Chlamydia pneumoniae infection as a potential etiologic factor in atherosclerosis
- Jeffrey L Anderson, MD
Jeffrey L Anderson, MD
- Professor of Medicine
- University of Utah School of Medicine
Atherosclerosis is a highly prevalent disease, responsible for the greatest morbidity and mortality in Western civilization. Many risk factors for the development of atherosclerosis, manifest as coronary heart disease (CHD) and myocardial infarction (MI), have been identified. These include hyperlipidemia, hypertension, smoking, and diabetes mellitus. (See "Overview of the risk equivalents and established risk factors for cardiovascular disease".) However, much of the attributable risk remains unexplained.
Inflammation plays a central role in the pathogenesis of atherosclerosis, suggesting the possible involvement of infectious agents. Among the organisms that have been implicated are cytomegalovirus, Helicobacter pylori, and Chlamydia (also referred to as Chlamydophila) pneumoniae (figure 1). Strong associations have been noted between C. pneumoniae and atherosclerosis, which provided the rationale for antibiotic therapy directed against C. pneumoniae.
The data regarding C. pneumoniae infection will be reviewed here. As will be seen, the data fail to support a benefit from anti-C. pneumoniae therapy.
C. pneumoniae is a recently recognized and characterized human pathogen; isolates from respiratory infections were first reported in 1986 . Subsequent epidemiologic studies found it to be the cause of 5 to 10 percent of respiratory infections in adults and children, making it the third most common etiologic agent . (See "Pneumonia caused by Chlamydia pneumoniae in adults".) Antibody prevalence studies suggest that over 50 percent of adults worldwide have been exposed to C. pneumoniae .
ASSOCIATION WITH ATHEROSCLEROSIS
C. pneumoniae is transported from the respiratory tract to the vascular wall by circulating monocytes, and may persist within the monocytes for at least 10 days without cellular lysis . Case reports have documented the ability of C. pneumoniae to cause vasculitis and myocarditis (figure 1). It also has been noted to cause accelerated atherosclerosis in animal models, possibly by inducing procoagulant protein (plasminogen activator inhibitor-1 and tissue factor) and proinflammatory cytokine (interleukin-6) expression . More direct evidence of an association with atherosclerotic disease has been derived from serologic and pathologic studies.
- Grayston JT, Kuo CC, Wang SP, Altman J. A new Chlamydia psittaci strain, TWAR, isolated in acute respiratory tract infections. N Engl J Med 1986; 315:161.
- Grayston JT. Infections caused by Chlamydia pneumoniae strain TWAR. Clin Infect Dis 1992; 15:757.
- Aldous MB, Grayston JT, Wang SP, Foy HM. Seroepidemiology of Chlamydia pneumoniae TWAR infection in Seattle families, 1966-1979. J Infect Dis 1992; 166:646.
- Gieffers J, Füllgraf H, Jahn J, et al. Chlamydia pneumoniae infection in circulating human monocytes is refractory to antibiotic treatment. Circulation 2001; 103:351.
- Dechend R, Maass M, Gieffers J, et al. Chlamydia pneumoniae infection of vascular smooth muscle and endothelial cells activates NF-kappaB and induces tissue factor and PAI-1 expression: a potential link to accelerated arteriosclerosis. Circulation 1999; 100:1369.
- Hu H, Pierce GN, Zhong G. The atherogenic effects of chlamydia are dependent on serum cholesterol and specific to Chlamydia pneumoniae. J Clin Invest 1999; 103:747.
- Muhlestein JB, Anderson JL, Hammond EH, 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.
- Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet 1997; 350:430.
- Wong YK, Dawkins KD, Ward ME. Circulating Chlamydia pneumoniae DNA as a predictor of coronary artery disease. J Am Coll Cardiol 1999; 34:1435.
- Danesh J, Whincup P, Walker M, et al. Chlamydia pneumoniae IgG titres and coronary heart disease: prospective study and meta-analysis. BMJ 2000; 321:208.
- Danesh J, Whincup P, Lewington S, et al. Chlamydia pneumoniae IgA titres and coronary heart disease; prospective study and meta-analysis. Eur Heart J 2002; 23:371.
- Filardo S, Di Pietro M, Farcomeni A, et al. Chlamydia pneumoniae-Mediated Inflammation in Atherosclerosis: A Meta-Analysis. Mediators Inflamm 2015; 2015:378658.
- Siscovick DS, Schwartz SM, Corey L, et al. Chlamydia pneumoniae, herpes simplex virus type 1, and cytomegalovirus and incident myocardial infarction and coronary heart disease death in older adults : the Cardiovascular Health Study. Circulation 2000; 102:2335.
