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Anti-viral Treatment in Patients with Virus-Induced Cardiomyopathy

  • Conference paper
Chronic Viral and Inflammatory Cardiomyopathy

Part of the book series: Ernst Schering Research Foundation Workshop ((SCHERING FOUND,volume 55))

Abstract

Ongoing viral persistence in the myocardium is associated with an adverse prognosis of cardiomyopathy eventually resulting in a reduced capacity for work and thus it is associated with enormous social costs. Experimental and clinical data highlight that an imbalance of the cytokine network and a defect in the cytokine-induced immune response may constitute major causes leading to the development of virus persistence and progression of myocardial dysfunction. Reversibility of cardiac impairment during the early stages of the disease and the arising chance of specific treatment options demand early diagnosis and treatment of the disease. Our pilot data on anti-viral treatment using INF-β showed beneficial clinical effects and suggest that some of the ventricular dysfunction and wall motion abnormalities resolved after elimination of the responsible agents. The data also suggest that elimination of cardiotropic viruses and associated clinical effects may occur even in DCM patients presenting with a long history.

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References

  • Baboonian C, Treasure T (1997) Meta-analysis of the association of enteroviruses with human heart disease. Heart 78:539–543

    PubMed  CAS  Google Scholar 

  • Bachmaier K, Neu N, Pummerer C, Duncan GS, Mak TW, Matsuyama T, Penninger JM (1997) iNOS expression and nitrotyrosine formation in the myocardium in response to inflammation is controlled by the interferon regulatory transcription factor 1. Circulation 96:585–591

    PubMed  CAS  Google Scholar 

  • Badorff C, Noutsias M, Kühl U, Schultheiss HP (1997) Cell-mediated cytotoxicity in hearts with dilated cardiomyopathy: correlation with interstitial fibrosis and foci of activated T lymphocytes. J Am Coll Cardiol 29:429–434

    Article  PubMed  CAS  Google Scholar 

  • 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 [see comments]. Nat Med 5:320–326

    Article  PubMed  CAS  Google Scholar 

  • Baron S (1992) Introduction to the interferon system. In: Baron S (ed) Interferon: principles and medical applications. The University of Texas Medical Branch at Galveston, Dept. of Microbiology, Galveston, pp 1–15

    Google Scholar 

  • Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP (1999) Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 17:189–220

    Article  PubMed  CAS  Google Scholar 

  • Bowles NE, Richardson PJ, Olsen EG, Archard LC (1986) Detection of coxsackie-B-virus-specific RNA sequences in myocardial biopsy samples from patients with myocarditis and dilated cardiomyopathy. Lancet 1:1120–1123

    Article  PubMed  CAS  Google Scholar 

  • Bozkurt B, Kribbs SB, Clubb FJ Jr, Michael LH, Didenko VV, Hornsby PJ, Seta Y, Oral H, Spinale FG, Mann DL (1998) Pathophysiologically relevant concentrations of tumor necrosis factor-alpha promote progressive left ventricular dysfunction and remodeling in rats. Circulation 97:1382–1391

    PubMed  CAS  Google Scholar 

  • Bultmann BD, Klingel K, Sotlar K, Bock CT, Baba HA, Sauter M, Kandolf R (2003) Fatal parvovirus B19-associated myocarditis clinically mimicking ischemic heart disease: an endothelial cell-mediated disease. Hum Pathol 34:92–95

    Article  PubMed  Google Scholar 

  • Clerici M, Shearer GM (1993) A Th1 to Th2 switch is a critical step in the etiology of HIV infection. Immunol Today 14:73–92

    Article  Google Scholar 

  • Dec GW, Fuster V (1994) Idiopathic dilated cardiomyopathy. N Engl J Med 331:1564–1575

    Article  PubMed  CAS  Google Scholar 

  • Dec GW Jr, Palacios IF, Fallon JT, Aretz HT, Mills J, Lee DC, Johnson RA (1985) Active myocarditis in the spectrum of acute dilated cardiomyopathies. Clinical features, histologic correlates, and clinical outcome. N Engl J Med 312:885–890

