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The spectrum of myocarditis: from pathology to the clinics

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Abstract

Myocarditis is an inflammatory disease of the myocardium, which may occur in isolation or as part of systemic infectious/immune/autoimmune conditions, characterized by vast aetiologic, clinical and histopathologic heterogeneity. The broad spectrum of myocarditis can be categorized according to the prevalent histopathologic pattern including lymphocytic, lympho-histiocytic, eosinophilic and neutrophilic forms, giant cell myocarditis and myocarditis with granulomata. Diverse histopathologic substrates generally reflect different aetiologies and pathogenetic mechanisms and may be critical to clinical decision-making. Active vasculitis, when present, completes the inflammatory spectrum. Unfortunately, the correlation of histopathologic patterns, clinical presentation and disease course in myocarditis is still largely unresolved, due to limited availability of bioptic samples at specific stages of disease and impracticality of serial sampling. We here review the elements supporting an aetiology-driven diagnostic work-up in myocarditis, emphasizing the importance of integrating pathologic studies with clinical features and information derived from multimodality imaging. Furthermore, we explore myocardial inflammation in genetic cardiomyopathies, its role in driving clinical variability and the potential of transcriptomic and proteomic analysis in our understanding of these complex interrelations.

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Abbreviations

cMRI:

Cardiac magnetic resonance imaging

ICD:

Implantable cardioverter defibrillator

EMB:

Endomyocardial biopsy

EGPA:

Eosinophilic granulomatosis with polyangiitis

ESC:

European Society of Cardiology

GCM:

Giant cell myocarditis

HSM:

Hypersensitivity myocarditis

HES:

Idiopathic hypereosinophilic syndrome

IHC:

Immunohistochemistry

LM:

Lymphocytic myocarditis

PCR:

Polymerase chain reaction

SCD:

Sudden cardiac death

SLE:

Systemic lupus erythematosus

TM:

Toxic myocarditis

References

  1. Campuzano O, Fernández-Falgueras A, Sarquella-Brugada G, Sanchez O, Cesar S, Mademont I, Allegue C, Mates J, Pérez-Serra A, Coll M, Alcalde M, Iglesias A, Tiron C, Gallego MÁ, Ferrer-Costa C, Hospital A, Escribano C, Dasí C, Borondo JC, Castellà J, Arbelo E, Medallo J, Brugada J, Brugada R (2015) A genetically vulnerable myocardium may predispose to myocarditis. J Am Coll Cardiol 66(25):2913–2914. https://doi.org/10.1016/j.jacc.2015.10.049

    Article  PubMed  Google Scholar 

  2. Belkaya S, Kontorovich AR, Byun M, Mulero-Navarro S, Bajolle F, Cobat A, Josowitz R, Itan Y, Quint R, Lorenzo L, Boucherit S, Stoven C, Di Filippo S, Abel L, Zhang SY, Bonnet D, Gelb BD, Casanova JL (2017) Autosomal recessive cardiomyopathy presenting as acute myocarditis. J Am Coll Cardiol 69(13):1653–1665. https://doi.org/10.1016/j.jacc.2017.01.043

    Article  PubMed  PubMed Central  Google Scholar 

  3. Cooper LT Jr, Onuma OK, Sagar S, Oberg AL, Mahoney DW, Asmann YW, Liu P (2010) Genomic and proteomic analysis of myocarditis and dilated cardiomyopathy. Heart Fail Clin 6:75–85. https://doi.org/10.1016/j.hfc.2009.08.012

    Article  PubMed  Google Scholar 

  4. Caforio AL, Pankuweit S, Arbustini E, Basso C, Gimeno-Blanes J, Felix SB, Fu M, Heliö T, Heimans S, Jahns R, Klingel K, Linhart A, Maisch B, McKenna W, Morgensen J, Pinto YM, Ristic A, Schultheiss HP, Seggewiss H, Tavazzi L, Thiene G, Ylmaz A, Charron P, Elliott PM (2013) Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial diseases. Eur Heart Journal 34:2636–2648. https://doi.org/10.1093/eurheartj/eht210

