Coxsackievirus-induced murine myocarditis and immunomodulatory interventions

  • Michel Noutsias
  • Peter Liu
Part of the Progress in Inflammation Research book series (PIR)


Human acute myocarditis (AMC) and its sequelae, inflammatory cardiomyopathy (DCMi), are mostly caused by cardiotropic viral infections in the Western world. Insights from coxsackievirus B (CVB)-induced experimental myocarditis have substantially contributed to a better understanding of the complex pathogenesis of myocarditis, and have also helped to explain the highly differential courses of human disease. Several inbred murine strains are available for modeling acute myocarditis and chronic ongoing myocarditis after intraperitoneal CVB inoculation. Acute, subacute and chronic phases can be differentiated. The onset and the differential courses of CVB-induced myocarditis are orchestrated by complex virus-host interactions. Several immunomodulatory regimens targeting key players of the innate and the adaptive immune system have unraveled the underlying mechanisms, and identified promising intervention strategies. The latter may, once they have been clinically evaluated, translate to novel treatment strategies for patients.


Viral Myocarditis Acute Myocarditis Immunomodulatory Intervention Inflammatory Cardiomyopathy Murine Myocarditis 
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.


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  1. 1.
    Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, O’Connell J, Olsen E, Thiene G, Goodwin J, Gyarfas I et al (1996) Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation 93: 841–2PubMedGoogle Scholar
  2. 2.
    Taylor DO, Edwards LB, Boucek MM, Trulock EP, Waltz DA, Keck BM, Hertz MI (2006) Registry of the International Society for Heart and Lung Transplantation: Twenty-third official adult heart transplantation report — 2006. J Heart Lung Transplant 25: 869–79PubMedGoogle Scholar
  3. 3.
    Karjalainen J, Heikkila J (1999) Incidence of three presentations of acute myocarditis in young men in military service. A 20-year experience. Eur Heart J 20: 1120–5PubMedGoogle Scholar
  4. 4.
    D’Ambrosio A, Patti G, Manzoli A, Sinagra G, Di Lenarda A, Silvestri F, Di Sciascio G (2001) The fate of acute myocarditis between spontaneous improvement and evolution to dilated cardiomyopathy: A review. Heart 85: 499–504PubMedGoogle Scholar
  5. 5.
    Noutsias M, Seeberg B, Schultheiss HP, Kühl U (1999) Expression of cell adhesion molecules in dilated cardiomyopathy: Evidence for endothelial activation in inflammatory cardiomyopathy. Circulation 99: 2124–31PubMedGoogle Scholar
  6. 6.
    Kühl U, Pauschinger M, Bock T, Klingel K, Schwimmbeck CP, Seeberg B, Krautwurm L, Noutsias M, Poller W, Schultheiss HP et al (2003) Parvovirus B19 infection mimicking acute myocardial infarction. Circulation 108: 945–50PubMedGoogle Scholar
  7. 7.
    Kühl U, Pauschinger M, Noutsias M, Seeberg B, Bock T, Lassner D, Poller W, Kandolf R, Schultheiss HP (2005) High prevalence of viral genomes and multiple viral infections in the myocardium of adults with ‘idiopathic’ left ventricular dysfunction. Circulation 111: 887–93PubMedGoogle Scholar
  8. 8.
    Andreoletti L, Leveque N, Boulagnon C, Brasselet C, Fornes P (2009) Viral causes of human myocarditis. Arch Cardiovasc Dis 102: 559–68PubMedGoogle Scholar
  9. 9.
    Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, Stromberg A, van Veldhuisen DJ, Atar D, Hoes AW et al (2008) ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J 29: 2388–442PubMedGoogle Scholar
  10. 10.
    Noutsias M, Pauschinger M, Poller WC, Schultheiss HP, Kuhl U (2004) Immunomodulatory treatment strategies in inflammatory cardiomyopathy: Current status and future perspectives. Expert Rev Cardiovasc Ther 2: 37–51PubMedGoogle Scholar
  11. 11.
    Beck MA, Shi Q, Morris VC, Levander OA (1995) Rapid genomic evolution of a nonvirulent coxsackievirus B3 in selenium-deficient mice results in selection of identical virulent isolates. Nat Med 1: 433–6PubMedGoogle Scholar
  12. 12.
    Ilback NG, Wesslen L, Fohlman J, Friman G (1996) Effects of methyl mercury on cytok-ines, inflammation and virus clearance in a common infection (coxsackie B3 myocarditis). Toxicol Lett 89: 19–28PubMedGoogle Scholar
  13. 13.
    Woodruff JF, Woodruff JJ (1974) Involvement of T lymphocytes in the pathogenesis of coxsackie virus B3 heart disease. J Immunol 113: 1726–34PubMedGoogle Scholar
  14. 14.
