The Infectious Burden in Atherothrombosis

Abstract

Pathogenesis of atherosclerosis involves multiple mechanisms, including imbalanced lipid metabolism, disturbed equilibrium of the immune response, and chronic inflammation of the artery wall. Several reports have shown a relationship between the development of atherosclerosis and the presence of infectious diseases, widely occurring in the general population, often chronic and/or asymptomatic. Beyond Chlamydia pneumoniae, a large number of infectious agents have been linked with an increased risk of vascular disease, with variable strength of supporting data: Porphyromonas gingivalis, Helicobacter pylori, influenza A virus, herpes virus, hepatitis C virus, cytomegalovirus, and human immunodeficiency virus. Infections may contribute to atherosclerosis either via direct infection of vascular cells or via the indirect effects of cytokines or acute phase proteins induced by infection at “nonvascular” sites. More recently, investigators reported that the aggregate burden (“infectious burden”) of these chronic infections, rather than the effects of a single organism, might contribute to atherosclerosis and its thrombotic complications. However, the role of infection, as a proinflammatory cause of atherosclerosis, is still debated in the literature. This article will review available data suggesting a relationship between different infective pathogens and atherothrombosis, the hypothesized mechanisms, and the potential role for antimicrobial treatment.

Keywords

atherosclerosis - cardiovascular disease - infection - infectious burden - inflammation

• References

• 1 Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999; 340 (2) 115-126
• 2 Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105 (9) 1135-1143
• 3 Kol A, Libby P. The mechanisms by which infectious agents may contribute to atherosclerosis and its clinical manifestations. Trends Cardiovasc Med 1998; 8 (5) 191-199
• 4 O'Connor S, Taylor C, Campbell LA, Epstein S, Libby P. Potential infectious etiologies of atherosclerosis: a multifactorial perspective. Emerg Infect Dis 2001; 7 (5) 780-788
• 5 Kalayoglu MV, Libby P, Byrne GI. Chlamydia pneumoniae as an emerging risk factor in cardiovascular disease. JAMA 2002; 288 (21) 2724-2731
• 6 Rosenfeld ME, Campbell LA. Pathogens and atherosclerosis: update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis. Thromb Haemost 2011; 106 (5) 858-867
• 7 Jiang B, Hebert VY, Khandelwal AR, Stokes KY, Dugas TR. HIV-1 antiretrovirals induce oxidant injury and increase intima-media thickness in an atherogenic mouse model. Toxicol Lett 2009; 187 (3) 164-171
• 8 Jiang B, Khandelwal AR, Rogers LK , et al. Antiretrovirals induce endothelial dysfunction via an oxidant-dependent pathway and promote neointimal hyperplasia. Toxicol Sci 2010; 117 (2) 524-536
• 9 Elkind MSV. Infectious burden: a new risk factor and treatment target for atherosclerosis. Infect Disord Drug Targets 2010; 10 (2) 84-90
• 10 Elkind MSV, Luna JM, Moon YP , et al. Infectious burden and carotid plaque thickness: the northern Manhattan study. Stroke 2010; 41 (3) e117-e122
• 11 Elkind MSV. Inflammatory mechanisms of stroke. Stroke 2010; 41 (Suppl. 10) S3-S8
• 12 Zhu J, Quyyumi AA, Norman JE , et al. Effects of total pathogen burden on coronary artery disease risk and C-reactive protein levels. Am J Cardiol 2000; 85 (2) 140-146
• 13 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 (12) 1613-1617
• 14 Virok D, Kis Z, Karai L , et al. Chlamydia pneumoniae in atherosclerotic middle cerebral artery. Stroke 2001; 32 (9) 1973-1976
• 15 Shor A, Kuo CC, Patton DL. Detection of Chlamydia pneumoniae in coronary arterial fatty streaks and atheromatous plaques. S Afr Med J 1992; 82 (3) 158-161