    Article  Google Scholar 

  5. Ammirati E, Cipriani M, Lilliu M, Sormani P, Varrenti M, Raineri C, Petrella D, Garascia A, Pedrotti P, Roghi A, Bonacina E, Moreo A, Bottiroli M, Gagliardone MP, Mondino M, Ghio S, Totaro R, Turazza FM, Russo CF, Oliva F, Camici PG, Frigerio M (2017) Survival and left ventricular function changes in fulminant versus nonfulminant acute myocarditis. Circulation 136:529–545. https://doi.org/10.1161/CIRCULATIONAHA.117.026386

    Article  PubMed  Google Scholar 

  6. Gupta S, Markham DW, Drazner MH, Mammen PP (2008) Fulminant myocarditis. Nat Clin Pract Cardiovasc Med 5(11):693–706. https://doi.org/10.1038/ncpcardio1331

    Article  PubMed  Google Scholar 

  7. Schultheiss HP, Kühl U, Cooper LT (2011) The management of myocarditis. Eur Heart Journal 32:2616–2625. https://doi.org/10.1093/eutheartj/ehr165

    Article  Google Scholar 

  8. Sagar S, Liu PP, Cooper LT Jr (2012) Myocarditis. Lancet 379(9817):738–747. https://doi.org/10.1016/S0140-6736(11)60648-X

    Article  PubMed  Google Scholar 

  9. Kindermann I, Barth C, Mahfoud F, Ukena C, Lenski M, Yilmaz A, Klingel K, Kandolf R, Sechtem U, Cooper LT, Böhm M (2012) Update on myocarditis. J Am Coll Cardiol 59(9):779–792. https://doi.org/10.1016/j.jacc.2011.09.074

    Article  PubMed  Google Scholar 

  10. Cooper LT Jr, Keren A, Sliwa K, Matsumori A, Mensah GA (2014) The global burden of myocarditis: part 1: a systematic literature review for the global burden of diseases, injuries, and risk factors 2010 study. Glob Heart 9:121–129. https://doi.org/10.1016/j.gheart.2014.01.007

    Article  PubMed  Google Scholar 

  11. Fung G, Luo H, Qiu Y, Yang D, McManus B (2016) Myocarditis. Circ Res 118:496–514. https://doi.org/10.1161/CIRCRESAHA.115.306573

    Article  CAS  PubMed  Google Scholar 

  12. Kühl U, Schultheiss HP (2014) Viral myocarditis. Swiss Med Wkly 144:w14010. https://doi.org/10.4414/smw.2014.14010

    Article  PubMed  Google Scholar 

  13. Punukollu G, Gowda RM, Khan IA, Navarro VS, Vasavada BC (2007) Clinical aspects of the Chagas’ heart disease. Int J Cardiol 115:279–283. https://doi.org/10.1016/J.iJcard.2006.03.004

    Article  PubMed  Google Scholar 

  14. Andrade DV, Gollob KJ, Dutra WO (2014) Acute Chagas disease: new global challenges for an old neglected disease. PLoS Neglect Tropical Dis 8:e3010. https://doi.org/10.1371/journal.pntd.0003010

    Article  Google Scholar 

  15. Hidron A, Vogenthaler N, Santos-Preciado JI, Rodriguez-Morales AJ, Franco-Paredes C, Rassi A Jr (2010) Cardiac involvement with parasitic infections. Clin Microbiol Rev 23:324–349. https://doi.org/10.1128/CMR.00054-09

    Article  PubMed  PubMed Central  Google Scholar 

  16. Bocchi EA, Fiorelli A (2001) The Brazilian experience with heart transplantation: a multicenter report. J Heart Lung Transplant 20(6):637–645

    Article  CAS  PubMed  Google Scholar 

  17. Dominguez F, Kühl U, Pieske B, Garcia-Pavia P, Tschöpe C (2016) Update on myocarditis and inflammatory cardiomyopathy: reemergence of endomyocardial biopsy. Rev Esp Cardiol (Engl Ed) 69(2):178–187. https://doi.org/10.1016/j.rec.2015.10.015