    Article  PubMed  Google Scholar 

  • Doerner A, Pauschinger M, Schwimmbeck PL, Kühl U, Schultheiss HP (2000) The shift in the myocardial adenine nucleotide translocator isoform expression pattern is associated with an enteroviral infection in the absence of an active T-cell dependent immune response in human inflammatory heart disease. J Am Coll Cardiol 35:1778–1784

    Article  Google Scholar 

  • Feldmann AM, McNamara D (2000) Myocarditis. N Engl J Med 343:1388–1398

    Article  Google Scholar 

  • Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL (1992) Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 257:387–389

    PubMed  CAS  Google Scholar 

  • Freeman GL, Colston JT, Zabalgoitia M, Chandrasekar B (1998) Contractile depression and expression of proinflammatory cytokines and iNOS in viral myocarditis. Am J Physiol 274:H249–H258

    PubMed  CAS  Google Scholar 

  • 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 107:857–863

    Article  PubMed  Google Scholar 

  • Fujioka S, Kitaura Y, Ukimura A, Deguchi H, Kawamura K, Isomura T, Suma H, Shimizu A (2000) Evaluation of viral infection in the myocardium of patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 36:1920–1926

    Article  PubMed  CAS  Google Scholar 

  • Grogan M, Redfield MM, Bailey KR, Reeder GS, Gersh BJ, Edwards WD, Rodeheffer RJ (1995) Long-term outcome of patients with biopsy-proved myocarditis: comparison with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 26:80–84

    Article  PubMed  CAS  Google Scholar 

  • Heim A, Canu A, Kirschner P, Simon T, Mall G, Hofschneider PH, Kandolf R (1992) Synergistic interaction of interferon-beta and interferon-gamma in coxsackievirus B3-infected carrier cultures of human myocardial fibroblasts. J Infect Dis 166:958–965

    PubMed  CAS  Google Scholar 

  • Heim A, Stille-Siegener M, Kandolf R, Kreuzer H, Figulla HR (1994) Enterovirus-induced myocarditis: hemodynamic deterioration with immunosuppressive therapy and successful application of interferon-alpha. Clin Cardiol 17:563–565

    Article  PubMed  CAS  Google Scholar 

  • Horwitz MS, La Cava A, Fine C, Rodriguez E, Ilic A, Sarvetnik N (2000a) Pancreatic expression of interferon-gamma protects mice from lethal coxsackievirus B3 infection and subsequent myocarditis. Nat Med 6: 693–697

    Article  PubMed  CAS  Google Scholar 

  • Huang S, Hendrix W, Althage A, Bluethmann H, Kamijo R, Vilcek J, Zinkernagel RM, Aguet M (1993) Immune response in mice that lack the interferon-gamma receptor. Science 259:1742–1745

    PubMed  CAS  Google Scholar 

  • Hunter CA, Reiner SL (2000) Cytokines and T cells in host defense. Curr Opin Immunol 12:413–418

    Article  PubMed  CAS  Google Scholar 

  • Kandolf R, Ameis D, Kirschner P, Canu A, Hofschneider PH (1987) In situ detection of enteroviral genomes in myocardial cells by nucleic acid hybridization: an approach to the diagnosis of viral heart disease. Proc Natl Acad Sci U S A 84:6272–6276

    Article  PubMed  CAS  Google Scholar 

  • Katze MG, He Y, Gale M (2002) Viruses and interferon: a fight for supremacy. Nat Rev Immunol 2:675–687

    Article  PubMed  CAS  Google Scholar 

  • Kawai C (1999) From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death: learning from the past for the future. Circulation 99:1091–1100

    PubMed  CAS  Google Scholar 

  • 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 88:79–85

    PubMed  CAS  Google Scholar 

  • Klingel K, Rieger P, Mall G, Selinka HC, Huber M, Kandolf R (1998) Visualization of enteroviral replication in myocardial tissue by ultrastructural in situ hybridization: identification of target cells and cytopathic effects. Lab Invest 78:1227–1237

