WJCD  Vol.4 No.6 , May 2014
Idiopathic Giant Cell Myocarditis: State of the Art
Giant cell myocarditis (GCM) is a rare, rapidly progressive and highly lethal disease in young and middle-aged adults. It is attributed to an inflammation of the heart muscle, and mediated by T lymphocytes and anti-myosin autoantibodies. Making diagnosis of GCM with multiple noninvasive imaging modalities is possible in a small percentage of patients, so myocardial tissue diagnosis is often required. An early diagnosis is very important, because immunosuppressive treatment may significantly improve clinical course and survival of these patients. GCM often escapes diagnosis until autopsy or transplantation and has defied proper treatment trials for its rarity and deadly behavior. This review will focus on the diagnostic approach to patients with suspected GCM and currently evidence-based treatment strategy for this disease.

Cite this paper
Veia, A. , Cavallino, C. , Bacchini, S. , Pastore, F. , Lupi, A. , Rognoni, A. , Rametta, F. and Bongo, A. (2014) Idiopathic Giant Cell Myocarditis: State of the Art. World Journal of Cardiovascular Diseases, 4, 316-324. doi: 10.4236/wjcd.2014.46041.
[1]   Elliott, P., Andersson, B., Arbustini, E., et al. (2008) Classification of the Cardiomyopathies: A Position Statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Disease. European Heart Journal, 29, 270-276.

[2]   Lindenfeld, J., Albert, N.M. and Boehmer, J.P. (2010) HFSA 2010 Comprehensive Heart Failure Practice Guideline. Journal of Cardiac Failure, 16, e1-e2.

[3]   Saltykow, S. (1905) Uber Diffuse Myokarditis. Virchows Archiv fur Pathologische Anatomie, 182, 1-39.

[4]   Baumgartner, H. (1915) Uber Spezifische Diffuse Produktive Myocarditis. Frankfurt. Ztschr.f.Path., 16, 91-120.

[5]   Jonas, A.F. (1939) Granulomatous Myocarditis. Bulletin of the Johns Hopkins Hospital, 15, 749-756

[6]   Magner, D. (1939) A Case of Fatal Subacute Myocarditis of Unknown Etiology. American Journal of the Medical Sciences, 198, 246-252

[7]   Palmer, H. and Michael, I. (1965) Giant-Cell Myocarditis with Multiple Organ Involvement. Archives of Internal Medicine, 116, 444-447.

[8]   Tesluk, H. (1956) Giant cell vs Granulomatous Myocarditis. American Journal of Clinical Pathology, 26, 1326.

[9]   Okura, Y., Dec, G.W., Hare, J.M., et al. (2003) A Clinical and Histopatologic Comparison of Cardiac Sarcoidosis and Idiopathic Giant Cell Myocarditis. Journal of the American College of Cardiology, 41, 322-328.

[10]   Vaideeswar, P. and Cooper, L. (2013) Giant Cell Myocarditis: Clinical and Pathological Disease Characteristics in an Indian Population. Cardiovascular Pathology, 22, 70-74.

[11]   Whitehead, R. (1965) Isolated Myocarditis. British Heart Journal, 27, 220-230.

[12]   Okada, R. and Wakafuji, S (1986) Twenty Year Autopsy Statistics of Myocarditis Incidence in Japan. Japanese Circulation Journal, 50, 1288-1293.

[13]   December, G.W. (2003) Introduction to Clinical Myocarditis. In: Cooper Jr., L.T., Ed., Myocarditis from the Bench to the Bedside, Humana Press, Totowa, 257-281.

[14]   Winters, G. and Costanzo-Nordin, M. (1991) Pathological Findings in 2300 Consecutive Endomyocardial Biopsies. Modern Pathology, 4, 441-448.

[15]   Drut, R.M. and Drut, R. (1986) Giant Cell Myocarditis in a Newborn with Congenital Herpes Simplex Virus (HSV) Infection: an Immunohistochemical Study on the Origin of the Giant Cells. Fetal & Pediatric Pathology, 6, 431-437.

[16]   Meyer, T., Grumbach, I.M., Kreuzer, H. and Morguet, A.J. (1997) Giant Cell Myocarditis Due to Coxackie B2 Virus Infection. Cardiology, 88, 296-299.

[17]   Lee, M., Kwon, G.Y., Kim, J.S. and Jeon, E.S. (2010) Giant Cell Myocarditis Associated with Coxsackievirus Infection. Journal of the American College of Cardiology, 56, Article ID: e19.

[18]   Dennert, R., Schalla, S., Suylen, R.J., Eurlings, L. and Heymans, S. (2009) Giant Cell Myocarditis Triggered by Parvovirus B19 Infection. International Journal of Cardiology, 134, 115-116.