    Huber SA, Lodge PA (1986) Coxsackievirus B-3 myocarditis. Identification of different pathogenic mechanisms in DBA/2 and Balb/c mice. Am J Pathol 122: 284–91PubMedGoogle Scholar
  15. 15.
    Lane JR, Neumann DA, Lafond-Walker A, Herskowitz A, Rose NR (1991) LPS promotes CB3-induced myocarditis in resistant B10.A mice. Cell Immunol 136: 219–33PubMedGoogle Scholar
  16. 16.
    Heymans S, Pauschinger M, De Palma A, Kallwellis-Opara A, Rutschow S, Swinnen M, Vanhoutte D, Gao F, Torpai R, Baker AH et al (2006) Inhibition of urokinase-type plasminogen activator or matrix metalloproteinases prevents cardiac injury and dysfunction during viral myocarditis. Circulation 114: 565–73PubMedGoogle Scholar
  17. 17.
    Wolfgram LJ, Beisel KW, Herskowitz A, Rose NR (1986) Variations in the susceptibility to Coxsackievirus B3-induced myocarditis among different strains of mice. J Immunol 136: 1846–52PubMedGoogle Scholar
  18. 18.
    Chow LH, Gauntt CJ, McManus BM (1991) Differential effects of myocarditic variants of Coxsackievirus B3 in inbred mice. A pathologic characterization of heart tissue damage. Lab Invest 64: 55–64PubMedGoogle Scholar
  19. 19.
    Mall G, Klingel K, Albrecht M, Seemann M, Rieger P, Kandolf R (1991) Natural history of Coxsackievirus B3-induced myocarditis in ACA/Sn mice: Viral persistence demonstrated by quantitative in situ hybridization histochemistry. Eur Heart J 12 Suppl D: 121–3PubMedGoogle Scholar
  20. 20.
    Klingel K, Kandolf R (1993) The role of enterovirus replication in the development of acute and chronic heart muscle disease in different immunocompetent mouse strains. Scand J Infect Dis Suppl 88: 79–85PubMedGoogle Scholar
  21. 21.
    Feldman AM, McNamara D (2000) Myocarditis. N Engl J Med 343: 1388–98PubMedGoogle Scholar
  22. 22.
    Rutschow S, Leschka S, Westermann D, Puhl K, Weitz A, Ladyszenskij L, Jaeger S, Zeichhardt H, Noutsias M, Schultheiss HP et al (2010) Left ventricular enlargement in coxsackievirus-B3 induced chronic myocarditis — Ongoing inflammation and an imbalance of the matrix degrading system. Eur J Pharmacol 630: 145–51PubMedGoogle Scholar
  23. 23.
    Gluck B, Schmidtke M, Merkle I, Stelzner A, Gemsa D (2001) Persistent expression of cytokines in the chronic stage of CVB3-induced myocarditis in NMRI mice. J Mol Cell Cardiol 33: 1615–26PubMedGoogle Scholar
  24. 24.
    Nakamura H, Yamamoto T, Yamamura T, Nakao F, Umemoto S, Shintaku T, Yamaguchi K, Liu P, Matsuzaki M (1999) Repetitive coxsackievirus infection induces cardiac dilatation in post-myocarditic mice. Jpn Circ J 63: 794–802PubMedGoogle Scholar
  25. 25.
    Takata S, Nakamura H, Umemoto S, Yamaguchil K, Sekine T, Kato T, Nishioka K, Matsuzaki M (2004) Identification of autoantibodies with the corresponding antigen for repetitive coxsackievirus infection-induced cardiomyopathy. Circ J 68: 677–82PubMedGoogle Scholar
  26. 26.
    Woodruff JF (1980) Viral myocarditis. A review. Am J Pathol 101: 425–84PubMedGoogle Scholar
  27. 27.
    Olbrich HG (2001) [Epidemiology-etiology of dilated cardiomyopathy]. Z Kardiol 90 Suppl 1: 2–9PubMedGoogle Scholar
  28. 28.
    Aly M, Wiltshire S, Chahrour G, Osti JC, Vidal SM (2007) Complex genetic control of host susceptibility to coxsackievirus B3-induced myocarditis. Genes Immun 8: 193–204PubMedGoogle Scholar
  29. 29.
    Badorff C, Lee GH, Lamphear BJ, Martone ME, Campbell KP, Rhoads RE, Knowlton KU (1999) Enteroviral protease 2A cleaves dystrophin: Evidence of cytoskeletal disruption in an acquired cardiomyopathy. Nat Med 5: 320–6PubMedGoogle Scholar
  30. 30.
