C pneumoniae antigen may trigger an early signal transduction cascade in target cells, leading to endothelial activation, inflammation, and thrombosis. Reviews of the role of C pneumoniae in cardiovascular disease have focused on the organism's pathogenic mechanisms and on methods of testing for C pneumoniae infection. For vascular surgeons, C pneumoniae is not well characterized as a risk factor for atherosclerosis outside of the coronary circulation. The purpose of this report is to examine the role of C pneumoniae in vascular disease by reviewing human and animal laboratory studies, clinical trials, and in vitro studies of the interactions between C pneumoniae and key inflammatory cells. The presence of C pneumoniae in atheroma has been detected by serology by using specific antibodies against C pneumoniae, including immunoglobulin (Ig) G, IgM, and IgA,9Grayston J.T. Campbell L.A. Kuo C.C. Mordhorst C.H. Saikku P. Thom D.H. et al.A new respiratory tract pathogenChlamydia pneumoniae strain TWAR.J Infect Dis. 1990; 161: 618-625Crossref PubMed Scopus (661) Google Scholar, 10Saikku P. Leinonen M. Tenkanen L. Linnanmaki E. Ekman M.R. Manninen V. et al.Chronic Chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart Study.Ann Intern Med. 1992; 116: 273-278Crossref PubMed Scopus (734) Google Scholar and confirmed by immunohistochemistry,7Kuo C.C. Gown A.M. Benditt E.P. Grayston J.T. Detection of Chlamydia pneumoniae in aortic lesions of atherosclerosis by immunocytochemical stain.Arterioscler Thromb. 1993; 13: 1501-1504Crossref PubMed Scopus (303) Google Scholar, 11Kuo C.C. Grayston J.T. Campbell L.A. et al.Chlamydia pneumoniae (TWAR) in coronary arteries of young adults (15-34 years old).Proc Natl Acad Sci U S A. 1995; 92: 6911-6914Crossref PubMed Scopus (361) Google Scholar polymerase chain reaction (PCR),6Grayston J.T. Kuo C.C. Coulson A.S. Campbell L.A. Lawrence R.D. Lee M.J. et al.Chlamydia pneumoniae (TWAR) in atherosclerosis of the carotid artery.Circulation. 1995; 92: 3397-3400Crossref PubMed Scopus (312) Google Scholar, 7Kuo C.C. Gown A.M. Benditt E.P. Grayston J.T. Detection of Chlamydia pneumoniae in aortic lesions of atherosclerosis by immunocytochemical stain.Arterioscler Thromb. 1993; 13: 1501-1504Crossref PubMed Scopus (303) Google Scholar, 11Kuo C.C. Grayston J.T. Campbell L.A. et al.Chlamydia pneumoniae (TWAR) in coronary arteries of young adults (15-34 years old).Proc Natl Acad Sci U S A. 1995; 92: 6911-6914Crossref PubMed Scopus (361) Google Scholar, 12Kuo C.C. Shor A. Campbell L.A. Goo Y.A. Wissler R.W. Benditt E.P. et al.Demonstration of Chlamydia pneumoniae in atherosclerotic lesions of coronary arteries.J Infect Dis. 1993; 167: 841-849Crossref PubMed Scopus (670) Google Scholar Southern hybridization, in situ hybridization, electron microscopy, and electron-microscopic immunohistochemistry.13Shi Y. Tokunaga O. Chlamydia pneumoniae and multiple infections in the aorta contribute to atherosclerosis.Pathol Int. 2002; 52: 755-763Crossref PubMed Scopus (28) Google Scholar In addition, viable organisms have been found in the atherosclerotic lesion in the patient with coronary artery disease.14Ramirez J.A. Isolation of Chlamydia pneumoniae from the coronary artery of a patient with coronary atherosclerosis. The Chlamydia pneumoniae/Atherosclerosis Study Group.Ann Intern Med. 1996; 125: 979-982Crossref PubMed Scopus (444) Google Scholar In general, the prevalence of C pneumoniae infection increases with age; positive antibody titers are found in 80% of men and 70% of women aged ≥65 years compared with 50% in age 20.2Grayston J.T. Background and current knowledge of Chlamydia pneumoniae and atherosclerosis.J Infect Dis. 2000; 181: S402-S410Crossref PubMed Scopus (262) Google Scholar This age-related difference in prevalence, combined with the lack of standardized methods to document this age relationship, have caused various studies to produce conflicting findings about the association of circulating C pneumoniae DNA and antibody titers with C pneumoniae infections in atherosclerotic patients. Another possible explanation for the lack of coherence among study findings is that C pneumoniae in atheromas exists in a noncultivatable, persistent form that makes isolating viable organisms more difficult.15Beatty W.L. Morrison R.P. Byrne G.I. Persistent chlamydiae from cell culture to a paradigm for Chlamydial pathogenesis.Microbiol Rev. 1994; 58: 686-699Crossref PubMed Google Scholar Saikku et al4Saikku P. Leinonen M. Mattila K. Ekman M.R. Nieminen M.S. Makela P.H. et al.Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction.Lancet. 1988; 2: 983-986Abstract PubMed Scopus (1394) Google Scholar found that patients with acute myocardial infarction (MI) have higher antibody titers against C pneumoniae than matched normal individuals. The ultrastructural presence of C pneumoniae has also been detected during autopsy in the coronary arterial fatty streaks and intimal smooth muscle cells (SMCs) of deceased patients with coronary atherosclerosis.16Shor A. Kuo C.C. Patton D.L. Detection of Chlamydia pneumoniae in coronary arterial fatty streaks and atheromatous plaques.S Afr Med J. 1992; 82: 158-161PubMed Google Scholar These findings were reproduced by Kuo et al,11Kuo C.C. Grayston J.T. Campbell L.A. et al.Chlamydia pneumoniae (TWAR) in coronary arteries of young adults (15-34 years old).Proc Natl Acad Sci U S A. 1995; 92: 6911-6914Crossref PubMed Scopus (361) Google Scholar who found histologic and PCR-based evidence of C pneumoniae in 86% of atheromas in the coronary arteries of young adults (ie, 15 to 34 years old). In addition, most of these patients with coronary atherosclerosis tested positive for C pneumoniae by PCR, immunocytochemistry, electron microscopy, or in situ hybridization.14Ramirez J.A. Isolation of Chlamydia pneumoniae from the coronary artery of a patient with coronary atherosclerosis. The Chlamydia pneumoniae/Atherosclerosis Study Group.Ann Intern Med. 1996; 125: 979-982Crossref PubMed Scopus (444) Google Scholar In 1996, Muhlestein et al17Muhlestein J.B. Hammond E.H. Carlquist J.F. Radicke E. Thomson M.J. Karagounis L.A. et al.Increased incidence of Chlamydia species within the coronary arteries of patients with symptomatic atherosclerotic versus other forms of cardiovascular disease.J Am Coll Cardiol. 1996; 27: 1555-1561Abstract Full Text PDF PubMed Scopus (382) Google Scholar used immunofluorescence to detect the presence of C pneumoniae in 71 (79%) of 90 specimens of atherosclerotic tissue from symptomatic patients undergoing coronary atherectomy. In contrast, the organism was detected in only one specimen (4%) of nonatherosclerotic coronary tissue. More recently, Arcari et al18Arcari C.M. Gaydos C.A. Nieto F.J. Krauss M. Nelson K.E. et al.Association between Chlamydia pneumoniae and acute myocardial infarction in young men in the United States military the importance of timing of exposure measurement.Clin Infect Dis. 2005; 40: 1123-1130Crossref PubMed Scopus (35) Google Scholar found that high titers to C pneumoniae IgG and IgA were significantly associated with acute MI in a cohort of 30- to 50-year-old men in the United States military and suggested that recent or chronic active infections could be associated with an increased risk of acute MI. The link between C pneumoniae and coronary atherosclerosis is also substantiated by studies in which antibodies against members of the heat shock protein (HSP) family were detected in individuals with persistent C pneumoniae infections.19Mayr M. Metzler B. Kiechl S. Willeit J. Schett G. Xu Q. et al.Endothelial cytotoxicity mediated by serum antibodies to heat shock proteins of Escherichia coli and Chlamydia pneumoniaeimmune reactions to heat shock proteins as a possible link between infection and atherosclerosis.Circulation. 1999; 99: 1560-1566Crossref PubMed Scopus (272) Google Scholar, 20Ciervo A. Visca P. Petrucca A. Biasucci L.M. Maseri A. Cassone A. et al.Antibodies to 60-kilodalton heat shock protein and outer membrane protein 2 of Chlamydia pneumoniae in patients with coronary heart disease.Clin Diagn Lab Immunol. 