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Heart. Dec 1997; 78(6): 539–543.
PMCID: PMC1892342

Meta-analysis of the association of enteroviruses with human heart disease


The role of viruses in the genesis of both dilated cardiomyopathy (DCM) and acute myocarditis remains uncertain. Modern molecular techniques such as polymerase chain reaction (PCR) and in situ hybridisation are sensitive means of detecting viral genomic material in human myocardial tissue and may help to resolve the quest. Meta-analysis of the papers in the literature records studies of both acute myocarditis and DCM where molecular techniques were used to demonstrate enteroviruses. This review studies information from the published literature as well as statistical analysis of the cumulative molecular data relating enteroviruses to DCM, and to compare these findings with the information available on the role of enteroviruses in acute myocarditis. Twelve papers reported studies in acute myocarditis, of which 11 found higher percentages of enteroviral RNA positivity in the diseased population, giving an overall odds ratio of 4.4. Seventeen papers reported studies in DCM, with 11 recording higher positivity rates in these patients. Cumulative analysis of these data suggests an overall odds ratio of 3.8. The causative role of enteroviruses in acute myocarditis, particularly in children, is supported by meta-analysis of the available literature. The data on DCM is suggestive of an association but a proportion of the studies are negative.

Keywords: enteroviruses;  dilated cardiomyopathy;  myocarditis;  meta-analyses

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Selected References

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  • DE JAGER H, VAN CREVELD S. Myocarditis in newborns, caused by coxsackie virus; clinical and pathological data. Ann Paediatr. 1956 Jul-Aug;187(1-2):100–118. [PubMed]
  • JAVETT SN, HEYMANN S, MUNDEL B, PEPLER WJ, LURIE HI, GEAR J, MEASROCH V, KIRSCH Z. Myocarditis in the new newborn infant; a study of an outbreak associated with Coxsackie group B virus infection in a maternity home in Johannesburg. J Pediatr. 1956 Jan;48(1):1–22. [PubMed]
  • MONTGOMERY J, GEAR J, PRINSLOO FR, KAHN M, KIRSCH ZG. Myocarditis of the newborn; an outbreak in a maternity home in Southern Rhodesia associated with Coxsackie group-B virus infection. S Afr Med J. 1955 Jun 25;29(26):608–612. [PubMed]
  • Brown GC, Karunas RS. Relationship of congenital anomalies and maternal infection with selected enteroviruses. Am J Epidemiol. 1972 Mar;95(3):207–217. [PubMed]
  • Zvizdić S, Serić K, Radović S, Selak I. Izolacija virusa iz obdukcionog materijala za vrijeme epidemije coxsackie viroza, u Sarajevu 1985. god. Med Arh. 1990;44(1):39–42. [PubMed]
  • Burch GE, Sun SC, Chu KC, Sohal RS, Colcolough HL. Interstitial and coxsackievirus B myocarditis in infants and children. A comparative histologic and immunofluorescent study of 50 autopsied hearts. JAMA. 1968 Jan 1;203(1):1–8. [PubMed]
  • Basso NG, Fonseca ME, Garcia AG, Zuardi JA, Silva MR, Outani H. Enterovirus isolation from foetal and placental tissues. Acta Virol. 1990 Feb;34(1):49–57. [PubMed]
  • Dommergues M, Petitjean J, Aubry MC, Delezoide AL, Narcy F, Fallet-Bianco C, Freymuth F, Dumez Y, Lebon P. Fetal enteroviral infection with cerebral ventriculomegaly and cardiomyopathy. Fetal Diagn Ther. 1994 Mar-Apr;9(2):77–78. [PubMed]