    Huber SA, Budd RC, Rossner K, Newell MK (1999) Apoptosis in coxsackievirus B3-induced myocarditis and dilated cardiomyopathy. Ann N Y Acad Sci 887: 181–90PubMedGoogle Scholar
  31. 31.
    Wessely R, Henke A, Zell R, Kandolf R, Knowlton KU (1998) Low-level expression of a mutant coxsackieviral cDNA induces a myocytopathic effect in culture: An approach to the study of enteroviral persistence in cardiac myocytes. Circulation 98: 450–7PubMedGoogle Scholar
  32. 32.
    Gauntt CJ, Arizpe HM, Higdon AL, Wood HJ, Bowers DF, Rozek MM, Crawley R (1995) Molecular mimicry, anti-coxsackievirus B3 neutralizing monoclonal antibodies, and myocarditis. J Immunol 154: 2983–95PubMedGoogle Scholar
  33. 33.
    Caforio AL, Mahon NJ, Tona F, McKenna WJ (2002) Circulating cardiac autoantibodies in dilated cardiomyopathy and myocarditis: Pathogenetic and clinical significance. Eur J Heart Fail 4: 411–7PubMedGoogle Scholar
  34. 34.
    Cooper LT Jr (2009) Myocarditis. N Engl J Med 360: 1526–38PubMedGoogle Scholar
  35. 35.
    Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, Horwitz MS, Crowell RL, Finberg RW (1997) Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 275: 1320–3PubMedGoogle Scholar
  36. 36.
    Bergelson JM, Chan M, Solomon KR, St John NF, Lin H, Finberg RW (1994) Decayaccelerating factor (CD55), a glycosylphosphatidylinositol-anchored complement regulatory protein, is a receptor for several echoviruses. Proc Natl Acad Sci USA 91: 6245–9PubMedGoogle Scholar
  37. 37.
    Chow LH, Beisel KW, McManus BM (1992) Enteroviral infection of mice with severe combined immunodeficiency. Evidence for direct viral pathogenesis of myocardial injury. Lab Invest 66: 24–31PubMedGoogle Scholar
  38. 38.
    Tomioka N, Kishimoto C, Matsumori A, Kawai C (1986) Effects of prednisolone on acute viral myocarditis in mice. J Am Coll Cardiol 7: 868–72PubMedGoogle Scholar
  39. 39.
    Fuse K, Chan G, Liu Y, Gudgeon P, Husain M, Chen M, Yeh WC, Akira S, Liu PP (2005) Myeloid differentiation factor-88 plays a crucial role in the pathogenesis of Coxsackievirus B3-induced myocarditis and influences type I interferon production. Circulation 112: 2276–85PubMedGoogle Scholar
  40. 40.
    McManus BM, Chow LH, Wilson JE, Anderson DR, Gulizia JM, Gauntt CJ, Klingel KE, Beisel KW, Kandolf R (1993) Direct myocardial injury by enterovirus: A central role in the evolution of murine myocarditis. Clin Immunol Immunopathol 68: 159–69PubMedGoogle Scholar
  41. 41.
    Seko Y, Takahashi N, Yagita H, Okumura K, Yazaki Y (1997) Expression of cytokine mRNAs in murine hearts with acute myocarditis caused by coxsackievirus b3. J Pathol 183: 105–8PubMedGoogle Scholar
  42. 42.
    Ruppert V, Meyer T, Pankuweit S, Jonsdottir T, Maisch B (2008) Activation of STAT1 transcription factor precedes up-regulation of coxsackievirus-adenovirus receptor during viral myocarditis. Cardiovasc Pathol 17: 81–92PubMedGoogle Scholar
  43. 43.
    Kishimoto C, Kawamata H, Sakai S, Shinohara H, Ochiai H (2000) Role of MIP-2 in coxsackievirus B3 myocarditis. J Mol Cell Cardiol 32: 631–8PubMedGoogle Scholar
  44. 44.
    Li J, Schwimmbeck PL, Tschöpe C, Leschka S, Husmann L, Rutschow S, Reichenbach F, Noutsias M, Kobalz U, Poller W et al (2002) Collagen degradation in a murine myocarditis model: Relevance of matrix metalloproteinase in association with inflammatory induction. Cardiovasc Res 56: 235–47PubMedGoogle Scholar
  45. 45.
    Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: Critical proteins linking innate and acquired immunity. Nat Immunol 2: 675–80PubMedGoogle Scholar
  46. 46.
    Huang CH, Vallejo JG, Kollias G, Mann DL (2009) Role of the innate immune system in acute viral myocarditis. Basic Res Cardiol 104: 228–37PubMedGoogle Scholar
  47. 47.
