Associations between infective microorganisms and atherosclerosis

Part of the Developments in Cardiovascular Medicine book series (DICM, volume 218)


The idea that infection could be a causal factor in the pathogenesis of atherosclerosis is not new. Indeed, Sir William Osler and others first proposed such a mechanism as long ago as 1908.[1] Until recently, however, the suggestion had largely been dismissed. Fresh debate now focuses on whether or not common chronic infections contribute to the development and progression of atherosclerotic disease, not least because epidemiological variations in classical cardiovascular risk factors such as smoking, diabetes mellitus and hypercholesterolaemia do not account for the variations in the presence and severity of coronary heart disease (CHD) seen in the general population (see Chapter 1). In addition, in vitro experiments, animal studies, pathological examinations and clinical observations provide supporting evidence for associations between infectious diseases and atherosclerosis. At the same time, increasing understanding of inflammatory and haemostatic mediators and of the monocyte/macrophage system’s role in atherogenesis have facilitated research into whether or not infections have a direct pathogenetic role in CHD. In essence, while an inflammatory basis to atherosclerosis and CHD is now generally acknowledged, an aetiological role for chronic infections, through highly plausible, is by no means proven.


Coronary Heart Disease Arterial Smooth Muscle Cell Dental Infection Pylorus Seropositivity Coronary Artery Restenosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Osler W. Diseases of the arteries. In: Modern Medicine: Its Practice and Theory (Osler W, ed.). Lea & Febiger, Philadephia, USA, 1908; pp. 429–47.Google Scholar
  2. 2.
    Nieminen MS, Mattila K, Valtonen V. Infection and inflammation as risk factors for myocardial infarction. Eur Heart J 1993; 14(Suppl. K): 12–6.PubMedGoogle Scholar
  3. 3.
    Buja LM. Does atherosclerosis have an infectious etiology? Circulation 1996; 94: 872–3.PubMedGoogle Scholar
  4. 4.
    Hennekens CH. Increasing burden of cardiovascular disease: current knowledge and future directions for research on risk factors. Circulation 1998; 97: 1095–102.PubMedGoogle Scholar
  5. 5.
    Gupta S, Camm AJ. Is there an infective aetiology to atherosclerosis? Drugs Aging 1998; 13: 1–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Ridker PM. Inflammation, infection and cardiovascular risk: How good is the clinical evidence? Circulation 1998; 97: 1671–4.PubMedGoogle Scholar
  7. 7.
    Marshall BJ. Helicobacter pylori in peptic ulcer: Have Koch’s postulates been fulfilled? Ann Med 1995; 27: 565–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Silman AJ. Is rheumatoid arthritis an infectious disease? BMJ 1991; 303: 200–1.PubMedGoogle Scholar
  9. 9.
    Sanderson JD, Moss MT, Tizard ML, Hermon-Taylor J. Mycobacterium paratuberculosis DNA in Crohn’s disease tissues. Gut 1992; 33: 890–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Soldan SS, Bertri R, Salem N et al. Association of human herpes virus 6 (HHV-6) with multiple sclerosis: increased IgG response to HHV-6 early antigen and detection of serum HHV-6 DNA. Nature Medicine 1998; 3: 1394–7.CrossRefGoogle Scholar
  11. 11.
    Saboor SA, Johnson N, McFadden J. Detection of mycobacterial DNA in sarcoidosis and tuberculosis with polymerase chain reaction. Lancet 1992; 339: 1012–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Ho DD, Rota TR, Andrews CA, Hirsch MS. Replication of human cytomegalovirus in endothelial cells. J Infect Dis 1984; 150: 956–7.PubMedGoogle Scholar
  14. 14.
    Hajjar DP. Viral pathogenesis of atherosclerosis. Am J Pathol 1991; 139: 1195–210.PubMedGoogle Scholar
  15. 15.