[19]   Shariff, S., Straatman, L., Allard, M. and Ignaszewski, A. (2004) Novel Associations of Giant Cell Myocarditis: Two Case Reports and a Review of the Literature. Canadian Journal of Cardiology, 20, 557-561.

[20]   Schumann, C., Faust, M., Gerharz, M., Ortmann, M., Schubert, M. and Krone, W. (2005) Autoimmune Polyglandular Syndrome Associated with Idiopathic Giant Cell Myocarditis. Experimental and Clinical Endocrinology & Diabetes, 113, 302-307.

[21]   Burke, J.S., Medline, N.M. and Kratz, A. (1969) Giant Cell Myocarditis and Myositis: Associated with Thymoma and Myastenia Gravis. Archives of Pathology, 88, 359-366.

[22]   Nash, C.L., Panaccione, R., Sutherland, L.R. and Meddings, J.B. (2001) Giant Cell Myocarditis, in a Patient with Crohn’s Disease, Treated with Etanercept—A Tumor Necrosis Factor-Alpha Antagonist. Canadian Journal of Gastroenterology, 15, 607-611.

[23]   Ariza, A., Lopez, M.D., Mate, J.L., Curos, A., Villagrasa, M. and Navas-Palacios, J.J. (1995) Giant Cell Myocarditis: Monocytic Immunophenotype of Giant Cells in a Case Associated with Ulcerative Colitis. Human Pathology, 26, 121-123.

[24]   Hales, S.A., Theaker, J.M. and Gatter, K.C. (1987) Giant Cell Myocarditis Associated with Lymphoma: An Immunocytochemical Study. Journal of Clinical Pathology, 40, 1310-1313.

[25]   Anderson, K., Carrier, M., Romeo, P., Pelletier, G.B. and Ducharme, A. (2013) An Unusual Case of Giant Cell Myocarditis Missed in a Heartmate-2 Left Ventricle Apical-Wedge Section: A Case Report and Review of the Literature. Journal of Cardiothoracic Surgery, 8, 12.

[26]   Daniles, P.R., Berry, G.J., Tazelaar, H.D., Berry, G.J. and Cooper, L.T. (2002) The Role of Right Ventricular Endomyocardial Biopsy for Idiopathic Giant Cell Myocarditis. Journal of Cardiac Failure, 8, 74-78.

[27]   Kodama, M., Matsumoto, Y., Fujiwara, M., Masani, F., Izumi, T. and Shibata, A. (1990) A Novel Experimental Model of Giant Cell Myocarditis Induced in Rats by Immunization with Cardiac Myosin Fraction. Clinical Immunology and Immunopathology, 57, 250-262.

[28]   Kodama, M., Matsumoto, Y. and Fujiwara, M. (1992) In Vivo Lymphocyte-Mediated Myocardial Injuries Demonstrated by Adoptive Transfer of Experimental Autoimmune Myocarditis. Circulation, 85, 1918-1926.

[29]   Caforio, A.L., Goldman, J.H., Haven, A.J., Baig, K.M., Libera, L.D., McKenna, W.J. and Myocarditis Treatment Trial Investigators (1997) Circulating Cardiac-Specific Autoantibodies as Markers of Autoimmunity in Clinical and Biopsy-Proven Myocarditis. European Heart Journal, 18, 270-275.

[30]   Fuse, K., Kodama, M., Aizawa, Y., Yamaura, M., Tanabe, Y., Takahashi, K., Sakai, K., Miida, T., Oda, H. and Higuma, N. (2001) Th1/Th2 Balance Alteration in the Clinical Course of a Patient with Acute Viral Myocarditis. Japanese Circulation Journal, 65, 1082-1084.

[31]   Hirono, S., Oslam, M.O., Nakazawa, M., Yoshida, Y., Kodama, M., Shibata, A., Izumi, T. and Imai, S. (1997) Expression of Inducible Nitric Oxide Synthase in Rat Experimental Autoimmune Myocarditis with Special Reference to Changes in Cardiac Hemodynamics. Circulation Research, 80, 11-20.

[32]   Chang, H., Hanawa, H., Yoshida, T., et al. (2008) Alteration of IL-17 Related Protein Expression in Experimental Autoimmune Myocarditis and Inhibition of IL-17 by IL-10-Ig Fusion Gene Transfer. Circulation Journal, 72, 813-819.

[33]   Shioji, K., Kishimoto, C., Nakayama, Y. and Sasayama, S. (2000) Strain Differences in Rats with Experimental Giant Cell Myocarditis. Japanese Circulation Journal, 64, 283-286.

[34]   Kittlesson, M., Minhas, K., Irizarry, R., Ye, S.Q., Edness, G., Breton, E., Conte, J.V., Tomaselli, G., Garcia, J.G. and Hare, J.M. (2005) Gene Expression in Giant Cell Myocarditis: Altered Expression of Immune Response Genes. International Journal of Cardiology, 102, 333-340.