    Article  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bowles NE, Ni J, Kearney DL, Pauschinger M, Schultheiss HP, McCarthy R, Hare J, Bricker JT, Kr B, Towbin JA (2003) Detection of viruses in myocardial tissues by polymerase chain reaction. Evidence of Adenovirus as a common cause of myocarditis in children and adults. J Am Coll Cardiol 42:466–472

    Article  PubMed  Google Scholar 

  20. Lassner D, Rohde M, Siegismund CS, Kühl U, Gross UM, Escher F, Tschöpe C, Schultheiss HP (2014) Myocarditis—personalized medicine by expanded endomyocardial biopsy diagnostics. World J Cardiovasc Dis 4:325–340. https://doi.org/10.4236/wjcd.2014.46042

    Article  Google Scholar 

  21. Esfandiarei M, McManus BM (2008) Molecular biology and pathogenesis of viral myocarditis. Annu Rev Pathol 3:127–155. https://doi.org/10.1146/annurev.pathmechdis.3.121806.151534

    Article  CAS  PubMed  Google Scholar 

  22. Pankuweit S, Klingel K (2013) Viral myocarditis: from experimental models to molecular diagnosis in patients. Heart Fail Rev 18:683–702. https://doi.org/10.1007/s10741-012-9357-4

    Article  CAS  PubMed  Google Scholar 

  23. Kühl U, Pauschinger M, Noutsias M, Seeberg B, Bock T, Lassner D, Poller W, Kandorf R, Schultheiss H-P (2005) High prevalence of viral genomes and multiple viral infections in the myocardium of adults with “idiopathic” left ventricular dysfunction. Circulation 111:887–893. https://doi.org/10.1161/01.CIR.0000155616.07901.35

    Article  PubMed  Google Scholar 

  24. Breinholt JP, Moulik M, Dreyer WJ, Denfield SW, Kim JJ, Jefferies JL, Rossano JW, Gates CM, Clunie SK, Bowles KR, Kearney DL, Bowles NE, Towbin JA (2010) Viral epidemiologic shift in inflammatory heart disease: the increasing involvement of parvovirus B19 in the myocardium of pediatric cardiac transplant patients. J Heart Lung Transplant 29:739–746. https://doi.org/10.1016/j.healun.2010.03.003

    Article  PubMed  PubMed Central  Google Scholar 

  25. Bock CT, Klingel K, Aberle S, Duechting A, Lupescu A, Lang F, Kandolf R (2005) Human parvovirus B19: a new emerging pathogen of inflammatory cardiomyopathy. J Vet Med B Infect Dis Vet Public Health 52:340–343. https://doi.org/10.1111/j.1439-0450.2005.00867.x

    Article  CAS  PubMed  Google Scholar 

  26. Schmidt-Lucke C, Spillmann F, Bock T, Kühl U, Van Linthout S, Schultheiss HP, Tschöpe C (2010) Interferon beta modulates endothelial damage in patients with cardiac persistence of human Parvovirus B19 infection. J Infect Dis 201:936–945. https://doi.org/10.1086/650700

    Article  PubMed  Google Scholar 

  27. Koepsell SA, Anderson DR, Radio SJ (2012) Parvovirus B19 is a bystander in adult myocarditis. Cardiovasc Pathol 21(6):476–481. https://doi.org/10.1016/j.carpath.2012.02.002

    Article  CAS  PubMed  Google Scholar 

  28. Bock CT, Klingel K, Kandolf R (2010) Human parvovirus B19-associated myocarditis. N Engl J Med 362(13):1248–1249. https://doi.org/10.1056/NEJMc0911362

    Article  CAS  PubMed  Google Scholar 

  29. Nielsen TS, Hansen J, Nielsen LP, Baandrup UT, Banner J (2014) The presence of enterovirus, adenovirus, and parvovirus B19 in myocardial tissue samples from autopsies: an evaluation of their frequencies in deceased individuals with myocarditis and in non-inflamed control hearts. Forensic Sci Med Pathol 10(3):344–350. https://doi.org/10.1007/s12024-014-9570-7