2002; 9: 66-74PubMed Google Scholar, 21Fong I.W. Chiu B. Viira E. Tucker W. Wood H. Peeling R.W. Chlamydial heat-shock protein-60 antibody and correlation with Chlamydia pneumoniae in atherosclerotic plaques.J Infect Dis. 2002; 186: 1469-1473Crossref PubMed Scopus (28) Google Scholar, 22Huittinen T. Leinonen M. Tenkanen L. Manttari M. Virkkunen H. Pithanen T. Autoimmunity to human heat shock protein 60, Chlamydia pneumoniae infection, and inflammation in predicting coronary risk.Arterioscler Thromb Vasc Biol. 2002; 22: 431-437Crossref PubMed Scopus (92) Google Scholar, 23Mahdi O.S. Horne B.D. Mullen K. Muhlestein J.B. Byrne G.I. Serum immunoglobulin G antibodies to chlamydial heat shock protein 60 but not to human and bacterial homologs are associated with coronary artery disease.Circulation. 2002; 106: 1659-1663Crossref PubMed Scopus (46) Google Scholar, 24Biasucci L.M. Liuzzo G. Ciervo A. Pertucca A. Piro M. Angiolillo D.J. et al.Antibody response to chlamydial heat shock protein 60 is strongly associated with acute coronary syndromes.Circulation. 2003; 107: 3015-3017Crossref PubMed Scopus (64) Google Scholar Elevated levels of these Chlamydia heat shock proteins (cHSPs) produce a local inflammatory state. This persistent intracellular infection may explain how C pneumoniae can resist antibiotic treatment, and it may be the mechanism linking atherogenesis with chronic latent infections.15Beatty W.L. Morrison R.P. Byrne G.I. Persistent chlamydiae from cell culture to a paradigm for Chlamydial pathogenesis.Microbiol Rev. 1994; 58: 686-699Crossref PubMed Google Scholar The detection of C pneumoniae by using immunocytochemistry and PCR in atheromatous plaque tissue removed during carotid endarterectomy6Grayston J.T. Kuo C.C. Coulson A.S. Campbell L.A. Lawrence R.D. Lee M.J. et al.Chlamydia pneumoniae (TWAR) in atherosclerosis of the carotid artery.Circulation. 1995; 92: 3397-3400Crossref PubMed Scopus (312) Google Scholar inspired many more studies of the possible association between C pneumoniae infection and carotid atherosclerosis. In one such study, viable C pneumoniae bacteria were detected in 18 (38%) of 48 samples of carotid plaque after endarterectomy. The presence of the organism was associated with elevated levels of the acute phase protein and proinflammatory markers such as C-reactive protein.25Johnston S.C. Messina L.M. Browner W.S. Lawton M.T. Morris C. Dean C. C-reactive protein levels and viable Chlamydia pneumoniae in carotid artery atherosclerosis.Stroke. 2001; 32: 2748-2752Crossref PubMed Scopus (62) Google Scholar In another study, Sessa et al5Sessa R. Di Pietro M. Schiavoni G. Santino I. Benedetti-Valentini F. Perna R. et al.Chlamydia pneumoniae DNA in patients with symptomatic carotid atherosclerotic disease.J Vasc Surg. 2003; 37: 1027-1031Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar found serologic evidence supporting the association between C pneumoniae DNA in peripheral blood mononuclear cells and symptomatic carotid atherosclerotic disease. The organism was detected in 72.2% of patients with symptomatic carotid atherosclerotic disease but only in 30.3% of patients with asymptomatic disease. The authors suggested using C pneumoniae DNA in peripheral blood mononuclear cells as a surrogate marker of risk for endovascular Chlamydia infection. The association between atherogenic risk and seropositivity to C pneumoniae, Helicobacter pylori, and cytomegalovirus was further verified in a prospective, population-based study by Mayr et al.26Mayr M. Kiechl S. Willeit J. Wick G. Xu Q. Infections, immunity, and atherosclerosis associations of antibodies to Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus with immune reactions to heat-shock protein 60 and carotid or femoral atherosclerosis.Circulation. 