    Fairweather D, Yusung S, Frisancho S, Barrett M, Gatewood S, Steele R, Rose NR (2003) IL-12 receptor beta 1 and Toll-like receptor 4 increase IL-1 beta-and IL-18-associated myocarditis and coxsackievirus replication. J Immunol 170: 4731–7PubMedGoogle Scholar
  48. 48.
    Frisancho-Kiss S, Davis SE, Nyland JF, Frisancho JA, Cihakova D, Barrett MA, Rose NR, Fairweather D (2007) Cutting edge: Cross-regulation by TLR4 and T cell Ig mucin-3 determines sex differences in inflammatory heart disease. J Immunol 178: 6710–4PubMedGoogle Scholar
  49. 49.
    Godeny EK, Gauntt CJ (1987) Murine natural killer cells limit coxsackievirus B3 replication. J Immunol 139: 913–8PubMedGoogle Scholar
  50. 50.
    Kishimoto C, Kuribayashi K, Masuda T, Tomioka N, Kawai C (1985) Immunologic behavior of lymphocytes in experimental viral myocarditis: Significance of T lymphocytes in the severity of myocarditis and silent myocarditis in BALB/c-nu/nu mice. Circulation 71: 1247–54PubMedGoogle Scholar
  51. 51.
    Seko Y, Tsuchimochi H, Nakamura T, Okumura K, Naito S, Imataka K, Fujii J, Takaku F, Yazaki Y (1990) Expression of major histocompatibility complex class I antigen in murine ventricular myocytes infected with Coxsackievirus B3. Circ Res 67: 360–7PubMedGoogle Scholar
  52. 52.
    Seko Y, Matsuda H, Kato K, Hashimoto Y, Yagita H, Okumura K, Yazaki Y (1993) Expression of intercellular adhesion molecule-1 in murine hearts with acute myocarditis caused by coxsackievirus B3. J Clin Invest 91: 1327–36PubMedGoogle Scholar
  53. 53.
    Seko Y, Yagita H, Okumura K, Yazaki Y (1994) T-cell receptor V beta gene expression in infiltrating cells in murine hearts with acute myocarditis caused by coxsackievirus B3. Circulation 89: 2170–5PubMedGoogle Scholar
  54. 54.
    Gebhard JR, Perry CM, Harkins S, Lane T, Mena I, Asensio VC, Campbell IL, Whitton JL (1998) Coxsackievirus B3-induced myocarditis: Perforin exacerbates disease, but plays no detectable role in virus clearance. Am J Pathol 153: 417–28PubMedGoogle Scholar
  55. 55.
    Huber SA, Feldman AM, Sartini D (2006) Coxsackievirus B3 induces T regulatory cells, which inhibit cardiomyopathy in tumor necrosis factor-alpha transgenic mice. Circ Res 99: 1109–16PubMedGoogle Scholar
  56. 56.
    Li K, Xu W, Guo Q, Jiang Z, Wang P, Yue Y, Xiong S (2009) Differential macrophage polarization in male and female BALB/c mice infected with coxsackievirus B3 defines susceptibility to viral myocarditis. Circ Res 105: 353–64PubMedGoogle Scholar
  57. 57.
    Huber SA, Job LP (1983) Cellular immune mechanisms in Coxsackievirus group B, type 3 induced myocarditis in Balb/C mice. Adv Exp Med Biol 161: 491–508PubMedGoogle Scholar
  58. 58.
    Seko Y, Takahashi N, Ishiyama S, Nishikawa T, Kasajima T, Hiroe M, Suzuki S, Ishiwata S, Kawai S, Azuma M et al (1998) Expression of costimulatory molecules B7-1, B7-2, and CD40 in the heart of patients with acute myocarditis and dilated cardiomyopathy. Circulation 97: 637–9PubMedGoogle Scholar
  59. 59.
    Huber SA, Pfaeffle B (1994) Differential Th1 and Th2 cell responses in male and female BALB/c mice infected with coxsackievirus group B type 3. J Virol 68: 5126–32PubMedGoogle Scholar
  60. 60.
    Seko Y, Takahashi N, Oshima H, Shimozato O, Akiba H, Kobata T, Yagita H, Okumura K, Azuma M, Yazaki Y (1999) Expression of tumour necrosis factor (TNF) receptor/ligand superfamily co-stimulatory molecules CD40, CD30L, CD27L, and OX40L in murine hearts with chronic ongoing myocarditis caused by coxsackie virus B3. J Pathol 188: 423–30PubMedGoogle Scholar
  61. 61.
    Rutschow S, Li J, Schultheiss HP, Pauschinger M (2006) Myocardial proteases and matrix remodeling in inflammatory heart disease. Cardiovasc Res 69: 646–56PubMedGoogle Scholar
  62. 62.