    PubMed  CAS  Google Scholar 

  • Kühl U, Noutsias M, Seeberg B, Schultheiss HP (1996) Immunohistological evidence for a chronic intramyocardial inflammatory process in dilated cardiomyopathy. Heart 75:295–300

    PubMed  Google Scholar 

  • Kühl U, Pauschinger M, Bock T, Klingel K, Schwimmbeck PL, Seeberg B, Krautwurm L, Schultheiß HP, Kandolf R (2003a) Parvovirus B19 infection mimicking acute myocardial infarction. Circulation 108:945–950

    Article  PubMed  CAS  Google Scholar 

  • Kühl U, Pauschinger M, Schwimmbeck PL, Seeberg B, Lober C, Noutsias M, Poller W, Schultheiss HP (2003b) Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 107:2793–2798

    Article  PubMed  CAS  Google Scholar 

  • Kühl U, Pauschinger M, Michel Noutsias M, Seeberg B, Bock T, Lassner D, 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 (in press)

    Google Scholar 

  • Li Y, Bourlet T, Andreoletti L (2000a) Enteroviral capsid protein VP1 is present in myocardial tissues from some patients with myocarditis or dilated cardiomyopathy. Circulation 101:231–234

    PubMed  CAS  Google Scholar 

  • Li YY, McTiernan CF, Feldman AM (2000c) Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling. Cardiovasc Res 46:214–224

    Article  PubMed  CAS  Google Scholar 

  • Li YY, Feng Y, McTiernan CF, Pei W, Moravec CS, Wang P, Rosenblum W, Kormos RL, Feldman AM (2001) Downregulation of matrix metalloproteinases and reduction in collagen damage in the failing human heart after support with left ventricular assist devices. Circulation 104:1147–1152

    PubMed  CAS  Google Scholar 

  • Libby P, Lee RT (2000) Matrix matters. Circulation 102:1874–1876

    PubMed  CAS  Google Scholar 

  • Liu P, Aitken K, Kong Y, Opavsky MA, Martino T, Dawood F, Wen W, Kozieradzki I, Bachmaier K, Straus D, Mak TW, Penninger JM (2000b) The tyrosine kinase p56Ick is essential in coxsackievirus B3-mediated heart disease. Nat Med 6:429–434

    Article  PubMed  CAS  Google Scholar 

  • Lowenstein CJ, Hill SL, Lafond Walker A, Wu J, Allen G, Landavere M, Rose NR, Herskowitz A (1996) Nitric oxide inhibits viral replication in murine myocarditis. J Clin Invest 97:1837–1843

    Article  PubMed  CAS  Google Scholar 

  • Mann DL, Taegtmeyer H (2001) Dynamic regulation of the extracellular matrix after mechanical unloading of the failing human heart: recovering the missing link in left ventricular remodeling. Circulation 104:1089–1091

    PubMed  CAS  Google Scholar 

  • Matsumori A (2001) Hepatitis C virus and cardiomyopathy. Intern Med 40:78–79

    PubMed  CAS  Google Scholar 

  • Matsumori A, Tomioka N, Kawai C (1988) Protective effect of recombinant alpha interferon on coxsackievirus B3 myocarditis in mice. Am Heart J 115:1229–1232

    Article  PubMed  CAS  Google Scholar 

  • Matsumori A, Yamada T, Suzuki H, Matoba Y, Sasayama S (1994) Increased circulating cytokines in patients with myocarditis and cardiomyopathy. Br Heart J 72:561–566

    PubMed  CAS  Google Scholar 

  • McCarthy RE, Boehmer JP, hruban RH, Hutchins GM, Kasper EK, Hare JM, Baughman KL (2000) Long-term outcome of fulminant myocarditis as compared with acute (non-fulminant) myocarditis. N Engl J Med 342:734–735