• 16 Maass M, Bartels C, Engel PM, Mamat U, Sievers HH. Endovascular presence of viable Chlamydia pneumoniae is a common phenomenon in coronary artery disease. J Am Coll Cardiol 1998; 31 (4) 827-832
• 17 Jackson LA, Campbell LA, Kuo CC, Rodriguez DI, Lee A, Grayston JT. Isolation of Chlamydia pneumoniae from a carotid endarterectomy specimen. J Infect Dis 1997; 176 (1) 292-295
• 18 Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link?. Lancet 1997; 350 (9075) 430-436
• 19 Mosorin M, Surcel HM, Laurila A , et al. Detection of Chlamydia pneumoniae-reactive T lymphocytes in human atherosclerotic plaques of carotid artery. Arterioscler Thromb Vasc Biol 2000; 20 (4) 1061-1067
• 20 Benagiano M, D'Elios MM, Amedei A , et al. Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques. J Immunol 2005; 174 (10) 6509-6517
• 21 Kern JM, Maass V, Maass M. Chlamydia pneumoniae adversely modulates vascular cell properties by direct interaction with signalling cascades. Thromb Haemost 2009; 102 (6) 1064-1070
• 22 Campbell LA, Yaraei K, Van Lenten B , et al. The acute phase reactant response to respiratory infection with Chlamydia pneumoniae : implications for the pathogenesis of atherosclerosis. Microbes Infect 2010; 12 (8-9) 598-606
• 23 Naiki Y, Sorrentino R, Wong MH , et al. TLR/MyD88 and liver X receptor alpha signaling pathways reciprocally control Chlamydia pneumoniae-induced acceleration of atherosclerosis. J Immunol 2008; 181 (10) 7176-7185
• 24 Chen S, Sorrentino R, Shimada K , et al. Chlamydia pneumoniae-induced foam cell formation requires MyD88-dependent and -independent signaling and is reciprocally modulated by liver X receptor activation. J Immunol 2008; 181 (10) 7186-7193
• 25 Erkkilä L, Laitinen K, Haasio K , et al. Heat shock protein 60 autoimmunity and early lipid lesions in cholesterol-fed C57BL/6JBom mice during Chlamydia pneumoniae infection. Atherosclerosis 2004; 177 (2) 321-328
• 26 Nakano K, Inaba H, Nomura R , et al. Detection of cariogenic Streptococcus mutans in extirpated heart valve and atheromatous plaque specimens. J Clin Microbiol 2006; 44 (9) 3313-3317
• 27 Kozarov E, Sweier D, Shelburne C, Progulske-Fox A, Lopatin D. Detection of bacterial DNA in atheromatous plaques by quantitative PCR. Microbes Infect 2006; 8 (3) 687-693
• 28 Trevisan M, Dorn J. The relationship between periodontal disease (PD) and cardiovascular disease (CVD). Mediterr J Hematol Infect Dis 2010; 2 (3) e2010030
• 29 Teles R, Wang CY. Mechanisms involved in the association between periodontal diseases and cardiovascular disease. Oral Dis 2011; 17 (5) 450-461
• 30 Glurich I, Grossi S, Albini B , et al. Systemic inflammation in cardiovascular and periodontal disease: comparative study. Clin Diagn Lab Immunol 2002; 9 (2) 425-432
• 31 Buhlin K, Hultin M, Norderyd O , et al. Periodontal treatment influences risk markers for atherosclerosis in patients with severe periodontitis. Atherosclerosis 2009; 206 (2) 518-522
• 32 Lalla E, Lamster IB, Hofmann MA , et al. Oral infection with a periodontal pathogen accelerates early atherosclerosis in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol 2003; 23 (8) 1405-1411
• 33 Madan M, Bishayi B, Hoge M, Messas E, Amar S. Doxycycline affects diet- and bacteria-associated atherosclerosis in an ApoE heterozygote murine model: cytokine profiling implications. Atherosclerosis 2007; 190 (1) 62-72
• 34 Hayashi C, Viereck J, Hua N , et al. Porphyromonas gingivalis accelerates inflammatory atherosclerosis in the innominate artery of ApoE deficient mice. Atherosclerosis 2011; 215 (1) 52-59