- Gabriel AS, Gnarpe H, Gnarpe J, et al. The prevalence of chronic Chlamydia pneumoniae infection as detected by polymerase chain reaction in pharyngeal samples from patients with ischaemic heart disease. Eur Heart J 1998; 19:1321.
- Toss H, Gnarpe J, Gnarpe H, et al. Increased fibrinogen levels are associated with persistent Chlamydia pneumoniae infection in unstable coronary artery disease. Eur Heart J 1998; 19:570.
- Ridker PM, Kundsin RB, Stampfer MJ, et al. Prospective study of Chlamydia pneumoniae IgG seropositivity and risks of future myocardial infarction. Circulation 1999; 99:1161.
- Gupta S, Leatham EW, Carrington D, et al. Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction. Circulation 1997; 96:404.
- Smieja M, Gnarpe J, Lonn E, et al. Multiple infections and subsequent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation 2003; 107:251.
- Chandra HR, Choudhary N, O'Neill C, et al. Chlamydia pneumoniae exposure and inflammatory markers in acute coronary syndrome (CIMACS). Am J Cardiol 2001; 88:214.
- Anderson JL, Carlquist JF, Muhlestein JB, et al. Evaluation of C-reactive protein, an inflammatory marker, and infectious serology as risk factors for coronary artery disease and myocardial infarction. J Am Coll Cardiol 1998; 32:35.
- Melnick SL, Shahar E, Folsom AR, et al. Past infection by Chlamydia pneumoniae strain TWAR and asymptomatic carotid atherosclerosis. Atherosclerosis Risk in Communities (ARIC) Study Investigators. Am J Med 1993; 95:499.
- Lehto S, Niskanen L, Suhonen M, et al. Association between Chlamydia pneumoniae antibodies and intimal calcification in femoral arteries of nondiabetic patients. Arch Intern Med 2002; 162:594.
- van der Ven AJ, Hommels MJ, Kroon AA, et al. Chlamydia pneumoniae seropositivity and systemic and renovascular atherosclerotic disease. Arch Intern Med 2002; 162:786.
- Davidson M, Kuo CC, Middaugh JP, et al. Confirmed previous infection with Chlamydia pneumoniae (TWAR) and its presence in early coronary atherosclerosis. Circulation 1998; 98:628.
- Sander D, Winbeck K, Klingelhöfer J, et al. Enhanced progression of early carotid atherosclerosis is related to Chlamydia pneumoniae (Taiwan acute respiratory) seropositivity. Circulation 2001; 103:1390.
- Laek B, Szklo M, McClelland RL, et al. The prospective association of Chlamydia pneumoniae and four other pathogens with development of coronary artery calcium: the multi-ethnic study of atherosclerosis (MESA). Atherosclerosis 2013; 230:268.
- Player MS, Mainous AG 3rd, Everett CJ, et al. Chlamydia pneumoniae and progression of subclinical atherosclerosis. Eur J Prev Cardiol 2014; 21:559.
- Elkind MS, Lin IF, Grayston JT, Sacco RL. Chlamydia pneumoniae and the risk of first ischemic stroke : The Northern Manhattan Stroke Study. Stroke 2000; 31:1521.
- Kuo CC, Shor A, Campbell LA, et al. Demonstration of Chlamydia pneumoniae in atherosclerotic lesions of coronary arteries. J Infect Dis 1993; 167:841.
- Vink A, Poppen M, Schoneveld AH, et al. Distribution of Chlamydia pneumoniae in the human arterial system and its relation to the local amount of atherosclerosis within the individual. Circulation 2001; 103:1613.
- Ericson K, Saldeen TG, Lindquist O, et al. Relationship of Chlamydia pneumoniae infection to severity of human coronary atherosclerosis. Circulation 2000; 101:2568.
- Thomas M, Wong Y, Thomas D, et al. Relation between direct detection of Chlamydia pneumoniae DNA in human coronary arteries at postmortem examination and histological severity (Stary grading) of associated atherosclerotic plaque. Circulation 1999; 99:2733.
- Muhlestein JB, Hammond EH, Carlquist JF, 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.
- Maass M, Bartels C, Engel PM, et al. Endovascular presence of viable Chlamydia pneumoniae is a common phenomenon in coronary artery disease. J Am Coll Cardiol 1998; 31:827.
- Grayston JT, Kuo CC, Coulson AS, et al. Chlamydia pneumoniae (TWAR) in atherosclerosis of the carotid artery. Circulation 1995; 92:3397.