[35]   Asimaki, A., Tandri, H., Duffy, E.R., et al. (2011) Altered Desmosomal Proteins in Granulomatous Myocarditis and Potential Pathogenic Links to Arrhythmogenic Right Ventricular Cardiomyopathy. Circulation: Arrhythmia and Electrophysiology, 4, 743-752.

[36]   Fairweather, D., Petri, M.A., Coronado, M.J. and Cooper, L.T. (2012) Autoimmune Heart Disease: Role of Sex Hormones and Autoantibodies in Disease Pathogenesis. Expert Review of Clinical Immunology, 8, 269-284.

[37]   Cooper Jr., L.T., Berry, G.J., Shabetai, R. and Multicenter Giant Cell Myocarditis Study Group Investigators (1997) Idiopathic Giant-Cell Myocarditis-Natural History and Treatment. New England Journal of Medicine, 336, 1860-1866.

[38]   Cooper Jr., L.T. and Blauwet, L.A. (2011) When Should High-Grade Heart Block Trigger a Search for a Treatable Cardiomyopathy? Circulation: Arrhythmia and Electrophysiology, 4, 260-261.

[39]   Ren, H., Poston, R., Hruban, R.H., Baumgartner, W.A., Baughman, K.L. and Hutchins, G.M. (1993) Long Survival with Giant Cell Myocarditis. Modern Pathology, 6, 402-407.

[40]   Davies, R.A., Veinot, J.P., Smith, S., Struthers, C., Hendry, P. and Masters, R. (2002) Giant Cell Myocarditis: Clinical Presentation, Bridge to Transplantation with Mechanical Circulatory Support, and Long-Term Outcome. Journal of Heart and Lung Transplantation, 21, 674-679.

[41]   Mendes, L.A., Dec, G.W., Picard, M.H., Palacios, I.F., Newell, J. and Davidoff, R. (1994) Right Ventricular Dysfunction: An Independent Predictor of Adverse Outcome in Patients with Myocarditis. American Heart Journal, 128, 301-307.

[42]   Felker, G.M., Boehmer, J.P., Hruban, R.H., Hutchins, G.M., Kasper, E.K., Baughman, K.L. and Hare, J.M. (2000) Echocardiographic Findings in Fulminant and Acute Myocarditis. Journal of the American College of Cardiology, 36, 227-232.

[43]   Friedrich, M.G., Sechtem, U., Schulz-Menger, J., Holmvang, G., Alakija, P., et al. (2009) Cardiovascular Magnetic Resonance in Myocarditis: A JACC White Paper. International Consensus Group on Cardiovascular Magnetic Resonance in Myocarditis. Journal of the American College of Cardiology, 53, 1475-1487.

[44]   Mahrholdt, H., Goedecke, C., Wagner, A., Meinhardt, G., Athanasiadis, A., Vogelsberg, H., Fritz, P., Klingel, K., Kandolf, R. and Sechtem, U. (2004) Cardiovascular Magnetic Resonance Assessment of Human Myocarditis: A Comparison to Histology and Molecular Pathology. Circulation, 109, 1250-1258.

[45]   Abdel-Aty, H., Boyé, P., Zagrosek, A., Wassmuth, R., Kumar, A., Messroghli, D., Bock, P., Dietz, R., Friedrich, M.G. and Schulz-Menger, J. (2005) Diagnostic Performance of Cardiovascular Magnetic Resonance in Patients with Suspected Acute Myocarditis: Comparison of Different Approaches. Journal of the American College of Cardiology, 45, 1815-1822.

[46]   Yilmaz, A., Ferreira, V., Klingel, K., Kandolf, R., Neubauer, S. and Sechtem, U. (2013) Role of Cardiovascular Magnetic Resonance Imaging (CMR) in the Diagnosis of Acute and Chronic Myocarditis. Heart Failure Reviews, 18, 747-760.

[47]   Baccouche, H., Mahrholdt, H., Meinhardt, G., Merher, R., Voehringer, M., Hill, S., Klingel, K., Kandolf, R., Sechtem, U. and Yilmaz, A. (2009) Diagnostic Synergy of Non-Invasive Cardiovascular Magnetic Resonance and Invasive Endomyocardial Biopsy in Troponin-Positive Patients without Coronary Artery Disease. European Heart Journal, 30, 2869-2879.

[48]   Shields, R.C., Tazelaar, H.D., Berry, G.J. and Cooper Jr., L.T. (2002) The Role of Right Ventricular Endomyocardial Biopsy for Idiopathic Giant Cell Myocarditis. Journal of Cardiac Failure, 8, 74-78.