• 35 Li L, Messas E, Batista Jr EL, Levine RA, Amar S. Porphyromonas gingivalis infection accelerates the progression of atherosclerosis in a heterozygous apolipoprotein E-deficient murine model. Circulation 2002; 105 (7) 861-867
• 36 Hayashi C, Madrigal AG, Liu X , et al. Pathogen-mediated inflammatory atherosclerosis is mediated in part via toll-like receptor 2-induced inflammatory responses. J Innate Immun 2010; 2 (4) 334-343
• 37 Griffiths R, Barbour S. Lipoproteins and lipoprotein metabolism in periodontal disease. Clin Lipidol 2010; 5 (3) 397-411
• 38 Ameriso SF, Fridman EA, Leiguarda RC, Sevlever GE. Detection of Helicobacter pylori in human carotid atherosclerotic plaques. Stroke 2001; 32 (2) 385-391
• 39 Kaplan M, Yavuz SS, Cinar B , et al. Detection of Chlamydia pneumoniae and Helicobacter pylori in atherosclerotic plaques of carotid artery by polymerase chain reaction. Int J Infect Dis 2006; 10 (2) 116-123
• 40 Kowalski M. Helicobacter pylori (H. pylori) infection in coronary artery disease: influence of H. pylori eradication on coronary artery lumen after percutaneous transluminal coronary angioplasty. The detection of H. pylori specific DNA in human coronary atherosclerotic plaque. J Physiol Pharmacol 2001; 52 (Suppl. 01) 3-31
• 41 Latsios G, Saetta A, Michalopoulos NV, Agapitos E, Patsouris E. Detection of cytomegalovirus, Helicobacter pylori and Chlamydia pneumoniae DNA in carotid atherosclerotic plaques by the polymerase chain reaction. Acta Cardiol 2004; 59 (6) 652-657
• 42 Brenner H, Berg G, Fröhlich M, Boeing H, Koenig W. Chronic infection with Helicobacter pylori does not provoke major systemic inflammation in healthy adults: results from a large population-based study. Atherosclerosis 1999; 147 (2) 399-403
• 43 Elizalde JI, Pérez-Pujol S, Heras M , et al. Effects of Helicobacter pylori eradication on platelet activation and disease recurrence in patients with acute coronary syndromes. Helicobacter 2004; 9 (6) 681-689
• 44 Stone AF, Mendall MA, Kaski J-C , 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 (10) 1219-1223
• 45 Rafferty B, Dolgilevich S, Kalachikov S , et al. Cultivation of Enterobacter hormaechei from human atherosclerotic tissue. J Atheroscler Thromb 2011; 18 (1) 72-81
• 46 Völzke H, Wolff B, Lüdemann J , et al. Seropositivity for anti-Borrelia IgG antibody is independently associated with carotid atherosclerosis. Atherosclerosis 2006; 184 (1) 108-112
• 47 Fateh-Moghadam S, Bocksch W, Wessely R, Jäger G, Hetzer R, Gawaz M. Cytomegalovirus infection status predicts progression of heart-transplant vasculopathy. Transplantation 2003; 76 (10) 1470-1474
• 48 Grattan MT, Moreno-Cabral CE, Starnes VA, Oyer PE, Stinson EB, Shumway NE. Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. JAMA 1989; 261 (24) 3561-3566
• 49 Roberts ET, Haan MN, Dowd JB, Aiello AE. Cytomegalovirus antibody levels, inflammation, and mortality among elderly Latinos over 9 years of follow-up. Am J Epidemiol 2010; 172 (4) 363-371
• 50 Haji SA, Starling RC, Avery RK , et al. Donor hepatitis-C seropositivity is an independent risk factor for the development of accelerated coronary vasculopathy and predicts outcome after cardiac transplantation. J Heart Lung Transplant 2004; 23 (3) 277-283
• 51 Boddi M, Abbate R, Chellini B , et al. Hepatitis C virus RNA localization in human carotid plaques. J Clin Virol 2010; 47 (1) 72-75
• 52 Boddi M, Abbate R, Chellini B , et al. HCV infection facilitates asymptomatic carotid atherosclerosis: preliminary report of HCV RNA localization in human carotid plaques. Dig Liver Dis 2007; 39 (Suppl. 01) S55-S60
• 53 Warren-Gash C, Smeeth L, Hayward AC. Influenza as a trigger for acute myocardial infarction or death from cardiovascular disease: a systematic review. Lancet Infect Dis 2009; 9 (10) 601-610