    Kirkpatrick CJ, Bultmann BD, Gruler H. Interaction between enteroviruses and human endothelial cells in vitro. Alterations in the physical properties of endothelial cell plasma membrane and adhesion of human granulocytes. Am J Pathol 1985; 118: 15–25.PubMedGoogle Scholar
  16. 16.
    Kaukoranta-Tolvanen SS, Laitinen K, Saikku P, Leinonen M. Chlamydia pneumoniae multiplies in human endothelial cells in vitro. Microbial Pathog 1994; 16: 313–9.CrossRefGoogle Scholar
  17. 17.
    Reidy MA, Bowyer DE. Distortion of endothelial repair. The effect of hypercholesterolemia on regulation of aortic endothelium following injury by endotoxin. A scanning microscopy study. Atherosclerosis 1978; 29: 459–66.PubMedCrossRefGoogle Scholar
  18. 18.
    Pesonen E, Kaprio E, Rapola J, Soveri T, Oksanen H. Endothelial cell damage in piglet coronary artery after administration of E. coli endotoxin. A scanning and transmission electron-microscopic study. Atherosclerosis 1981; 40: 65–73.PubMedCrossRefGoogle Scholar
  19. 19.
    Hansson GK, Jonasson L, Seifert PS, Stemme S. Immune mechanisms in atherosclerosis. Arteriosclerosis 1989; 9: 567–78.PubMedGoogle Scholar
  20. 20.
    Etingin OR, Hajjar DP. Evidence for cytokine regulation of cholesterol metabolism in herpesvirus-infected arterial cells by the lipoxygenase pathway. J Lipid Res 1990; 31: 299–305.PubMedGoogle Scholar
  21. 21.
    Hajjar DP, Falcone DJ, Fabricant CG, Fabricant J. Altered cholesteryl ester cycle is associated with lipid accumulation in herpesvirus-infected arterial smooth muscle cells. J Biol Chem 1985; 260: 6124–8.PubMedGoogle Scholar
  22. 22.
    Leatham EW, Bath PM, Tooze JA, Camm AJ. Increased monocyte tissue factor expression in coronary disease. Br Heart J 1995; 73: 10–13.PubMedCrossRefGoogle Scholar
  23. 23.
    Visser MR, Tracey PB, Vercellottii GM et al. Enhanced thrombin generation and platelet binding on herpes simplex virus-infected endothelium. Proc Natl Acad Sci USA 1988; 85: 8227–30.PubMedCrossRefGoogle Scholar
  24. 24.
    Paterson J, Cottral GE. Experimental coronary sclerosis. Lymphomatosis as a cause of coronary sclerosis in chickens. Arch Pathol 1950; 49: 699.Google Scholar
  25. 25.
    Fabricant CG, Fabricant J, Litrenta MM, Minick CR. Virus-induced atherosclerosis. J Exp Med 1978; 148: 335–40.PubMedCrossRefGoogle Scholar
  26. 26.
    Fabricant CG, Fabricant J, Minick CR, Litrenta MM. Herpesvirus-induced atherosclerosis in chickens. Fed Proc 1983; 42: 2467–9.Google Scholar
  27. 27.
    Minick CR, Fabricant CG, Fabricant J, Litrenta MM. Atheroarteriosclerosis induced by infection with a herpesvirus. Am J Path 1979; 96: 673–706.PubMedGoogle Scholar
  28. 28.
    Fabricant CG, Hajjar DP, Minick CR, Fabricant J. Herpesvirus infcetion enhances cholesterol and cholesteryl ester accumulation in cultured arterial smooth muscle cells. Am J Path 1981; 105: 176–84.PubMedGoogle Scholar
  29. 29.
    Pyrzak R, Shih JC. Detection of specific DNA segments of Marek’s disease herpes virus in quail susceptible to atherosclerosis. Atherosclerosis 1987; 68: 77–85.PubMedCrossRefGoogle Scholar
  30. 30.
    Span AH, Grauls G, Bosman F, Van Boven CP, Bruggeman CA. Cytomegalovirus infection induces vascular injury in the rat. Artherosclerosis 1992; 93: 41–52.CrossRefGoogle Scholar
  31. 31.