  • Longson M, Cole FM, Davies D. Isolation of a Coxsackie virus group B, type 5, from the heart of a fatal case of myocarditis in an adult. J Clin Pathol. 1969 Nov;22(6):654–658. [PMC free article] [PubMed]
  • Soutar CA. Unusual case of viral pericarditis. Lancet. 1971 Mar 6;1(7697):498–498. [PubMed]
  • El-Hagrassy MM, Banatvala JE, Coltart DJ. Coxsackie-B-virus-specific IgM responses in patients with cardiac and other diseases. Lancet. 1980 Nov 29;2(8205):1160–1162. [PubMed]
  • Bell EJ, McCartney RA. A study of Coxsackie B virus infections, 1972-1983. J Hyg (Lond) 1984 Oct;93(2):197–203. [PMC free article] [PubMed]
  • McCartney RA, Banatvala JE, Bell EJ. Routine use of mu-antibody-capture ELISA for the serological diagnosis of Coxsackie B virus infections. J Med Virol. 1986 Jul;19(3):205–212. [PubMed]
  • Hilton DA, Variend S, Pringle JH. Demonstration of Coxsackie virus RNA in formalin-fixed tissue sections from childhood myocarditis cases by in situ hybridization and the polymerase chain reaction. J Pathol. 1993 May;170(1):45–51. [PubMed]
  • Martin AB, Webber S, Fricker FJ, Jaffe R, Demmler G, Kearney D, Zhang YH, Bodurtha J, Gelb B, Ni J, et al. Acute myocarditis. Rapid diagnosis by PCR in children. Circulation. 1994 Jul;90(1):330–339. [PubMed]
  • Jin O, Sole MJ, Butany JW, Chia WK, McLaughlin PR, Liu P, Liew CC. Detection of enterovirus RNA in myocardial biopsies from patients with myocarditis and cardiomyopathy using gene amplification by polymerase chain reaction. Circulation. 1990 Jul;82(1):8–16. [PubMed]
  • Nicholson F, Ajetunmobi JF, Li M, Shackleton EA, Starkey WG, Illavia SJ, Muir P, Banatvala JE. Molecular detection and serotypic analysis of enterovirus RNA in archival specimens from patients with acute myocarditis. Br Heart J. 1995 Nov;74(5):522–527. [PMC free article] [PubMed]
  • Weiss LM, Movahed LA, Billingham ME, Cleary ML. Detection of Coxsackievirus B3 RNA in myocardial tissues by the polymerase chain reaction. Am J Pathol. 1991 Feb;138(2):497–503. [PMC free article] [PubMed]
  • Petitjean J, Kopecka H, Freymuth F, Langlard JM, Scanu P, Galateau F, Bouhour JB, Ferrière M, Charbonneau P, Komajda M. Detection of enteroviruses in endomyocardial biopsy by molecular approach. J Med Virol. 1992 May;37(1):76–82. [PubMed]
  • Giacca M, Severini GM, Mestroni L, Salvi A, Lardieri G, Falaschi A, Camerini F. Low frequency of detection by nested polymerase chain reaction of enterovirus ribonucleic acid in endomyocardial tissue of patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1994 Oct;24(4):1033–1040. [PubMed]
  • Koide H, Kitaura Y, Deguchi H, Ukimura A, Kawamura K, Hirai K. Genomic detection of enteroviruses in the myocardium--studies on animal hearts with coxsackievirus B3 myocarditis and endomyocardial biopsies from patients with myocarditis and dilated cardiomyopathy. Jpn Circ J. 1992 Oct;56(10):1081–1093. [PubMed]
  • Satoh M, Tamura G, Segawa I. Enteroviral RNA in endomyocardial biopsy tissues of myocarditis and dilated cardiomyopathy. Pathol Int. 1994 May;44(5):345–351. [PubMed]
  • Bowles NE, Richardson PJ, Olsen EG, Archard LC. Detection of Coxsackie-B-virus-specific RNA sequences in myocardial biopsy samples from patients with myocarditis and dilated cardiomyopathy. Lancet. 1986 May 17;1(8490):1120–1123. [PubMed]
  • Ueno H, Yokota Y, Shiotani H, Yokoyama M, Itoh H, Ishido S, Maeda S, Katayama Y, Hotta H. Significance of detection of enterovirus RNA in myocardial tissues by reverse transcription-polymerase chain reaction. Int J Cardiol. 1995 Sep;51(2):157–164. [PubMed]