    Huber SA, Mortensen A, Moulton G (1996) Modulation of cytokine expression by CD4+ T cells during coxsackievirus B3 infections of BALB/c mice initiated by cells expressing the gamma delta+ T-cell receptor. J Virol 70: 3039–44PubMedGoogle Scholar
  63. 63.
    Deonarain R, Cerullo D, Fuse K, Liu PP, Fish EN (2004) Protective role for interferonbeta in coxsackievirus B3 infection. Circulation 110: 3540–3PubMedGoogle Scholar
  64. 64.
    Kubota T, Miyagishima M, Frye CS, Alber SM, Bounoutas GS, Kadokami T, Watkins SC, McTiernan CF, Feldman AM (2001) Overexpression of tumor necrosis factor-alpha activates both anti-and pro-apoptotic pathways in the myocardium. J Mol Cell Cardiol 33: 1331–44PubMedGoogle Scholar
  65. 65.
    Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, Demetris AJ, Feldman AM (1997) Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ Res 81: 627–35PubMedGoogle Scholar
  66. 66.
    Shioi T, Matsumori A, Sasayama S (1996) Persistent expression of cytokine in the chronic stage of viral myocarditis in mice. Circulation 94: 2930–7PubMedGoogle Scholar
  67. 67.
    Latif N, Zhang H, Archard LC, Yacoub MH, Dunn MJ (1999) Characterization of anti-heart antibodies in mice after infection with coxsackie B3 virus. Clin Immunol 91: 90–8PubMedGoogle Scholar
  68. 68.
    Fairweather D, Rose NR (2007) Coxsackievirus-induced myocarditis in mice: A model of autoimmune disease for studying immunotoxicity. Methods 41: 118–22PubMedGoogle Scholar
  69. 69.
    Kyu B, Matsumori A, Sato Y, Okada I, Chapman NM, Tracy S (1992) Cardiac persistence of cardioviral RNA detected by polymerase chain reaction in a murine model of dilated cardiomyopathy. Circulation 86: 522–30PubMedGoogle Scholar
  70. 70.
    Kindermann I, Kindermann M, Kandolf R, Klingel K, Bultmann B, Muller T, Lindinger A, Bohm M (2008) Predictors of outcome in patients with suspected myocarditis. Circulation 118: 639–48PubMedGoogle Scholar
  71. 71.
    Baughman KL (2006) Diagnosis of myocarditis: Death of Dallas criteria. Circulation 113: 593–5PubMedGoogle Scholar
  72. 72.
    Wang WZ, Matsumori A, Yamada T, Shioi T, Okada I, Matsui S, Sato Y, Suzuki H, Shiota K, Sasayama S (1997) Beneficial effects of amlodipine in a murine model of congestive heart failure induced by viral myocarditis. A possible mechanism through inhibition of nitric oxide production. Circulation 95: 245–51PubMedGoogle Scholar
  73. 73.
    Azuma RW, Suzuki J, Ogawa M, Futamatsu H, Koga N, Onai Y, Kosuge H, Isobe M (2004) HMG-CoA reductase inhibitor attenuates experimental autoimmune myocarditis through inhibition of T cell activation. Cardiovasc Res 64: 412–20PubMedGoogle Scholar
  74. 74.
    Yuan Z, Kishimoto C, Shioji K, Nakamura H, Yodoi J, Sasayama S (2003) Temocapril treatment ameliorates autoimmune myocarditis associated with enhanced cardiomyocyte thioredoxin expression. Mol Cell Biochem 248: 185–92PubMedGoogle Scholar
  75. 75.
    Nishio R, Shioi T, Sasayama S, Matsumori A (2003) Carvedilol increases the production of interleukin-12 and interferon-gamma and improves the survival of mice infected with the encephalomyocarditis virus. J Am Coll Cardiol 41: 340–5PubMedGoogle Scholar
  76. 76.
    Fohlman J, Pauksen K, Hyypia T, Eggertsen G, Ehrnst A, Ilback NG, Friman G (1996) Antiviral treatment with WIN 54 954 reduces mortality in murine coxsackievirus B3 myocarditis. Circulation 94: 2254–9PubMedGoogle Scholar
  77. 77.
    Pauksen K, Ilback NG, Friman G, Fohlman J (1993) Therapy of coxsackie virus B3-induced myocarditis with WIN 54954 in different formulations. Scand J Infect Dis Suppl 88: 125–30PubMedGoogle Scholar
  78. 78.
    Kyto V, Saraste A, Fohlman J, Ilback NG, Harvala H, Vuorinen T, Hyypia T (2002) Cardiomyocyte apoptosis after antiviral WIN 54954 treatment in murine coxsackievirus B3 myocarditis. Scand Cardiovasc J 36: 187–92PubMedGoogle Scholar
  79. 79.