    Lemstrom KB, Bruning JH, Bruggeman CA et al. Cytomegalovirus infection enhances smooth muscle cell proliferation and intimal thickening of rat aortic allograft. J Clin Invest 1993; 92: 549–58.PubMedGoogle Scholar
  32. 32.
    Melnick JL, Adam E, Debakey ME. Cytomegalovirus and atherosclerosis. Eur Heart J 1993; 14(Suppl K): 30–8.PubMedGoogle Scholar
  33. 33.
    Melnick JL, Petrie BL, Dreesman GR et al. Cytomegalovirus antigen within human arterial smooth muscle cells. Lancet 1983; 2: 644–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Gyorkey F, Melnick JL, Guinn GA, Gyorkey P, DeBakey ME. Herpesviridae in the endothelial and smooth muscle cells of the proximal aorta in arteriosclerotic patients. Exp Mol Pathol 1984; 40: 328–39.PubMedCrossRefGoogle Scholar
  35. 35.
    Hendrix MG, Dormans PH, Kitslaar P, Bosman F, Bruggeman CA. The presence of cytomegalovirus nucleic acids in arterial walls of atherosclerotic and non-atherosclerotic patients. Am J Pathol 1989; 134: 1151–7.PubMedGoogle Scholar
  36. 36.
    Hendrix MG, Salimans MM, van Boven CP, Bruggeman CA. High prevalence of latently present cytomegalovirus in arterial walls of patients suffering from grade III atherosclerosis. Am J Pathol 1990; 136: 23–8.PubMedGoogle Scholar
  37. 37.
    Hendrix MG, Daemen M, Bruggeman CA. Cytomegalovirus nucleic acid distribution within the human vascular tree. Am J Pathol 1991; 138: 563–7.PubMedGoogle Scholar
  38. 38.
    Bruggeman CA, Dam-Mieras MC. The possible role of cytomegalovirus in atherogenesis. In: Progress in Medical Virology (Melnick JL, ed) vol 38. Karger, Basel, Switzerland, 1991; pp. 1–26.Google Scholar
  39. 39.
    Yamashiroya HM, Ghosh L, Yang R, Robertson AL Jr. Herpesviridae in the coronary arteries and aorta of young trauma victims. Am J Pathol 1988; 130: 71–9.PubMedGoogle Scholar
  40. 40.
    Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet 1997; 350: 430–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Adam E, Melnick JL, Probtsfield JL et al. High levels of cytomegalovirus antibody in patients requiring vascular surgery for atherosclerosis. Lancet 1987; 2: 291–3.PubMedCrossRefGoogle Scholar
  42. 42.
    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: 499–504.PubMedCrossRefGoogle Scholar
  43. 43.
    Heiss G, Sharrett AR, Barnes R et al. Carotid atherosclerosis measured by B-mode ultrasound in populations: associations with cardiovascular risk factors in the ARIC Study. Am J Epidemiol 1991; 134: 250–6.PubMedGoogle Scholar
  44. 44.
    Sorlie PD, Adam E, Melnick JL et al. Cytomegalovirus/herpesvirus and carotid atherosclerosis: the ARIC study. J Med Virol 1994; 42: 33–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Nieto FJ, Adam E, Sorlie P et al. Cohort study of cytomegalovirus infection as a risk factor for carotid intimal-medial thickening, a measure of subclinical atherosclerosis. Circulation 1996; 94: 922–7.PubMedGoogle Scholar
  46. 46.
    Alder SP, Hur JK, Wang JB et al. Prior infection with cytomegalovirus is not a major risk factor for angiographically demonstrated coronary artery atherosclerosis. J Infect Dis 1998; 177: 209–12.Google Scholar
  47. 47.
    Chiu B, Viira E, Tucker W, Fong IA. Chlamydia pneumoniae, cytomegalovirus, and herpes simplex virus in atherosclerosis of the carotid artery. Circulation 1997; 96: 2144–8.PubMedGoogle Scholar
  48. 48.