[49]   Cooper, L.T., Baughman, K.L., Feldman, A.M., et al. (2007) The Role of Endomyocardial Biopsy in the Management of Cardiovascular Disease: A Scientific Statement from the American Heart Association, the American College of Cardiology and the European Society of Cardiology. Circulation, 116, 2216-2233.

[50]   Kandolin, R., Lehtonen, J. and Kupari, M. (2011) Cardiac Sarcoidosis and Giant Cell Myocarditis as Causes of Atrio-ventricular Block in Young and Middle-Aged Adults. Circulation: Arrhythmia and Electrophysiology, 4, 303-309.

[51]   Kandolin, R., Lehtonen, J., Salmenkivi, K., Raisanen-Sokolowski, A. and Kupari, M. (2013) Diagnosis, Treatment and Outcome of Giant Cell Myocarditis in the Era of Combined Immunosoppression. Circulation: Heart Failure, 6, 15-22.

[52]   Davies, M.J., Pomerance, A. and Teare, R.D. (1975) Idiopathic Giant Cell Myocarditis a Distinctive Clinico-Pathological Entity. British Heart Journal, 37, 192-195.

[53]   Litovsky, S.H., Burke, A.P. and Virmani, R. (1996) Giant Cell Myocarditis: An Entity Distinct from Sarcoidosis Characterized by Multiphasic Myocyte Destruction by Cytotoxic T Cells and Histiocytic Giant Cells. Modern Pathology, 9, 1126-1134.

[54]   Wu, L. and Cooper, L. (2004) Potential of the Right Ventricular Endomyocardial Biopsy to Diagnose and Assist in the Management of Congestive Heart Failure: Insights from Recent Cinical Trials. Congestive Heart Failure, 10, 133-139.

[55]   Dickstein, K., Cohen-Solal, A., Filippatos, G., 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). European Heart Journal, 29, 2388-2442.

[56]   Mason, J.W., O’Connel, J.B., Herskowitz, A., Rose, N.R., McManus, B.M., Billingham, M.E. and Moon, T.E. (1995) A Clinical Trial of Immunosuppressive Therapy for Myocarditis. The Myocarditis Treatment Trial Investigators. New England Journal of Medicine, 333, 269-275.

[57]   Cooper, L.T., Berry, G.J. and Shabetai, R. (1997) Idiopathic Giant Cell Myocarditis—Natural History and Treatment. Multicenter Giant Cell Myocarditis Study Group Investigators. New England Journal of Medicine, 336, 1860-1866.

[58]   Cooper, L.T., Hare, J.M., Tazelaar, H.D., Edwards, W.D., Starling, R.C., Deng, M.C., Menon, S., Mullen, G.M., Jaski, B., Bailey, K.R., Cunningham, M.W., Dec, G.W. and Giant Cell Myocarditis Treatment Trial Investigators (2008) Usefulness of Immunosuppression for Giant Cell Myocarditis. American Journal of Cardiology, 102, 1535-1539.

[59]   Menghini, V.V., Savcenko, V., Olson, L.J., Tazelaar, H.D., Dec, G.W., Kao, A. and Cooper, J.T. (1999) Combined Immunosuppression for the Treatment of Idiopathic Giant Cell Myocarditis. Mayo Clinic Proceedings, 74, 1221-1226.

[60]   Cooper, L.T., Orellana, V., Kuhl, U. and Schultheiss, H.P. (2012) Long Term Risk of Death, Transplantation, and Disease Recurrence in Giant Cell Myocarditis. Journal of the American College of Cardiology, 59, E1547.

[61]   Stoica, S.C., Goddard, M., Tsui, S., Dunning, J., McNeil, K., Parameshwar, J. and Large, S.R. (2003) Ventricular Assist Surprise: Giant Cell Myocarditis or Sarcoidosis? Journal of Thoracic and Cardiovascular Surgery, 126, 2072-2074.

[62]   Eid, S.M., Schamp, D., Haluschka, M.K. and Barouch, L.A. (2009) Resolution of Giant Cell Myocarditis after Extended Ventricular Assistance. Archives of Pathology & Laboratory Medicine, 133, 138-141.

[63]   Marelli, D., Kermani, R., Bresson, J., Fishbein, M.C., Hamilton, M., Moriguchi, J., Fonarow, G.C., Cohen, B., Kobashigawa, J. and Laks, H. (2003) Support with the BVS 5000 Assist Device during Treatment of Acute Giant Cell Myocarditis. Texas Heart Institute Journal, 30, 50-56.

[64]   Brilaki, E., Olson, L., Berry, G., Daly, R.C., Loisance, D., Zucker, M. and Cooper, L.T. (2000) Survival Outcomes of Patients with Giant Cell Myocarditis Bridged to Transplantation with Ventricular Assist Devices. ASAIO Journal, 46, 569-572.