    Article  Google Scholar 

  • Michels V, Moll P, Miller FA, Tajik AJ, Chu JS, Driscoll DJ, Burnett JC, Rodeheffer RJ, Chesebro JH, Tazelaar HD (1992) The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med 326:77–82

    Article  PubMed  CAS  Google Scholar 

  • Miric M, Vasiljevic J, Bojic M, Popovic Z, Keserovic N, Pesic M (1996) Longterm follow up of patients with dilated heart muscle disease treated with human leucocytic interferon alpha or thymic hormones initial results. Heart 75:596–601

    PubMed  CAS  Google Scholar 

  • Noutsias M, Fechner H, de Jonge H, Wang X, Dekkers D, Houtsmuller AB, Pauschinger M, Bergelson J, Warraich R, Yacoub M, Hetzer R, Lamers J, Schultheiss HP, Poller W (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 104:275–280

    PubMed  CAS  Google Scholar 

  • Pauschinger M, Bowles NE, Fuentes-Garcia FJ, Pham V, Kühl U, Schwimmbeck PL, Schultheiss HP, Towbin JA (1999a) Detection of adenoviral genome in the myocardium of adult patients with idiopathic left ventricular dysfunction. Circulation 99:1348–1354

    PubMed  CAS  Google Scholar 

  • Pauschinger M, Doerner A, Kuehl U, Schwimmbeck PL, Poller W, Kandolf R, Schultheiss HP (1999b) Enteroviral RNA replication in the myocardium of patients with left ventricular dysfunction and clinically suspected myocarditis. Circulation 99:889–895

    PubMed  CAS  Google Scholar 

  • Pauschinger M, Knopf D, Petschauer S, Doerner A, Poller W, Schwimmbeck PL, Kühl U, Schultheiss HP (1999c) Dilated cardiomyopathy is associated with significant changes in collagen type I/III ratio. Circulation 99:2750–2756

    PubMed  CAS  Google Scholar 

  • Poller W, Fechner H, Noutsias M, Tschoepe C, Schultheiss HP (2002) Highly variable expression of virus receptors in the human cardiovascular system. Implications for cardiotropic viral infections and gene therapy. Z Kardiol 91:978–991

    Article  PubMed  CAS  Google Scholar 

  • Ramshaw IA, Ramsay A, Karupiah G, Rolph MS, Mahalingam S, Ruby JC (1997) Cytokines and immunity to viral infection. Immunol Rev 159:119–135

    Article  PubMed  CAS  Google Scholar 

  • Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, J OC, Olsen E, Thiene G, Goodwin J, Gyarfas I, Martin I, Nordet P (1996) Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies [news]. Circulation 93:841–842

    PubMed  CAS  Google Scholar 

  • Schulze K, Witzenbichler B, Christmann C, Schultheiss HP (1999) Disturbance of myocardial energy metabolism in experimental virus myocarditis by antibodies against the adenine nucleotide translocator. Cardiovasc Res 44:91–100

    Article  PubMed  CAS  Google Scholar 

  • Seko Y, Shinkai Y, Kawasaki A, Yagita H, Okumura K, Yazaki Y (1993) Evidence of perforin-mediated cardiac myocyte injury in acute murine myocarditis caused by coxsackie virus B3. J Pathol 170:53–58

    Article  PubMed  CAS  Google Scholar 

  • Sher A, Coffman RL (1992) Regulation of immunity to parasites by T cells and T-cell derived cytokines. Annu Rev Immunol 10:385–409

    Article  PubMed  CAS  Google Scholar 

  • Shioi T, Matsumori A, Sasayama S (1996) Persistent expression of cytokine in the chronic stage of viral myocarditis in mice. Circulation 94:2930–2937

    PubMed  CAS  Google Scholar 

  • Shioi T, Matsumori A, Nishio R, Ono K, Kakio T, Sasayama S (1997) Protective role of interleukin-12 in viralmyocarditis. J Mol Cell Cardiol 29:2327–2334