    Speir E, Modali R, Huang ES et al. Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. Science 1994; 265: 391–4.PubMedCrossRefGoogle Scholar
  49. 49.
    Zhou YF, Leon MB, Waclawiw MA. Association between prior cytomegalovirus infection and the risk of restenosis after coronary atherectomy. N Engl J Med 1996; 335: 624–30.PubMedCrossRefGoogle Scholar
  50. 50.
    Radke PW, Merkelbach S, Dörge H et al. Low frequency of detectable human cytomegalovirus DNA in coronary atherosclerotic lesions obtained by coronary endatherectomy. J Am Coll Cardiol 1998; 271-A: 1111–31 [abstract].Google Scholar
  51. 51.
    Kol A, Sperti G, Shani J et al. Cytomegalovirus replication is not a cause of instability in unstable angina. Circulation 1995; 91: 1910–3.PubMedGoogle Scholar
  52. 52.
    Grattan MT, Moreno-Cabral CE, Starnes VA et al. Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. JAMA 1989; 261: 3561–6.PubMedCrossRefGoogle Scholar
  53. 53.
    Johnson DE, Gao SZ, Schroeder JS, DeCampli WM, Billingham ME. The spectrum of coronary artery pathological findings in human cardiac allografts. J Heart Transplant 1989; 8: 349–59.PubMedGoogle Scholar
  54. 54.
    Grattan MT. Accelerated graft atherosclerosis following cardiac transplantation: Clinical perspectives. Clin Cardiol 1991; 14(Suppl II): 16–20.Google Scholar
  55. 55.
    McDonald K, Rector TS, Braunlin EA, Kubo SH, Olirari MT. Association of coronary artery disease in cardiac transplant recipients with cytomegalovirus infection. Am J Cardiol 1989; 64: 359–62.PubMedCrossRefGoogle Scholar
  56. 56.
    Wu TC, Hruban RH, Ambinder RF et al. Demonstration of cytomegalovirus nucleic acids in the coronary arteries of transplanted hearts. Am J Pathol 1992; 140: 739–47.PubMedGoogle Scholar
  57. 57.
    Libby P, Egan D, Skarlatos S. Roles of infectious agents in atherosclerosis and restenosis: an assessment of the current evidence and need for future research. Circulation 1997; 96: 4095–103.PubMedGoogle Scholar
  58. 58.
    Key NS, Vercellotti GM, Winkelmann JC et al. Infection of vascular endothelial cells with herpes simplex virus enhances tissue factor activity and reduces thrombomodulin expression. Proc Natl Acad Sci USA 1990; 87: 7095–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Etingin OR, Silverstein RL, Hajjar DP. Identification of monocyte receptor on herpes-infected endothelial cells. Proc Natl Acad Sci USA 1991; 88: 7200–3.PubMedCrossRefGoogle Scholar
  60. 60.
    Dummer S, Lee A, Breinig MK et al. Investigation of cytomegalovirus infection as a risk factor for coronary atherosclerosis in the explanted hearts of patients undergoing heart transplantation. J Med Virol 1994; 44: 305–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Mendall MA, Goggin P, Molineaux N et al. Childhood living conditions and Helicobacter seropositivity in adult life. Lancet 1992; i: 896–7.CrossRefGoogle Scholar
  62. 62.
    Langman MJ, Cooke AR. Gastric and duodenal ulcer and their associated diseases. Lancet 1976; i: 680–3.CrossRefGoogle Scholar
  63. 63.
    Mendall MA, Goggin PM, Molineaux N et al. Relation of Helicobacter pylori infection and coronary heart disease. Br Heart J 1994; 71: 437–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Patel P, Mendall MA, Carrington D et al. Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors. BMJ 1995; 311: 711–4.PubMedGoogle Scholar
  65. 65.