    See DM, Tilles JG (1993) WIN 54954 treatment of mice infected with a diabetogenic strain of group B coxsackievirus. Antimicrob Agents Chemother 37: 1593–8PubMedGoogle Scholar
  80. 80.
    Heim A, Pfetzing U, Muller G, Grumbach IM (1998) Antiviral activity of WIN 54954 in coxsackievirus B2 carrier state infected human myocardial fibroblasts. Antiviral Res 37: 47–56PubMedGoogle Scholar
  81. 81.
    Noutsias M, Fechner H, de Jonge H, Wang X, Dekkers D, Houtsmuller AB, Pauschinger M, Bergelson J, Warraich R, Yacoub M et al (2001) Human coxsackie-adenovirus receptor is colocalized with integrins alpha(v)beta(3) and alpha(v)beta(5) on the cardiomyocyte sarcolemma and upregulated in dilated cardiomyopathy: Implications for cardiotropic viral infections. Circulation 104: 275–80PubMedGoogle Scholar
  82. 82.
    Yanagawa B, Spiller OB, Proctor DG, Choy J, Luo H, Zhang HM, Suarez A, Yang D, McManus BM (2004) Soluble recombinant coxsackievirus and adenovirus receptor abrogates coxsackievirus b3-mediated pancreatitis and myocarditis in mice. J Infect Dis 189: 1431–9PubMedGoogle Scholar
  83. 83.
    Shi Y, Chen C, Lisewski U, Wrackmeyer U, Radke M, Westermann D, Sauter M, Tschope C, Poller W, Klingel K et al (2009) Cardiac deletion of the coxsackievirusadenovirus receptor abolishes coxsackievirus b3 infection and prevents myocarditis in vivo. J Am Coll Cardiol 53: 1219–26PubMedGoogle Scholar
  84. 84.
    Pinkert S, Westermann D, Wang X, Klingel K, Dorner A, Savvatis K, Grossl T, Krohn S, Tschope C, Zeichhardt H et al (2009) Prevention of cardiac dysfunction in acute coxsackievirus B3 cardiomyopathy by inducible expression of a soluble coxsackievirusadenovirus receptor. Circulation 120: 2358–66PubMedGoogle Scholar
  85. 85.
    Dan M, Chantler JK (2005) A genetically engineered attenuated coxsackievirus B3 strain protects mice against lethal infection. J Virol 79: 9285–95PubMedGoogle Scholar
  86. 86.
    Henke A, Zell R, Martin U, Stelzner A (2003) Direct interferon-gamma-mediated protection caused by a recombinant coxsackievirus B3. Virology 315: 335–44PubMedGoogle Scholar
  87. 87.
    Matsumori A, Tomioka N, Kawai C (1988) Protective effect of recombinant alpha interferon on coxsackievirus B3 myocarditis in mice. Am Heart J 115: 1229–32PubMedGoogle Scholar
  88. 88.
    Wang YX, da Cunha V, Vincelette J, White K, Velichko S, Xu Y, Gross C, Fitch RM, Halks-Miller M, Larsen BR et al (2007) Antiviral and myocyte protective effects of murine interferon-beta and −{alpha}2 in coxsackievirus B3-induced myocarditis and epicarditis in Balb/c mice. Am J Physiol Heart Circ Physiol 293: H69–76PubMedGoogle Scholar
  89. 89.
    Wessely R, Klingel K, Knowlton KU, Kandolf R (2001) Cardioselective infection with coxsackievirus B3 requires intact type I interferon signaling: Implications for mortality and early viral replication. Circulation 103: 756–61PubMedGoogle Scholar
  90. 90.
    Kühl U, Pauschinger M, Schwimmbeck PL, Seeberg B, Lober C, Noutsias M, Poller W, Schultheiss HP (2003) Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 107: 2793–8PubMedGoogle Scholar
  91. 91.
    Coletta AP, Clark AL, Cleland JG (2009) Clinical trials update from the Heart Failure Society of America and the American Heart Association meetings in 2008: SADHARTCHF, COMPARE, MOMENTUM, thyroid hormone analogue study, HF-ACTION, I-PRESERVE, ta-interferon study, BACH, and ATHENA. Eur J Heart Fail 11: 214–9Google Scholar
  92. 92.
    Kishimoto C, Crumpacker CS, Abelmann WH (1988) Ribavirin treatment of murine coxsackievirus B3 myocarditis with analyses of lymphocyte subsets. J Am Coll Cardiol 12: 1334–41PubMedGoogle Scholar
  93. 93.
    Hiraoka Y, Kishimoto C, Kurokawa M, Ochiai H, Sasayama S (1992) The effects of FK-506, a novel and potent immunosuppressant, upon murine Coxsackievirus B3 myocarditis. J Pharmacol Exp Ther 260: 1386–91PubMedGoogle Scholar
  94. 94.