  • Grasso M, Arbustini E, Silini E, Diegoli M, Percivalle E, Ratti G, Bramerio M, Gavazzi A, Vigano M, Milanesi G. Search for Coxsackievirus B3 RNA in idiopathic dilated cardiomyopathy using gene amplification by polymerase chain reaction. Am J Cardiol. 1992 Mar 1;69(6):658–664. [PubMed]
  • Liljeqvist JA, Bergström T, Holmström S, Samuelson A, Yousef GE, Waagstein F, Jeansson S. Failure to demonstrate enterovirus aetiology in Swedish patients with dilated cardiomyopathy. J Med Virol. 1993 Jan;39(1):6–10. [PubMed]
  • Muir P, Nicholson F, Illavia SJ, McNeil TS, Ajetunmobi JF, Dunn H, Starkey WG, Reetoo KN, Cary NR, Parameshwar J, et al. Serological and molecular evidence of enterovirus infection in patients with end-stage dilated cardiomyopathy. Heart. 1996 Sep;76(3):243–249. [PMC free article] [PubMed]
  • Keeling PJ, Jeffery S, Caforio AL, Taylor R, Bottazzo GF, Davies MJ, McKenna WJ. Similar prevalence of enteroviral genome within the myocardium from patients with idiopathic dilated cardiomyopathy and controls by the polymerase chain reaction. Br Heart J. 1992 Dec;68(6):554–559. [PMC free article] [PubMed]
  • Zoll GJ, Melchers WJ, Kopecka H, Jambroes G, van der Poel HJ, Galama JM. General primer-mediated polymerase chain reaction for detection of enteroviruses: application for diagnostic routine and persistent infections. J Clin Microbiol. 1992 Jan;30(1):160–165. [PMC free article] [PubMed]
  • Martí V, Coll P, Ballester M, Obrador D, Carrió I, Moya C, Lama E, Augè JM, Archard LC. Enterovirus persistence and myocardial damage detected by 111In-monoclonal antimyosin antibodies in patients with dilated cardiomyopathy. Eur Heart J. 1996 Apr;17(4):545–549. [PubMed]
  • Bowles NE, Rose ML, Taylor P, Banner NR, Morgan-Capner P, Cunningham L, Archard LC, Yacoub MH. End-stage dilated cardiomyopathy. Persistence of enterovirus RNA in myocardium at cardiac transplantation and lack of immune response. Circulation. 1989 Nov;80(5):1128–1136. [PubMed]
  • Schwaiger A, Umlauft F, Weyrer K, Larcher C, Lyons J, Mühlberger V, Dietze O, Grünewald K. Detection of enteroviral ribonucleic acid in myocardial biopsies from patients with idiopathic dilated cardiomyopathy by polymerase chain reaction. Am Heart J. 1993 Aug;126(2):406–410. [PubMed]
  • Khan M, Why H, Richardson P, Archard L. Nucleotide sequencing of PCR products shows the presence of Coxsackie-B3 virus in endomyocardial biopsies from patients with myocarditis or dilated cardiomyopathy. Biochem Soc Trans. 1994 May;22(2):176S–176S. [PubMed]
  • Andreoletti L, Wattre P, Decoene C, Lobert PE, Dewilde A, Hober D. Detection of enterovirus-specific RNA sequences in explanted myocardium biopsy specimens from patients with dilated or ischemic cardiomyopathy. Clin Infect Dis. 1995 Nov;21(5):1315–1317. [PubMed]
  • Chiang FT, Lin LI, Tseng YZ, Tseng CD, Hsu KL, Wu TL, Ho SW. Detection of enterovirus RNA in patients with idiopathic dilated cardiomyopathy by polymerase chain reaction. J Formos Med Assoc. 1992 Jun;91(6):569–574. [PubMed]
  • Keeling PJ, Lukaszyk A, Poloniecki J, Caforio AL, Davies MJ, Booth JC, McKenna WJ. A prospective case-control study of antibodies to coxsackie B virus in idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1994 Mar 1;23(3):593–598. [PubMed]
  • Cambridge G, MacArthur CG, Waterson AP, Goodwin JF, Oakley CM. Antibodies to Coxsackie B viruses in congestive cardiomyopathy. Br Heart J. 1979 Jun;41(6):692–696. [PMC free article] [PubMed]