2000; 102: 833-839Crossref PubMed Scopus (266) Google Scholar They found that the prevalence and severity of atherosclerosis in carotid and femoral arteries was significantly associated with the presence of IgA antibodies to C pneumoniae, regardless of whether the patient had other risk factors. However, the presence of C pneumoniae alone did not appear sufficient to explain the occurrence of cerebrovascular symptoms. Correlations between the presence of IgG antibodies against H pylori and vascular disease were limited. Also, antibody titers against cytomegalovirus do not appear to be markers for atherosclerosis in this population.27LaBiche R. Koziol D. Quinn T.C. Gaydos C. Azhar S. Ketron G. Presence of Chlamydia pneumoniae in human symptomatic and asymptomatic carotid atherosclerotic plaque.Stroke. 2001; 32: 855-860Crossref PubMed Scopus (85) Google Scholar Early reports suggested a link between C pneumoniae infection and abdominal aortic aneurysm (AAA) expansion, risk of rupture,28Lindholt J.S. Ashton H.A. Scott R.A. Indicators of infection with Chlamydia pneumoniae are associated with expansion of abdominal aortic aneurysms.J Vasc Surg. 2001; 34: 212-215Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar and the timing of elective repair.29Vammen S. Lindholt J.S. Andersen P.L. Henneberg E.W. Ostergaard L. Antibodies against Chlamydia pneumoniae predict the need for elective surgical intervention on small abdominal aortic aneurysms.Eur J Vasc Endovasc Surg. 2001; 22: 165-168Abstract Full Text PDF PubMed Scopus (24) Google Scholar However, the lack of standardized methods of testing for C pneumoniae infection led to conflicting findings.30Maraha B. den Heijer M. Kluytmans J. Peeters M. Impact of serological methodology on assessment of the link between Chlamydia pneumoniae and vascular diseases.Clin Diagn Lab Immunol. 2004; 11: 789-791PubMed Google Scholar C pneumoniae may induce immunologic activation, causing chronic endothelial cell damage that can mediate a proteolytic process in the wall of the abdominal aorta. It has been proposed that C pneumoniae outer membrane protein triggers an autoimmune reaction in the aortic wall, as shown by the strong cross-reaction between C pneumoniae outer membrane protein and human immunoglobulin. These reactions have been demonstrated by two-dimensional polyacrylamide gel electrophoresis, immunoblotting, and mass spectrometric protein identification.31Lindholt J.S. Stovring J. Ostergaard L. Urbonavicius S. Henneberg E.W. Honore B. et al.Serum antibodies against Chlamydia pneumoniae outer membrane protein cross-react with the heavy chain of immunoglobulin in the wall of abdominal aortic aneurysms.Circulation. 2004; 109: 2097-2102Crossref PubMed Scopus (25) Google Scholar An electron microscopy study found elementary bodies of C pneumoniae in macrophage-like cells in the intima of the atherosclerotic aorta.13Shi Y. Tokunaga O. Chlamydia pneumoniae and multiple infections in the aorta contribute to atherosclerosis.Pathol Int. 2002; 52: 755-763Crossref PubMed Scopus (28) Google Scholar Furthermore, Cheuk et al32Cheuk B.L. Ting A.C. Cheng S.W. Detection of C pneumoniae by polymerase chain reaction-enzyme immunoassay in abdominal aortic aneurysm walls and its association with rupture.Eur J Vasc Endovasc Surg. 2005; 29: 150-155Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar performed PCR-enzyme immunoassay in 16 patients with ruptured AAA and found C pneumoniae DNA in all of them. In the Blasi et al33Blasi F. Denti F. Erba M. Cosentini R. Racanelli R. Rinaldi A. et al.Detection of Chlamydia pneumoniae but not Helicobacter pylori in atherosclerotic plaques of aortic aneurysms.J Clin Microbiol. 1996; 34: 2766-2769PubMed Google Scholar study of 41 patients with AAA, C pneumoniae DNA was detected in both the peripheral blood mononuclear cells and the AAA tissues of 39% of the patients. The possibility of potential nonspecific findings on immunostaining was assessed by Vammen et al34Vammen S. Vorum H. Ostergaard L. Henneberg E.W. Lindholt J.S. Immunoblotting analysis of abdominal aortic aneurysms using antibodies against Chlamydia pneumoniae recombinant MOMP.Eur J Vasc Endovasc Surg. 2002; 24: 81-85Abstract Full Text PDF PubMed Scopus (15) Google Scholar in 20 surgical candidates with infrarenal AAA. Analysis was performed using polyacrylamide