    Article  PubMed  CAS  Google Scholar 

  • Stille Siegener M, Heim A, Figulla HR (1995) Subclassification of dilated cardiomyopathy and interferon treatment. Eur Heart J 16Suppl O:147–149

    PubMed  CAS  Google Scholar 

  • Talon J, Horvath CM, Polley R, Basler CF, Muster T, Palese P, Garcia-Sastre A (2000) Activation of interferon regulatory factor 3 is inhibited by the influenza A virus NS1 protein. J Virol 74:7989–7996

    Article  PubMed  CAS  Google Scholar 

  • Testa M, Yeh M, Lee P, Fanelli R, Loperfido F, Berman JW, LeJemtel TH (1996) Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. J Am Coll Cardiol 28:964–971

    Article  PubMed  CAS  Google Scholar 

  • Thomas CV, Coker ML, Zellner JL, Handy JR, Crumbley AJ 3rd, Spinale FG (1998) Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation 97:1708–1715

    PubMed  CAS  Google Scholar 

  • Torre Amione G, Kapadia S, Lee J, Durand JB, Bies RD, Young JB, Mann DL (1996) Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation 93:704–711

    PubMed  CAS  Google Scholar 

  • 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 98:450–457

    PubMed  CAS  Google Scholar 

  • Why HJ, Meany BT, Richardson PJ, Olsen EG, Bowles NE, Cunningham L, Freeke CA, Archard LC (1994) Clinical and prognostic significance of detection of enteroviral RNA in the myocardium of patients with myocarditis or dilated cardiomyopathy. Circulation 89:2582–2589

    PubMed  CAS  Google Scholar 

  • Yamada T, Matsumori A, Sasayama S (1994) Therapeutic effect of anti-tumor necrosis factor-alpha antibody on the murine model of viral myocarditis induced by encephalomyocarditis virus. Circulation 89:846–851

    PubMed  CAS  Google Scholar 

  • Yamamoto N, Shibamori M, Ogura M, Seko Y, Kikuchi M (1998) Effects of intranasal administration of recombinant murine interferon-gamma on murine acute myocarditis caused by encephalomyocarditis virus. Circulation 97:1017–1023

    PubMed  CAS  Google Scholar 

  • Yamamura M, Uyemura K, Deans RJ, Weinberg K, Rea TH, Bloom BR, Modlin RL (1991) Defining protective response to pathogens: cytokine profile in leprosy lesions. Science 254:277–279

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Cardiology and Pneumology, Campus-Benjamin Franklin, Charité University Medicine Berlin, Hindenburgdamm 30, 12200, Berlin, Germany

    U. Kühl, M. Pauschinger, W. Poller & H. -P. Schultheiss

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  1. U. Kühl
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  2. M. Pauschinger
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  3. W. Poller
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  4. H. -P. Schultheiss
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Editors and Affiliations

  1. Department of Cardiology and Pneumology, Campus Benjamin Franklin, Charité University Medicine Berlin, Hindenburgdamm 30, Germany

    H. -P. Schultheiss

  2. Specialized Therapeutics, M1/3-9, Berlex Inc., Montville, NJ, 07045, USA

    J. -F. Kapp

  3. Medical Development, Specialized Therapeutics, Cardiovascular Europe, Schering AG, 13342, Berlin, Germany

    G. Grötzbach

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© 2006 Springer-Verlag Berlin Heidelberg

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Kühl, U., Pauschinger, M., Poller, W., Schultheiss, H.P. (2006). Anti-viral Treatment in Patients with Virus-Induced Cardiomyopathy. In: Schultheiss, H.P., Kapp, J.F., Grötzbach, G. (eds) Chronic Viral and Inflammatory Cardiomyopathy. Ernst Schering Research Foundation Workshop, vol 55. Springer, Berlin, Heidelberg . https://doi.org/10.1007/3-540-30822-9_18

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  • DOI: https://doi.org/10.1007/3-540-30822-9_18

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-23971-0

  • Online ISBN: 978-3-540-30822-5

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