- Apfalter P, Barousch W, Nehr M, et al. No evidence of involvement of Chlamydia pneumoniae in severe cerebrovascular atherosclerosis by means of quantitative real-time polymerase chain reaction. Stroke 2004; 35:2024.
- Bartels C, Maass M, Bein G, et al. Detection of Chlamydia pneumoniae but not cytomegalovirus in occluded saphenous vein coronary artery bypass grafts. Circulation 1999; 99:879.
- Nyström-Rosander C, Edvinsson M, Thelin S, et al. Chlamydophila pneumonia: Specific mRNA in aorta ascendens in patients undergoing coronary artery by-pass grafting. Scand J Infect Dis 2006; 38:758.
- Wells BJ, Mainous AG 3rd, Dickerson LM. Antibiotics for the secondary prevention of ischemic heart disease: a meta-analysis of randomized controlled trials. Arch Intern Med 2004; 164:2156.
- Grayston JT, Kronmal RA, Jackson LA, et al. Azithromycin for the secondary prevention of coronary events. N Engl J Med 2005; 352:1637.
- Jespersen CM, Als-Nielsen B, Damgaard M, et al. Randomised placebo controlled multicentre trial to assess short term clarithromycin for patients with stable coronary heart disease: CLARICOR trial. BMJ 2006; 332:22.
- Anderson JL, Muhlestein JB, Carlquist J, et al. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for Chlamydia pneumoniae infection: The Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia (ACADEMIC) study. Circulation 1999; 99:1540.
- Muhlestein JB, Anderson JL, Carlquist JF, 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.
- O'Connor CM, Dunne MW, Pfeffer MA, et al. Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. JAMA 2003; 290:1459.
- Gurfinkel E, Bozovich G, Daroca A, et al. Randomised trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS Pilot Study. ROXIS Study Group. Lancet 1997; 350:404.
- Gurfinkel E, Bozovich G, Beck E, et al. 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.
- Cercek B, Shah PK, Noc M, et al. Effect of short-term treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial. Lancet 2003; 361:809.
- Stone AF, Mendall MA, Kaski JC, et al. Effect of treatment for Chlamydia pneumoniae and Helicobacter pylori on markers of inflammation and cardiac events in patients with acute coronary syndromes: South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA). Circulation 2002; 106:1219.
- Sinisalo J, Mattila K, Valtonen V, et al. Effect of 3 months of antimicrobial treatment with clarithromycin in acute non-q-wave coronary syndrome. Circulation 2002; 105:1555.
- Zahn R, Schneider S, Frilling B, et al. Antibiotic therapy after acute myocardial infarction: a prospective randomized study. Circulation 2003; 107:1253.
- Cannon CP, Braunwald E, McCabe CH, et al. Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med 2005; 352:1646.
- Neumann F, Kastrati A, Miethke T, et al. Treatment of Chlamydia pneumoniae infection with roxithromycin and effect on neointima proliferation after coronary stent placement (ISAR-3): a randomised, double-blind, placebo-controlled trial. Lancet 2001; 357:2085.
- Wiesli P, Czerwenka W, Meniconi A, 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.
- Sander D, Winbeck K, Klingelhöfer J, et al. Reduced progression of early carotid atherosclerosis after antibiotic treatment and Chlamydia pneumoniae seropositivity. Circulation 2002; 106:2428.
- Sander D, Winbeck K, Klingelhöfer J, et al. Progression of early carotid atherosclerosis is only temporarily reduced after antibiotic treatment of Chlamydia pneumoniae seropositivity. Circulation 2004; 109:1010.
- Danesh J. Antibiotics in the prevention of heart attacks. Lancet 2005; 365:365.
- Anderson JL. Infection, antibiotics, and atherothrombosis--end of the road or new beginnings? N Engl J Med 2005; 352:1706.
- Joshi R, Khandelwal B, Joshi D, Gupta OP. Chlamydophila pneumoniae infection and cardiovascular disease. N Am J Med Sci 2013; 5:169.
- ASSOCIATION WITH ATHEROSCLEROSIS
- Animal models
- Serologic and PCR studies
- - Meta-analyses
- - Case-control studies
- - Prospective studies
- - Asymptomatic atherosclerosis
- - Ischemic stroke
- Pathologic studies
- POSSIBLE ROLE OF ANTICHLAMYDIAL THERAPY
- Stable coronary disease
- Acute coronary syndrome
- Prevention of restenosis
- Peripheral artery disease
- Carotid artery disease
- Summary of therapeutic studies