    Kishimoto C, Abelmann WH (1989) Absence of effects of cyclosporine on myocardial lymphocyte subsets in Coxsackievirus B3 myocarditis in the aviremic stage. Circ Res 65: 934–45PubMedGoogle Scholar
  95. 95.
    Kishimoto C, Thorp KA, Abelmann WH (1990) Immunosuppression with high doses of cyclophosphamide reduces the severity of myocarditis but increases the mortality in murine Coxsackievirus B3 myocarditis. Circulation 82: 982–9PubMedGoogle Scholar
  96. 96.
    Mason JW, O’Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME, Moon TE (1995) A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med 333: 269–75PubMedGoogle Scholar
  97. 97.
    Frustaci A, Chimenti C, Calabrese F, Pieroni M, Thiene G, Maseri A (2003) Immunosuppressive therapy for active lymphocytic myocarditis: Virological and immunologic profile of responders versus nonresponders. Circulation 107: 857–63PubMedGoogle Scholar
  98. 98.
    Wojnicz R, Nowalany-Kozielska E, Wojciechowska C, Glanowska G, Wilczewski P, Niklewski T, Zembala M, Polonski L, Rozek MM, Wodniecki J (2001) Randomized, placebo-controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy: Two-year follow-up results. Circulation 104: 39–45PubMedGoogle Scholar
  99. 99.
    Frustaci A, Russo MA, Chimenti C (2009) Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: The TIMIC study. Eur Heart J 30: 1995–2002PubMedGoogle Scholar
  100. 100.
    Maisch B, Camerini F, Schultheiss HP (1995) Immunosuppressive therapy for myocarditis. N Engl J Med 333: 1713; author reply 1714PubMedGoogle Scholar
  101. 101.
    Opavsky MA, Penninger J, Aitken K, Wen WH, Dawood F, Mak T, Liu P (1999) Susceptibility to myocarditis is dependent on the response of alphabeta T lymphocytes to coxsackieviral infection. Circ Res 85: 551–8PubMedGoogle Scholar
  102. 102.
    Kishimoto C, Abelmann WH (1989) Monoclonal antibody therapy for prevention of acute coxsackievirus B3 myocarditis in mice. Circulation 79: 1300–8PubMedGoogle Scholar
  103. 103.
    Liu P, Aitken K, Kong YY, Opavsky MA, Martino T, Dawood F, Wen WH, Kozieradzki I, Bachmaier K, Straus D et al (2000) The tyrosine kinase p56lck is essential in coxsackievirus B3-mediated heart disease. Nat Med 6: 429–34PubMedGoogle Scholar
  104. 104.
    Irie-Sasaki J, Sasaki T, Matsumoto W, Opavsky A, Cheng M, Welstead G, Griffiths E, Krawczyk C, Richardson CD, Aitken K et al (2001) CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature 409: 349–54PubMedGoogle Scholar
  105. 105.
    Seko Y, Takahashi N, Azuma M, Yagita H, Okumura K, Yazaki Y (1998) Effects of in vivo administration of anti-B7-1/B7-2 monoclonal antibodies on murine acute myocarditis caused by coxsackievirus B3. Circ Res 82: 613–8PubMedGoogle Scholar
  106. 106.
    Schwimmbeck PL, Badorff C, Schultheiss HP, Strauer BE (1994) Transfer of human myocarditis into severe combined immunodeficiency mice. Circ Res 75: 156–64PubMedGoogle Scholar
  107. 107.
    Seko Y, Ishiyama S, Nishikawa T, Kasajima T, Hiroe M, Kagawa N, Osada K, Suzuki S, Yagita H, Okumura K et al (1995) Restricted usage of T cell receptor V alpha-V beta genes in infiltrating cells in the hearts of patients with acute myocarditis and dilated cardiomyopathy. J Clin Invest 96: 1035–41PubMedGoogle Scholar
  108. 108.
    Noutsias M, Rohde M, Block A, Klippert K, Lettau O, Blunert K, Hummel M, Kühl U, Lehmkuhl H, Hetzer R et al (2008) Preamplification techniques for real-time RT-PCR analyses of endomyocardial biopsies. BMC Mol Biol 9: 3PubMedGoogle Scholar
  109. 109.
    Perens G, Levi DS, Alejos JC, Wetzel GT (2007) Muronomab-CD3 for pediatric acute myocarditis. Pediatr Cardiol 28: 21–6PubMedGoogle Scholar
  110. 110.
    Matsumoto Y, Jee Y, Sugisaki M (2000) Successful TCR-based immunotherapy for autoimmune myocarditis with DNA vaccines after rapid identification of pathogenic TCR. J Immunol 164: 2248–54PubMedGoogle Scholar
  111. 111.