gel electrophoresis, immunoblotting, and mass spectrometric protein identification. C pneumoniae antigen was not found in any of samples of excised AAA tissues, but a cross-reacting protein was present in all AAA samples. Therefore, the direct detection of C pneumoniae by immunohistostaining should be interpreted with caution because of potential cross-reaction with non-Chlamydia proteins. In 1997, Kuo et al8Kuo C.C. Coulson A.S. Campbell L.A. Cappuccio A.L. Lawrence R.D. Wang S.P. et al.Detection of Chlamydia pneumoniae in atherosclerotic plaques in the walls of arteries of lower extremities from patients undergoing bypass operation for arterial obstruction.J Vasc Surg. 1997; 26: 29-31Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar reported finding C pneumoniae in surgically excised vascular tissues from patients undergoing lower-extremity bypass for claudication. Arterial biopsy specimens obtained from femoral and popliteal arteries were examined by using immunocytochemistry and PCR. The pathogen was detected in 11 (48%) of 23 patients. In another study, PCR was positive for C pneumoniae in 50 (59%) of 85 arterial tissue samples taken from patients who underwent surgery for peripheral vascular disease.35Wiesli P. Czerwenka W. Meniconi A. Maly F.E. Hoffman U. Vetter W. et al.Roxithromycin treatment prevents progression of peripheral arterial occlusive disease in Chlamydia pneumoniae seropositive men a randomized, double-blind, placebo-controlled trial.Circulation. 2002; 105: 2646-2652Crossref PubMed Scopus (73) Google Scholar Furthermore, azithromycin, an oral macrolide with an expanded spectrum of activity and few adverse effects, taken in doses of 300 mg/day for 28 days, has been shown to prevent progression of peripheral arterial occlusive disease in C pneumoniae seropositive men for 2.7 years.35Wiesli P. Czerwenka W. Meniconi A. Maly F.E. Hoffman U. Vetter W. et al.Roxithromycin treatment prevents progression of peripheral arterial occlusive disease in Chlamydia pneumoniae seropositive men a randomized, double-blind, placebo-controlled trial.Circulation. 2002; 105: 2646-2652Crossref PubMed Scopus (73) Google Scholar Taken together, the evidence that C pneumoniae DNA is present in peripheral artery atheromas suggests that C pneumoniae infection is important in the pathogenesis of peripheral vascular disease. It should be noted, however, that the presence of C pneumoniae in atherosclerotic vascular tissues merely suggests an association; it does not establish an etiologic relationship. Instead, C pneumoniae infection and atherosclerosis may both be secondary to inflammation or some other process. Treatment trials of antibiotics for the prevention of untoward cardiovascular events in animal models of atherosclerosis36Muhlestein J.B. Anderson J.L. Hammond E.H. Zhao L. Trehan S. Schwobe E.P. et al.Infection with Chlamydia pneumoniae accelerates the development of atherosclerosis and treatment with azithromycin prevents it in a rabbit model.Circulation. 1998; 97: 633-636Crossref PubMed Scopus (469) Google Scholar, 37Fong I.W. Antibiotics effects in a rabbit model of Chlamydia pneumoniae-induced atherosclerosis.J Infect Dis. 2000; 181: S514-S518Crossref PubMed Scopus (46) Google Scholar have produced results that were sufficiently encouraging to inspire multiple, small-scale secondary prevention trials in patients. In one such study, Gupta et al38Gupta S. Leatham E.W. Carrington D. Mendall M.A. Kaski J.C. Camm A.J. Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction.Circulation. 1997; 96: 404-407Crossref PubMed Scopus (661) Google Scholar administered 500 mg/day of azithromycin or placebo for 3 to 6 days to acute MI survivors who had high antibody titers to C pneumoniae. During the 18 months after this treatment, patients with high antibody titers who received placebo had four times as many adverse cardiovascular events as patients with low antibody titers. Antibiotic treatment significantly reduced the frequency of these events in the high-titer patients. In the Randomised Trial of Roxithromycin in non–Q-wave Coronary Syndromes (ROXIS) trial,39Gurfinkel E. Bozovich G. Daroca A. Beck E. Manther B. ROXIS Study GroupRandomised trial of roxithromycin in non-Q-wave coronary syndromes ROXIS Pilot Study.Lancet. 