(Circulation. 1999;99:1091-1100.)
© 1999 American Heart Association, Inc.
Current Perspective |
From Myocarditis to Cardiomyopathy: Mechanisms of Inflammation and Cell Death
Learning From the Past for the Future
Presented in part as a State-of-the-Art lecture at the Featured Research Sessions: Myocarditis—Mechanisms of Inflammation and Cell Death at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 13, 1996.
From Kyoto University and Kyoto Regional Study Center, University of the Air.
Correspondence to Chuichi Kawai, MD, Nishiiru Karasuma Shimochojamachi-dori, Kamikyoku, Kyoto 602-8002, Japan.
Abstract—A progression from
viral myocarditis to dilated cardiomyopathy has
long been hypothesized, but the actual extent of this progression has
been uncertain. However, a causal link between viral myocarditis and
dilated cardiomyopathy has become more evident than
before with the tremendous developments in the molecular
analyses of autopsy and endomyocardial
biopsy specimens, new techniques of viral gene amplification, and
modern immunology. The persistence of viral RNA in the
myocardium beyond 90 days after inoculation, confirmed by
the method of polymerase chain reaction, has given us new insights into
the pathogenesis of dilated cardiomyopathy.
Moreover, new knowledge of T-cell–mediated immune responses in murine
viral myocarditis has contributed a great deal to the understanding of
the mechanisms of ongoing disease processes. Apoptotic cell
death may provide the third concept to explain the pathogenesis of
dilated cardiomyopathy, in addition to persistent
viral RNA in the heart tissue and an immune system–mediated mechanism.
Beneficial effects of 
1-adrenergic blocking agents,
carteolol, verapamil, and ACE inhibitors have
been shown clinically and experimentally in the treatment of viral
myocarditis and dilated cardiomyopathy. Antiviral
agents should be more extensively investigated for clinical use. The
rather discouraging results obtained to date with immunosuppressive
agents in the treatment of viral myocarditis indicated the importance
of sparing neutralizing antibody production, which may be
controlled by B cells, and raised the possibility of promising
developments in immunomodulating therapy.
Key Words: viruses • myocarditis • cardiomyopathy • immune system • apoptosis
This article has been cited by other articles:
 |
|
 |
|
  L. Venteo, T. Bourlet, F. Renois, F. Douche-Aourik, J.-F. Mosnier, G. Lorain De la Grand Maison, M. Pluot, B. Pozzetto, and L. Andreoletti Enterovirus-related activation of the cardiomyocyte mitochondrial apoptotic pathway in patients with acute myocarditis Eur. Heart J., November 19, 2009; (2009) ehp489v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Sparrow, N. Merchant, Y. L. Provost, D. J. Doyle, E. T. Nguyen, and N. S. Paul CT and MR Imaging Findings in Patients with Acquired Heart Disease at Risk for Sudden Cardiac Death1 RadioGraphics, May 1, 2009; 29(3): 805 - 823. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. G. Friedrich, U. Sechtem, J. Schulz-Menger, G. Holmvang, P. Alakija, L. T. Cooper, J. A. White, H. Abdel-Aty, M. Gutberlet, S. Prasad, et al. Cardiovascular magnetic resonance in myocarditis: A JACC White Paper. J. Am. Coll. Cardiol., April 28, 2009; 53(17): 1475 - 1487. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Luk, E Ahn, G S Soor, and J Butany Dilated cardiomyopathy: a review J. Clin. Pathol., March 1, 2009; 62(3): 219 - 225. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Kindermann, M. Kindermann, R. Kandolf, K. Klingel, B. Bultmann, T. Muller, A. Lindinger, and M. Bohm Predictors of Outcome in Patients With Suspected Myocarditis Circulation, August 5, 2008; 118(6): 639 - 648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Cheung, D. Marchant, E. K.-Y. Walker, Z. Luo, J. Zhang, B. Yanagawa, M. Rahmani, J. Cox, C. Overall, R. M. Senior, et al. Ablation of Matrix Metalloproteinase-9 Increases Severity of Viral Myocarditis in Mice Circulation, March 25, 2008; 117(12): 1574 - 1582. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. L. Uhl Viral Myocarditis in Children Crit. Care Nurse, February 1, 2008; 28(1): 42 - 63. [Full Text] [PDF]