    Birnie DH, Holme ER, McKay IC et al. Association between antibodies to heat shock protein 65 and coronary atherosclerosis. Eur Heart J 1998; 19: 387–94.PubMedCrossRefGoogle Scholar
  66. 66.
    Parente F, Maconi G, Imbesi V et al. Helicobacter pylori infection and coagulation in healthy people. BMJ 1997; 314: 1318–9.PubMedGoogle Scholar
  67. 67.
    Murray LJ, Bamford KB, O’Reilly DP, McCrum EE, Evans AE. Helicobacter pylori infection: relation with cardiovascular risk factors, ischaemic heart disease, and social class. Br Heart J 1995; 74: 497–501.PubMedCrossRefGoogle Scholar
  68. 68.
    Whincup PH, Mendall MA, Perry I, Strachan DP, Walker M. Prospective relations between Helicobacter pylori infection, coronary heart disease and stroke in middle aged men. Heart 1996; 75: 568–72.PubMedCrossRefGoogle Scholar
  69. 69.
    Wald NJ, Law MR, Morris JK, Bagnall AM. Helicobacter pylori infection and mortality from ischaemic heart disease: negative results from a large, prospective study. BMJ 1997; 315: 1199–201.PubMedGoogle Scholar
  70. 70.
    Strandberg TE, Tilvis RS, Vuoristo M, Lindroos M, Kosunen TU. Prospective study of Helicobacter pylori seropositivity and cardiovascular diseases in a general elderly population. BMJ 1997; 314: 1317–8.PubMedGoogle Scholar
  71. 71.
    Strachan DP, Mendall MA, Carrington D et al. Relation of Helicobacter pylori infection to 13-year mortality and incident ischemic heart disease in the Caerphilly prospective heart disease study. Circulation 1998; 98: 1286–90.PubMedGoogle Scholar
  72. 72.
    Sandifer QD, Vuilo S, Crompton G. Association of Helicobacter pylori infection with coronary heart disease: association may not be causal. BMJ 1996; 312: 251 [letter].PubMedGoogle Scholar
  73. 73.
    Danesh J, Peto R. Risk factors for coronary heart disease and infection with Helicobacter pylori: meta-analysis of 18 studies. BMJ 1998; 316: 1130–2.PubMedGoogle Scholar
  74. 74.
    Blasi F, Denti F, Erba M et al. Detection of Chlamydia pneumoniae but not Helicobacter pylori in atherosclerotic plaques of aortic aneurysms. J Clin Microbiol 1996; 34: 2766–9.PubMedGoogle Scholar
  75. 75.
    Pasceri V, Cammarota G, Patti G et al. Association of virulent Helicobacter pylori strains with ischemic heart disease. Circulation 1998; 97: 1675–9.PubMedGoogle Scholar
  76. 76.
    Loesche WJ. Role of Streptococcus mutans in human dental decay. Microbiol Rev 1986; 50: 353–80.PubMedGoogle Scholar
  77. 77.
    Slots J, Listgarten MA. Bacteroides gingivalis, Bacteroides intermedius and Actinobacillus actinomycetemcomitans in human periodontal diseases. J Clin Periodontol 1988; 15: 85–93.PubMedCrossRefGoogle Scholar
  78. 78.
    Mackenzie RS, Millard HD. Interrelated effects of diabetes, arteriosclerosis and calculus on alveolar bone loss. J Am Dent Assoc 1963; 66: 192–8.Google Scholar
  79. 79.
    Syrjänen J, Peltola J, Valtonen V et al. Dental infections in association with cerebral infarction in young and middle-aged men. J Intern Med 1989; 225: 179–84.PubMedCrossRefGoogle Scholar
  80. 80.
    Mattila K, Nieminen M, Valtonen V et al. Association between dental health and acute myocardial infarction. BMJ 1989; 298: 779–82.PubMedGoogle Scholar
  81. 81.
    Paunio K, Impivaara O, Tickso J, Maki J. Missing teeth and ischaemic heart disease in men aged 45–64 years. Eur Heart J 1993; 14(Suppl K): 54–6.PubMedGoogle Scholar
  82. 82.