• 54 Naghavi M, Wyde P, Litovsky S , et al. Influenza infection exerts prominent inflammatory and thrombotic effects on the atherosclerotic plaques of apolipoprotein E-deficient mice. Circulation 2003; 107 (5) 762-768
• 55 Van Lenten BJ, Wagner AC, Anantharamaiah GM , et al. Influenza infection promotes macrophage traffic into arteries of mice that is prevented by D-4F, an apolipoprotein A-I mimetic peptide. Circulation 2002; 106 (9) 1127-1132
• 56 Haidari M, Wyde PR, Litovsky S , et al. Influenza virus directly infects, inflames, and resides in the arteries of atherosclerotic and normal mice. Atherosclerosis 2010; 208 (1) 90-96
• 57 Van Lenten BJ, Wagner AC, Nayak DP, Hama S, Navab M, Fogelman AM. High-density lipoprotein loses its anti-inflammatory properties during acute influenza a infection. Circulation 2001; 103 (18) 2283-2288
• 58 Hulten E, Mitchell J, Scally J, Gibbs B, Villines TC. HIV positivity, protease inhibitor exposure and subclinical atherosclerosis: a systematic review and meta-analysis of observational studies. Heart 2009; 95 (22) 1826-1835
• 59 Behrens GM, Stoll M, Schmidt RE. Lipodystrophy syndrome in HIV infection: what is it, what causes it and how can it be managed?. Drug Saf 2000; 23 (1) 57-76
• 60 Asztalos BF, Schaefer EJ, Horvath KV , et al. Protease inhibitor-based HAART, HDL, and CHD-risk in HIV-infected patients. Atherosclerosis 2006; 184 (1) 72-77
• 61 Kwon TW, Kim DK, Ye JS , et al. Detection of enterovirus, cytomegalovirus, and Chlamydia pneumoniae in atheromas. J Microbiol 2004; 42 (4) 299-304
• 62 Liu SC, Tsai CT, Wu CK , et al. Human parvovirus b19 infection in patients with coronary atherosclerosis. Arch Med Res 2009; 40 (7) 612-617
• 63 Benditt EP, Barrett T, McDougall JK. Viruses in the etiology of atherosclerosis. Proc Natl Acad Sci U S A 1983; 80 (20) 6386-6389
• 64 Lu M, Shenk T. Human cytomegalovirus infection inhibits cell cycle progression at multiple points, including the transition from G1 to S. J Virol 1996; 70 (12) 8850-8857
• 65 Khachigian LM, Lindner V, Williams AJ, Collins T. Egr-1-induced endothelial gene expression: a common theme in vascular injury. Science 1996; 271 (5254) 1427-1431
• 66 Bavendiek U, Libby P, Kilbride M, Reynolds R, Mackman N, Schönbeck U. Induction of tissue factor expression in human endothelial cells by CD40 ligand is mediated via activator protein 1, nuclear factor kappa B, and Egr-1. J Biol Chem 2002; 277 (28) 25032-25039
• 67 Chahine MN, Deniset J, Dibrov E , et al. Oxidized LDL promotes the mitogenic actions of Chlamydia pneumoniae in vascular smooth muscle cells. Cardiovasc Res 2011; 92 (3) 476-483
• 68 Zhou YF, Yu ZX, Wanishsawad C, Shou M, Epstein SE. The immediate early gene products of human cytomegalovirus increase vascular smooth muscle cell migration, proliferation, and expression of PDGF beta-receptor. Biochem Biophys Res Commun 1999; 256 (3) 608-613
• 69 Nelken NA, Coughlin SR, Gordon D, Wilcox JN. Monocyte chemoattractant protein-1 in human atheromatous plaques. J Clin Invest 1991; 88 (4) 1121-1127
• 70 Ylä-Herttuala S, Lipton BA, Rosenfeld ME, Goldberg IJ, Steinberg D, Witztum JL. Macrophages and smooth muscle cells express lipoprotein lipase in human and rabbit atherosclerotic lesions. Proc Natl Acad Sci U S A 1991; 88 (22) 10143-10147
• 71 Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 1998; 394 (6696) 894-897
• 72 Gu L, Okada Y, Clinton SK , et al. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell 1998; 2 (2) 275-281
• 73 Krüll M, Maass M, Suttorp N, Rupp J. Chlamydophila pneumoniae. Mechanisms of target cell infection and activation. Thromb Haemost 2005; 94 (2) 319-326