  • Kutaura Y. Experimental coxsackie B virus myocarditis in mice: 18 month histopathological and virological study. Jpn Circ J. 1981 Jul;45(7):747–762. [PubMed]
  • Morita H. Experimental coxsackie B-3 virus myocarditis in golden hamsters. Light and electron microscopy findings in a long-term follow-up study. Jpn Circ J. 1981 Jun;45(6):713–729. [PubMed]
  • Eschenhagen T, Diederich M, Kluge SH, Magnussen O, Mene U, Müller F, Schmitz W, Scholz H, Weil J, Sent U, et al. Bovine hereditary cardiomyopathy: an animal model of human dilated cardiomyopathy. J Mol Cell Cardiol. 1995 Jan;27(1):357–370. [PubMed]
  • Hajjar RJ, Liao R, Young JB, Fuleihan F, Glass MG, Gwathmey JK. Pathophysiological and biochemical characterisation of an avian model of dilated cardiomyopathy: comparison to findings in human dilated cardiomyopathy. Cardiovasc Res. 1993 Dec;27(12):2212–2221. [PubMed]
  • Gruver EJ, Glass MG, Marsh JD, Gwathmey JK. An animal model of dilated cardiomyopathy: characterization of dihydropyridine receptors and contractile performance. Am J Physiol. 1993 Nov;265(5 Pt 2):H1704–H1711. [PubMed]
  • Liao R, Nascimben L, Friedrich J, Gwathmey JK, Ingwall JS. Decreased energy reserve in an animal model of dilated cardiomyopathy. Relationship to contractile performance. Circ Res. 1996 May;78(5):893–902. [PubMed]
  • Genao A, Seth K, Schmidt U, Carles M, Gwathmey JK. Dilated cardiomyopathy in turkeys: an animal model for the study of human heart failure. Lab Anim Sci. 1996 Aug;46(4):399–404. [PubMed]
  • Chow LH, Beisel KW, McManus BM. Enteroviral infection of mice with severe combined immunodeficiency. Evidence for direct viral pathogenesis of myocardial injury. Lab Invest. 1992 Jan;66(1):24–31. [PubMed]
  • Khatib R, Chason JL, Silberberg BK, Lerner AM. Age-dependent pathogenicity of group B coxsackieviruses in Swiss-Webster mice: infectivity for myocardium and pancreas. J Infect Dis. 1980 Mar;141(3):394–403. [PubMed]
  • Henke A, Huber S, Stelzner A, Whitton JL. The role of CD8+ T lymphocytes in coxsackievirus B3-induced myocarditis. J Virol. 1995 Nov;69(11):6720–6728. [PMC free article] [PubMed]
  • Schwimmbeck PL, Badorff C, Rohn G, Schulze K, Schultheiss HP. The role of sensitized T-cells in myocarditis and dilated cardiomyopathy. Int J Cardiol. 1996 May;54(2):117–125. [PubMed]
  • Caforio AL. Role of autoimmunity in dilated cardiomyopathy. Br Heart J. 1994 Dec;72(6 Suppl):S30–S34. [PMC free article] [PubMed]
  • Tracy S, Chapman NM, Romero J, Ramsingh AI. Genetics of coxsackievirus B cardiovirulence and inflammatory heart muscle disease. Trends Microbiol. 1996 May;4(5):175–179. [PubMed]
  • Huber SA, Lodge PA. Coxsackievirus B-3 myocarditis. Identification of different pathogenic mechanisms in DBA/2 and Balb/c mice. Am J Pathol. 1986 Feb;122(2):284–291. [PMC free article] [PubMed]

Figures and Tables

Figure 1
Evidence for association of enteroviruses with idiopathic myocarditis. The bar charts show the percentage of samples found to be positive with error bars showing the standard error of the binomial distribution. (X is the number of samples with enteroviral ...
Figure 2
Evidence for association of enteroviruses with dilated cardiomyopathy. The bar charts show the percentage of samples found to be positive with error bars showing the standard error of the binomial distribution. (X is the number of samples with enteroviral ...

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