    Klingel K, Stephan S, Sauter M, Zell R, McManus BM, Bultmann B, Kandolf R (1996) Pathogenesis of murine enterovirus myocarditis: Virus dissemination and immune cell targets. J Virol 70: 8888–95PubMedGoogle Scholar
  112. 112.
    Cheung C, Marchant D, Walker EK, Luo Z, Zhang J, Yanagawa B, Rahmani M, Cox J, Overall C, Senior RM et al (2008) Ablation of matrix metalloproteinase-9 increases severity of viral myocarditis in mice. Circulation 117: 1574–82PubMedGoogle Scholar
  113. 113.
    Latif N, Baker CS, Dunn MJ, Rose ML, Brady P, Yacoub MH (1993) Frequency and specificity of antiheart antibodies in patients with dilated cardiomyopathy detected using SDS-PAGE and western blotting. J Am Coll Cardiol 22: 1378–84PubMedGoogle Scholar
  114. 114.
    Felix SB, Staudt A (2006) Non-specific immunoadsorption in patients with dilated cardiomyopathy: Mechanisms and clinical effects. Int J Cardiol 112: 30–3PubMedGoogle Scholar
  115. 115.
    Takada H, Kishimoto C, Hiraoka Y (1995) Therapy with immunoglobulin suppresses myocarditis in a murine coxsackievirus B3 model. Antiviral and anti-inflammatory effects. Circulation 92: 1604–11PubMedGoogle Scholar
  116. 116.
    Kishimoto C, Takamatsu N, Kawamata H, Shinohara H, Ochiai H (2000) Immunoglobulin treatment ameliorates murine myocarditis associated with reduction of neurohumoral activity and improvement of extracellular matrix change. J Am Coll Cardiol 36: 1979–84PubMedGoogle Scholar
  117. 117.
    McNamara DM, Holubkov R, Starling RC, Dec GW, Loh E, Torre-Amione G, Gass A, Janosko K, Tokarczyk T, Kessler P et al (2001) Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation 103: 2254–9PubMedGoogle Scholar
  118. 118.
    Reifenberg K, Lehr HA, Torzewski M, Steige G, Wiese E, Kupper I, Becker C, Ott S, Nusser P, Yamamura K et al (2007) Interferon-gamma induces chronic active myocarditis and cardiomyopathy in transgenic mice. Am J Pathol 171: 463–72PubMedGoogle Scholar
  119. 119.
    Nishio R, Matsumori A, Shioi T, Ishida H, Sasayama S (1999) Treatment of experimental viral myocarditis with interleukin-10. Circulation 100: 1102–8PubMedGoogle Scholar
  120. 120.
    Li J, Leschka S, Rutschow S, Schwimmbeck PL, Husmann L, Noutsias M, Westermann D, Poller W, Zeichhardt H, Klingel K et al (2007) Immunomodulation by interleukin-4 suppresses matrix metalloproteinases and improves cardiac function in murine myocarditis. Eur J Pharmacol 554: 60–8PubMedGoogle Scholar
  121. 121.
    Kania G, Blyszczuk P, Stein S, Valaperti A, Germano D, Dirnhofer S, Hunziker L, Matter CM, Eriksson U (2009) Heart-infiltrating prominin-1+/CD133+ progenitor cells represent the cellular source of transforming growth factor beta-mediated cardiac fibrosis in experimental autoimmune myocarditis. Circ Res 105: 462–70PubMedGoogle Scholar
  122. 122.
    Marchant D, McManus BM (2009) Matrix metalloproteinases in the pathogenesis of viral heart disease. Trends Cardiovasc Med 19: 21–6PubMedGoogle Scholar
  123. 123.
    Uematsu S, Akira S (2006) Toll-like receptors and innate immunity. J Mol Med 84: 712–25PubMedGoogle Scholar
  124. 124.
    Triantafilou K, Orthopoulos G, Vakakis E, Ahmed MA, Golenbock DT, Lepper PM, Triantafilou M (2005) Human cardiac inflammatory responses triggered by Coxsackie B viruses are mainly Toll-like receptor (TLR) 8-dependent. Cell Microbiol 7: 1117–26Google Scholar

Copyright information

© Springer Basel 2010

Authors and Affiliations

  • Michel Noutsias
    • 1
  • Peter Liu
    • 2
  1. 1.Department of Internal Medicine — CardiologyUniversity Hospital of Marburg and Giessen, Philipps-Universität MarburgMarburgGermany
  2. 2.Heart & Stroke Medicine and Physiology, Institute of Circulatory and Respiratory Health, Canadian Institutes of Health Research, Toronto General HospitalUniversity of TorontoTorontoCanada

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