• 74 Krüll M, Klucken AC, Wuppermann FN , et al. Signal transduction pathways activated in endothelial cells following infection with Chlamydia pneumoniae . J Immunol 1999; 162 (8) 4834-4841
• 75 Hsich E, Zhou YF, Paigen B, Johnson TM, Burnett MS, Epstein SE. Cytomegalovirus infection increases development of atherosclerosis in Apolipoprotein-E knockout mice. Atherosclerosis 2001; 156 (1) 23-28
• 76 Vliegen I, Duijvestijn A, Grauls G, Herngreen S, Bruggeman C, Stassen F. Cytomegalovirus infection aggravates atherogenesis in apoE knockout mice by both local and systemic immune activation. Microbes Infect 2004; 6 (1) 17-24
• 77 Chee MS, Bankier AT, Beck S , et al. Analysis of the protein-coding content of the sequence of human cytomegalovirus strain AD169. Curr Top Microbiol Immunol 1990; 154: 125-169
• 78 Streblow DN, Soderberg-Naucler C, Vieira J , et al. The human cytomegalovirus chemokine receptor US28 mediates vascular smooth muscle cell migration. Cell 1999; 99 (5) 511-520
• 79 Lalla E, Lamster IB, Hofmann MA , et al. Oral infection with a periodontal pathogen accelerates early atherosclerosis in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol 2003; 23 (8) 1405-1411
• 80 Van Lenten BJ, Wagner AC, Nayak DP, Hama S, Navab M, Fogelman AM. High-density lipoprotein loses its anti-inflammatory properties during acute influenza a infection. Circulation 2001; 103 (18) 2283-2288
• 81 Dechend R, Gieffers J, Dietz R , et al. Hydroxymethylglutaryl coenzyme A reductase inhibition reduces Chlamydia pneumoniae-induced cell interaction and activation. Circulation 2003; 108 (3) 261-265
• 82 Buono C, Binder CJ, Stavrakis G, Witztum JL, Glimcher LH, Lichtman AH. T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses. Proc Natl Acad Sci U S A 2005; 102 (5) 1596-1601
• 83 De Palma R, Del Galdo F, Abbate G , et al. Patients with acute coronary syndrome show oligoclonal T-cell recruitment within unstable plaque: evidence for a local, intracoronary immunologic mechanism. Circulation 2006; 113 (5) 640-646
• 84 Keller TT, van der Meer JJ, Teeling P , et al. Selective expansion of influenza A virus-specific T cells in symptomatic human carotid artery atherosclerotic plaques. Stroke 2008; 39 (1) 174-179
• 85 Perschinka H, Mayr M, Millonig G , et al. Cross-reactive B-cell epitopes of microbial and human heat shock protein 60/65 in atherosclerosis. Arterioscler Thromb Vasc Biol 2003; 23 (6) 1060-1065
• 86 Sasu S, LaVerda D, Qureshi N, Golenbock DT, Beasley D. Chlamydia pneumoniae and chlamydial heat shock protein 60 stimulate proliferation of human vascular smooth muscle cells via toll-like receptor 4 and p44/p42 mitogen-activated protein kinase activation. Circ Res 2001; 89 (3) 244-250
• 87 Haralambieva IH, Iankov ID, Ivanova PV, Mitev V, Mitov IG. Chlamydophila pneumoniae induces p44/p42 mitogen-activated protein kinase activation in human fibroblasts through toll-like receptor 4. J Med Microbiol 2004; 53 (Pt 12) 1187-1193
• 88 Ford PJ, Gemmell E, Timms P, Chan A, Preston FM, Seymour GJ. Anti-P. gingivalis response correlates with atherosclerosis. J Dent Res 2007; 86 (1) 35-40
• 89 Ayada K, Yokota K, Hirai K , et al. Regulation of cellular immunity prevents Helicobacter pylori-induced atherosclerosis. Lupus 2009; 18 (13) 1154-1168
• 90 Dentali F, Nicolini E, Ageno W. Venous and arterial thrombosis associated with HIV infection. Semin Thromb Hemost 2012; 38 (5) 524-529
• 91 Behrens GM, Stoll M, Schmidt RE. Lipodystrophy syndrome in HIV infection: what is it, what causes it and how can it be managed?. Drug Saf 2000; 23 (1) 57-76
• 92 Asztalos BF, Demissie S, Cupples LA , et al. LpA-I, LpA-I:A-II HDL and CHD-risk: The Framingham offspring study and the veterans affairs HDL intervention trial. Atherosclerosis 2006; 188 (1) 59-67