|
|
|
|
 |
|
 L. Brunetti and E. R. H. DeSantis Treatment of viral myocarditis caused by coxsackievirus B Am. J. Health Syst. Pharm., January 15, 2008; 65(2): 132 - 137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Song, Z. Liu, H. Wang, Y. Xin, X. Wang, J. Chen, Y. Shi, C. Zhang, and R. Hui QiHong Prevents Death in Coxsackievirus B3 Induced Murine Myocarditis Through Inhibition of Virus Attachment and Penetration Experimental Biology and Medicine, December 1, 2007; 232(11): 1441 - 1448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hausler, B. Sellhaus, S. Scheithauer, B. Gaida, S. Kuropka, K. Siepmann, A. Panek, W. Berg, A. Teubner, K. Ritter, et al. Myocarditis in newborn wild-type BALB/c mice infected with the murine gamma herpesvirus MHV-68 Cardiovasc Res, November 1, 2007; 76(2): 323 - 330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. E. F. Daubeney, A. W. Nugent, P. Chondros, J. B. Carlin, S. D. Colan, M. Cheung, A. M. Davis, C.W. Chow, R. G. Weintraub, and on behalf of the National Australian Childhood Car Clinical Features and Outcomes of Childhood Dilated Cardiomyopathy: Results From a National Population-Based Study Circulation, December 12, 2006; 114(24): 2671 - 2678. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Mahrholdt, A. Wagner, C. C. Deluigi, E. Kispert, S. Hager, G. Meinhardt, H. Vogelsberg, P. Fritz, J. Dippon, C. -T. Bock, et al. Presentation, Patterns of Myocardial Damage, and Clinical Course of Viral Myocarditis Circulation, October 10, 2006; 114(15): 1581 - 1590. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death--Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol., September 5, 2006; 48(5): 1064 - 1108. [Full Text] [PDF]
|
|
|
|
|
|
Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol., September 5, 2006; 48(5): e247 - e346. [Full Text] [PDF]
|
|
|
|
|
|
D. P. Zipes, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death--executive summary: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Eur. Heart J., September 1, 2006; 27(17): 2099 - 2140. [Full Text] [PDF]
|
|
|
|
 |
|
 Writing Committee Members, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 746 - 837. [Full Text] [PDF]
|
|
|
|
|
|
J. W. Magnani and G. W. Dec Myocarditis: Current Trends in Diagnosis and Treatment Circulation, February 14, 2006; 113(6): 876 - 890. [Full Text] [PDF]
|
|
|
|
 |
|
 J.-F. Wang, A. Meissner, S. Malek, Y. Chen, Q. Ke, J. Zhang, V. Chu, T. G. Hampton, C. S. Crumpacker, W. H. Abelmann, et al. Propranolol ameliorates and epinephrine exacerbates progression of acute and chronic viral myocarditis Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1577 - H1583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Yuan, M. Nimata, T.-a. Okabe, K. Shioji, K. Hasegawa, T. Kita, and C. Kishimoto Olmesartan, a novel AT1 antagonist, suppresses cytotoxic myocardial injury in autoimmune heart failure Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1147 - H1152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Mahrholdt, A. Wagner, R. M. Judd, U. Sechtem, and R. J. Kim Delayed enhancement cardiovascular magnetic resonance assessment of non-ischaemic cardiomyopathies Eur. Heart J., August 1, 2005; 26(15): 1461 - 1474. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Li, J. S. Heuser, S. D. Kosanke, M. Hemric, and M. W. Cunningham Protection against Experimental Autoimmune Myocarditis Is Mediated by Interleukin-10-Producing T Cells that Are Controlled by Dendritic Cells Am. J. Pathol., July 1, 2005; 167(1): 5 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-M. Kim, J.-H. Park, S.-K. Chung, J.-Y. Kim, H.-Y. Hwang, K.-C. Chung, I. Jo, S.-I. Park, and J.-H. Nam Coxsackievirus B3 Infection Induces cyr61 Activation via JNK To Mediate Cell Death J. Virol., December 15, 2004; 78(24): 13479 - 13488. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-M. Grinda, P. Chevalier, N. D'Attellis, M.-O. Bricourt, A. Berrebi, P. Guibourt, J.-N. Fabiani, and A. Deloche Fulminant myocarditis in adults and children: bi-ventricular assist device for recovery Eur. J. Cardiothorac. Surg., December 1, 2004; 26(6): 1169 - 1173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. W. Azuma, J.-i. Suzuki, M. Ogawa, H. Futamatsu, N. Koga, Y. Onai, H. Kosuge, and M. Isobe HMG-CoA reductase inhibitor attenuates experimental autoimmune myocarditis through inhibition of T cell activation Cardiovasc Res, December 1, 2004; 64(3): 412 - 420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. DeBiasi, B. A. Robinson, B. Sherry, R. Bouchard, R. D. Brown, M. Rizeq, C. Long, and K. L. Tyler Caspase Inhibition Protects against Reovirus-Induced Myocardial Injury In Vitro and In Vivo J. Virol., October 15, 2004; 78(20): 11040 - 11050. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M G. Gagliardi, M Bevilacqua, C Bassano, B Leonardi, R Boldrini, F D. Camassei, A Fierabracci, A G Ugazio, and G F Bottazzo Long term follow up of children with myocarditis treated by immunosuppression and of children with dilated cardiomyopathy Heart, October 1, 2004; 90(10): 1167 - 1171. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Mahrholdt, C. Goedecke, A. Wagner, G. Meinhardt, A. Athanasiadis, H. Vogelsberg, P. Fritz, K. Klingel, R. Kandolf, and U. Sechtem Cardiovascular Magnetic Resonance Assessment of Human Myocarditis: A Comparison to Histology and Molecular Pathology Circulation, March 16, 2004; 109(10): 1250 - 1258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Afanasyeva, D. Georgakopoulos, D. F. Belardi, A. C. Ramsundar, J. G. Barin, D. A. Kass, and N. R. Rose Quantitative Analysis of Myocardial Inflammation by Flow Cytometry in Murine Autoimmune Myocarditis: Correlation with Cardiac Function Am. J. Pathol., March 1, 2004; 164(3): 807 - 815. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Yuan, K. Shioji, Y. Kihara, H. Takenaka, Y. Onozawa, and C. Kishimoto Cardioprotective effects of carvedilol on acute autoimmune myocarditis: anti-inflammatory effects associated with antioxidant property Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H83 - H90. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W Mason Myocarditis and dilated cardiomyopathy: An inflammatory link Cardiovasc Res, October 15, 2003; 60(1): 5 - 10. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Yuan, Y. Liu, Y. Liu, J. Zhang, C. Kishimoto, Y. Wang, A. Ma, and Z. Liu Peroxisome proliferation-activated receptor-{gamma} ligands ameliorate experimental autoimmune myocarditis Cardiovasc Res, September 1, 2003; 59(3): 685 - 694. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Tanito, T. Takanashi, S. Kaidzu, Y. Yoshida, and A. Ohira Cytoprotective Effects of Rebamipide and Carteolol Hydrochloride against Ultraviolet B-Induced Corneal Damage in Mice Invest. Ophthalmol. Vis. Sci., July 1, 2003; 44(7): 2980 - 2985. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Kuhl, M. Pauschinger, P. L. Schwimmbeck, B. Seeberg, C. Lober, M. Noutsias, W. Poller, and H.-P. Schultheiss Interferon-{beta} Treatment Eliminates Cardiotropic Viruses and Improves Left Ventricular Function in Patients With Myocardial Persistence of Viral Genomes and Left Ventricular Dysfunction Circulation, June 10, 2003; 107(22): 2793 - 2798. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Poller, H. Fechner, M. Noutsias, C. Tschoepe, M. Pauschinger, and H.-P. Schultheiss The molecular basis of cardiotropic viral infections Eur. Heart J. Suppl., December 1, 2002; 4(suppl_I): I18 - I30. [Abstract] [PDF]
|
|
|
|
|
|
U. Kuhl, M. Pauschinger, M. Noutsias, J.-F. Kapp, and H.-P. Schultheiss Diagnosis and treatment of patients with virus induced inflammatory cardiomyopathy Eur. Heart J. Suppl., December 1, 2002; 4(suppl_I): I73 - I80. [Abstract] [PDF]