    Mattila K, Valle MS, Nieminen MS, Valtonen VV, Hietanieni KL. Dental infections and coronary atherosclerosis. Atherosclerosis 1993; 103: 205–11.PubMedCrossRefGoogle Scholar
  83. 83.
    Seymour RA, Steele JG. Is there a link between periodontal disease and coronary heart disease? Br Dent J 1998; 184: 33–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Kweider M, Lowe GD, Murray GD, Kinane DF, McGowen DA. Dental disease, fibrinogen and white cell counts: links with myocardial infarction? Scot MedJ 1993; 38: 73–4.Google Scholar
  85. 85.
    Mattila K, Rasi V, Nieminen MS et al. Von Willebrand factor antigen and dental infections. Thromb Res 1989; 56: 325–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Shapira L, Soskolne WA, Sela MN, Offenbacher S, Barak V. The secretion of PGE2, IL-1 beta, IL-6 and TNF-alpha by adherent mononuclear cells from early onset periodontitis patients. J Periodontol 1994; 65: 139–46.PubMedGoogle Scholar
  87. 87.
    Marchant B, Ranjadayalan K, Stevenson R, Wilkinson P, Timmis AD. Circadian and seasonal factors in the pathogenesis of acute myocardial infarction: the influence of environmental temperature. Br Heart J 1993; 69: 385–7.PubMedCrossRefGoogle Scholar
  88. 88.
    Woodhouse PR, Khaw TK, Plummer M, Foley A, Meade TW. Seasonal variations of plasma fibrinogen and factor VII activity in the elderly: winter infections and deaths from cardiovascular disease. Lancet 1994; 343: 435–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Enquselassie F, Dobson AJ, Alexander HM, Steele PL. Seasons, temperature and coronary disease. Int J Epidemiol 1993; 22: 632–6.PubMedCrossRefGoogle Scholar
  90. 90.
    Housworth J, Langmuir AD. Excess mortality from epidemic influenza, 1957–1966. Am J Epidemiol 1974; 100: 40–8.PubMedGoogle Scholar
  91. 91.
    Spodick DH, Flessas AP, Johnson MM. Association of acute respiratory symptoms with onset of acute myocardial infarction: prospective investigation of 150 consecutive patients and matched controls. Am J Cardiol 1984; 53: 481–2.PubMedCrossRefGoogle Scholar
  92. 92.
    Meier CR, Jick SS, Derby LE, Vasilakis C, Jick H. Acute respiratory-tract infections and risk of first-time acute myocardial infarction. Lancet 1998; 351: 1467–8.PubMedCrossRefGoogle Scholar
  93. 93.
    Lau RC. Coxsackie B virus-specific IgM responses in coronary care unit patients. J Med Virol 1986; 18: 193–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Hannington G, Booth JC, Bowes RJ, Stern JC. Coxsackie B virus-specific IgM antibody and myocardial infarction. J Med Microbiol 1986; 21: 287–91.PubMedCrossRefGoogle Scholar
  95. 95.
    Levi G, Scalvini S, Volterrani M et al. Coxsackie virus heart disease. Eur Heart J 1988; 9: 1303–7.PubMedGoogle Scholar
  96. 96.
    Roivainen M, Alfthan G, Jousilahti P et al. Enterovirus infections as a possible risk factor for myocardial infarction. Circulation 1998; 98: 2534–7.PubMedGoogle Scholar
  97. 97.
    Paton P, Tabib A, Loire R, Tete R. Coronary artery lesions and human immunodeficiency virus infection. Res Virol 1993; 144: 225–31.PubMedGoogle Scholar
  98. 98.
    Best PJM, Edwards WD, Holmes Jr DR, Lerman A. Unique coronary arteriopathy associated with human immunodeficiency virus. J Am Coll Cardiol 1998; 272A: 1111–32 [abstract].Google Scholar

Copyright information

© Kluwer Academic Publishers 1999

Personalised recommendations