• 93 Badiou S, Merle De Boever C, Dupuy AM, Baillat V, Cristol JP, Reynes J. Decrease in LDL size in HIV-positive adults before and after lopinavir/ritonavir-containing regimen: an index of atherogenicity?. Atherosclerosis 2003; 168 (1) 107-113
• 94 Stein JH, Klein MA, Bellehumeur JL , et al. Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation 2001; 104 (3) 257-262
• 95 de Larrañaga GF, Petroni A, Deluchi G, Alonso BS, Benetucci JA. Viral load and disease progression as responsible for endothelial activation and/or injury in human immunodeficiency virus-1-infected patients. Blood Coagul Fibrinolysis 2003; 14 (1) 15-18
• 96 Buonaguro L, Barillari G, Chang HK , et al. Effects of the human immunodeficiency virus type 1 Tat protein on the expression of inflammatory cytokines. J Virol 1992; 66 (12) 7159-7167
• 97 Dhawan S, Puri RK, Kumar A, Duplan H, Masson JM, Aggarwal BB. Human immunodeficiency virus-1-tat protein induces the cell surface expression of endothelial leukocyte adhesion molecule-1, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 in human endothelial cells. Blood 1997; 90 (4) 1535-1544
• 98 Calza L, Verucchi G, Pocaterra D , et al. Cardiovascular risk factors and ultrasound evaluation of carotid atherosclerosis in patients with HIV-1 infection. Int J STD AIDS 2009; 20 (10) 683-689
• 99 Coll B, Parra S, Alonso-Villaverde C , et al. HIV-infected patients with lipodystrophy have higher rates of carotid atherosclerosis: the role of monocyte chemoattractant protein-1. Cytokine 2006; 34 (1-2) 51-55
• 100 Guaraldi G, Stentarelli C, Zona S , et al. Lipodystrophy and anti-retroviral therapy as predictors of sub-clinical atherosclerosis in human immunodeficiency virus infected subjects. Atherosclerosis 2010; 208 (1) 222-227
• 101 Eugenin EA, Morgello S, Klotman ME , et al. Human immunodeficiency virus (HIV) infects human arterial smooth muscle cells in vivo and in vitro: implications for the pathogenesis of HIV-mediated vascular disease. Am J Pathol 2008; 172 (4) 1100-1111
• 102 O'Connor CM, Dunne MW, Pfeffer MA , et al; Investigators in the WIZARD Study. Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. JAMA 2003; 290 (11) 1459-1466
• 103 Grayston JT, Kronmal RA, Jackson LA , et al; ACES Investigators. Azithromycin for the secondary prevention of coronary events. N Engl J Med 2005; 352 (16) 1637-1645
• 104 Cannon CP, Braunwald E, McCabe CH , et al; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med 2005; 352 (16) 1646-1654
• 105 Jespersen CM, Als-Nielsen B, Damgaard M , et al; CLARICOR Trial Group. Randomised placebo controlled multicentre trial to assess short term clarithromycin for patients with stable coronary heart disease: CLARICOR trial. BMJ 2006; 332 (7532) 22-27
• 106 Danesh J. Antibiotics in the prevention of heart attacks. Lancet 2005; 365 (9457) 365-367
• 107 Epstein SE, Zhu J, Najafi AH, Burnett MS. Insights into the role of infection in atherogenesis and in plaque rupture. Circulation 2009; 119 (24) 3133-3141
• 108 Grayston JT. Chlamydia pneumoniae and atherosclerosis. Clin Infect Dis 2005; 40 (8) 1131-1132
• 109 Beatty WL, Morrison RP, Byrne GI. Persistent chlamydiae: from cell culture to a paradigm for chlamydial pathogenesis. Microbiol Rev 1994; 58 (4) 686-699
• 110 Kutlin A, Roblin PM, Hammerschlag MR. Effect of prolonged treatment with azithromycin, clarithromycin, or levofloxacin on Chlamydia pneumoniae in a continuous-infection Model. Antimicrob Agents Chemother 2002; 46 (2) 409-412
• 111 Gieffers J, Füllgraf H, Jahn J , et al. Chlamydia pneumoniae infection in circulating human monocytes is refractory to antibiotic treatment. Circulation 2001; 103 (3) 351-356