|
|
|
|
|
|
A. Hjalmarson, M. Fu, and R. Mobini Who are the enemies? Inflammation and autoimmune mechanisms Eur. Heart J. Suppl., November 1, 2002; 4(suppl_G): G27 - G32. [Abstract] [PDF]
|
|
|
|
|
|
M. Sato, T. Toyozaki, K. Odaka, T. Uehara, Y. Arano, H. Hasegawa, K. Yoshida, K. Imanaka-Yoshida, T. Yoshida, M. Hiroe, et al. Detection of Experimental Autoimmune Myocarditis in Rats by 111In Monoclonal Antibody Specific for Tenascin-C Circulation, September 10, 2002; 106(11): 1397 - 1402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Afanasyeva and N. R. Rose Cardiomyopathy Is Linked to Complement Activation Am. J. Pathol., August 1, 2002; 161(2): 351 - 357. [Full Text] [PDF]
|
|
|
|
|
|
T. P. Zwaka, D. Manolov, C. Ozdemir, N. Marx, Z. Kaya, M. Kochs, M. Hoher, V. Hombach, and J. Torzewski Complement and Dilated Cardiomyopathy: A Role of Sublytic Terminal Complement Complex-Induced Tumor Necrosis Factor-{alpha} Synthesis in Cardiac Myocytes Am. J. Pathol., August 1, 2002; 161(2): 449 - 457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B.-K. Lim, S.-C. Choe, J.-O. Shin, S.-H. Ho, J.-M. Kim, S.-S. Yu, S. Kim, and E.-S. Jeon Local Expression of Interleukin-1 Receptor Antagonist by Plasmid DNA Improves Mortality and Decreases Myocardial Inflammation in Experimental Coxsackieviral Myocarditis Circulation, March 19, 2002; 105(11): 1278 - 1281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Parrillo Inflammatory Cardiomyopathy (Myocarditis) : Which Patients Should Be Treated With Anti-Inflammatory Therapy? Circulation, July 3, 2001; 104(1): 4 - 6. [Full Text] [PDF]
|
|
|
|
|
|
R. Wojnicz, E. Nowalany-Kozielska, C. Wojciechowska, G. Glanowska, P. Wilczewski, T. Niklewski, M. Zembala, L. Polonski, M. M. Rozek, and J. Wodniecki Randomized, Placebo-Controlled Study for Immunosuppressive Treatment of Inflammatory Dilated Cardiomyopathy : Two-Year Follow-Up Results Circulation, July 3, 2001; 104(1): 39 - 45. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Miyamoto, A. Matsumori, M.-W. Hwang, R. Nishio, H. Ito, and S. Sasayama Therapeutic effects of FTY720, a new immunosuppressive agent, in a murine model of acute viral myocarditis J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1713 - 1718. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. DeBiasi, C. L. Edelstein, B. Sherry, and K. L. Tyler Calpain Inhibition Protects against Virus-Induced Apoptotic Myocardial Injury J. Virol., January 1, 2001; 75(1): 351 - 361. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M T Kearney, J M Cotton, P J Richardson, and A M Shah Viral myocarditis and dilated cardiomyopathy: mechanisms, manifestations, and management Postgrad. Med. J., January 1, 2001; 77(903): 4 - 10. [Abstract] [Full Text]
|
|
|
|
|
|
K. Shan, R. J. Bick, B. J. Poindexter, S. F. Nagueh, S. Shimoni, M. S. Verani, F. Keng, M. J. Reardon, G. V. Letsou, J. F. Howell, et al. Altered Adrenergic Receptor Density in Myocardial Hibernation in Humans : A Possible Mechanism of Depressed Myocardial Function Circulation, November 21, 2000; 102(21): 2599 - 2606. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Feldman and D. McNamara Myocarditis N. Engl. J. Med., November 9, 2000; 343(19): 1388 - 1398. [Full Text] [PDF]
|
|
|
|
|
|
C. M Oakley GENERAL CARDIOLOGY: Myocarditis, pericarditis and other pericardial diseases Heart, October 1, 2000; 84(4): 449 - 454. [Full Text]
|
|
|
|
|
|
G. M. Felker, J. P. Boehmer, R. H. Hruban, G. M. Hutchins, E. K. Kasper, K. L. Baughman, and J. M. Hare Echocardiographic findings in fulminant and acute myocarditis J. Am. Coll. Cardiol., July 1, 2000; 36(1): 227 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-F. Wang, J. Zhang, J.-Y. Min, M. F. Sullivan, C. S. Crumpacker, W. H. Abelmann, and J. P. Morgan Cocaine enhances myocarditis induced by encephalomyocarditis virus in murine model Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H956 - H963. [Abstract] [Full Text] [PDF]
|
|