1997; 350: 404-407Abstract Full Text Full Text PDF PubMed Scopus (529) Google Scholar in which 202 patients with unstable angina or non–Q-wave MI were randomly assigned placebo or roxithromycin treatment (150 mg twice daily for 30 days), roxithromycin significantly reduced the incidence of recurrent angina, MI, and death ≤31 days of the start of treatment. The final report of the study showed that patients still had reduced rates of death and reinfarction for at least 6 months after treatment with roxithromycin.40Gurfinkel E. Bozovich G. Beck E. Testa E. Livellara B. Manther B. Treatment with the antibiotic roxithromycin in patients with acute non-Q-wave coronary syndromes. The final report of the ROXIS Study.Eur Heart J. 1999; 20: 121-127Crossref PubMed Scopus (291) Google Scholar In contrast, the Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia (ACADEMIC) trial,41Muhlestein J.B. Anderson J.L. Carlquist J.F. et al.Randomized secondary prevention trial of azithromycin in patients with coronary artery disease primary clinical results of the ACADEMIC study.Circulation. 2000; 102: 1755-1760Crossref PubMed Scopus (185) Google Scholar, 42Anderson J.L. Muhlestein J.B. The ACADEMIC study in perspective (Azithromycin in coronary artery disease elimination of myocardial infection with Chlamydia).J Infect Dis. 2000; 181: S569-S571Crossref PubMed Scopus (17) Google Scholar in which patients with coronary artery disease were randomly assigned to 3 months of treatment with placebo or azithromycin, found only a nonsignificant trend towards a treatment benefit 12 to 18 months later. No treatment benefit for secondary prevention of coronary heart disease was seen in the Weekly Intervention with Zithromax [Azithromycin] for Atherosclerosis and its Related Disorders (WIZARD) study.43O'Connor C.M. Dunne M.W. Pfeffer M.A. et al.Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial.JAMA. 2003; 290: 1459-1466Crossref PubMed Scopus (291) Google Scholar The patients in that study, however, had advanced atherosclerosis. In 2005, Grayston et al44Grayston J.T. Kronmal R.A. Jackson L.A. Muhlestein J.B. Yao L. Gupta S. et al.Azithromycin for the secondary prevention of coronary events.N Engl J Med. 2005; 352: 1637-1645Crossref PubMed Scopus (303) Google Scholar published the results of the Azithromycin and Coronary Event Study (ACES) trial sponsored by the National Institutes of Health. In this randomized, multicenter, prospective trial, 4012 patients with documented stable coronary artery disease received either 600 mg of azithromycin or placebo weekly for 1 year. Mean follow-up was 3.9 years. At 1 year, no significant risk reduction was noted in the azithromycin group with regard to the primary end points, which was a composite of death due to coronary heart disease, nonfatal MI, coronary revascularization, or hospitalization for unstable angina. Azithromycin treatment also did not significantly reduce the risk of stroke or of death from any cause. Similar findings were reported by Cannon et al,45Cannon C.P. Braunwald E. McCabe C.H. Grayston J.T. Muhlestein J.B. Giugliano R.P. et al.Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome.N Engl J Med. 2005; 352: 1646-1654Crossref PubMed Scopus (243) Google Scholar who performed a double-blind, randomized, placebo-controlled trial of long-term fluoroquinolone therapy (gatifloxacin 400 mg/day for a 2-week period that began 2 weeks after randomization, followed by a 10-day course every month for a mean duration of 2 years) in patients with acute coronary syndrome. At 2 years, the primary end point event—a composite of death from all causes, MI, documented unstable angina requiring rehospitalization, revascularization (performed at ≥30 days after randomization), and stroke—had occurred in 23.7% of
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