    Article  CAS  PubMed  Google Scholar 

  30. Norja P, Hokynar K, Aaltonen LM, Chen R, Ranki A, Partio EK, Kiviluoto O, Davidkin I, Leivo T, Eis-Hübinger AM, Schneider B, Fischer HP, Tolba R, Vapalahti O, Vaheri A, Söderlund-Venermo M, Hedman K (2006) Bioportfolio: lifelong persistence of variant and prototypic erythrovirus DNA genomes in human tissue. Proc Natl Acad Sci U S A 103(19):7450–7453. https://doi.org/10.1073/pnas.0602259103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chow LH, Beisel KW, McManus BM (1992) Enteroviral infection of mice with severe combined immunodeficiency. Evidence for direct viral pathogenesis of myocardial injury. Lab Investig 66:24–31

    CAS  PubMed  Google Scholar 

  32. Klingel K, Hohenadl C, Canu A, Albrecht M, Seemann M, Mall G, Kandolf R (1992) Ongoing enterovirus-induced myocarditis is associated with persistent heart muscle infection: quantitative analysis of virus replication, tissue damage, and inflammation. Proc Natl Acad Sci U S A 89(1):314–318. https://doi.org/10.1073/pnas.89.1.314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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(3):320–326. https://doi.org/10.1038/6543

    Article  CAS  PubMed  Google Scholar 

  34. Liu PP, Mason JW (2001) Advances in the understanding of myocarditis. Circulation 104(9):1076–1082

    Article  CAS  PubMed  Google Scholar 

  35. Gruhle S, Sauter M, Szalay G, Ettischer N, Kandolf R, Klingel K (2012) The prostacyclin agonist iloprost aggravates fibrosis and enhances viral replication in enteroviral myocarditis by modulation of ERK signalling and increase of iNOS expression. Basic Res Cardiol 107(5):287. https://doi.org/10.1007/s00395-012-0287-z

    Article  CAS  PubMed  Google Scholar 

  36. Heymans S, Eriksson U, Lehtonen J, Cooper LT Jr (2016) The quest for new approaches in myocarditis and inflammatory cardiomyopathy. J Am Coll Cardiol 68:2348–2364. https://doi.org/10.1016/j.jacc.2016.09.937

    Article  PubMed  Google Scholar 

  37. Seidman MA, McManus BM (2016) Myocarditis. In: Buja LM, Butany J (eds) Cardiovascular pathology, vol 9, 4th edn. Elsevier Inc, chap, Amsterdam, pp 341–359. https://doi.org/10.1016/B978-0-12-420219-1.00009-4

    Chapter  Google Scholar 

  38. Caforio ALP, Adler Y, Agostini C, Allanore Y, Anastasakis A, Arad M, Böhm M, Charron P, Elliott PM, Eriksson U, Felix SB, Garcia-Pavia P, Hachulla E, Heymans S, Imazio M, Klingel K, Marcolongo R, Matucci Cerinic M, Pantazis A, Plein S, Poli V, Rigopoulos A, Seferovic P, Shoenfeld Y, Zamorano JL, Linhart A (2017) Diagnosis and management of myocardial involvement in systemic immune-mediated diseases: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Disease. Eur Heart J 38(35):2649–2662. https://doi.org/10.1093/eurheartj/ehx321

    Article  CAS  PubMed  Google Scholar 

  39. McGonagle D, McDermott MF (2006) A proposed classification of the immunological diseases. PLoS Med 3:1242–1247. https://doi.org/10.1371/journal.pmed.0030297

    Article  CAS  Google Scholar 

  40. Lymphocytic and autoimmune myocarditis (2001) In: Burke A, Tavora F (eds) Practical cardiovascular pathology, 1st edn. Lippincott Williams & Wilkins, Philadelphia, chap 22, pp 241–248

    Google Scholar 

  41. Comarmond C, Cacoub P (2017) Myocarditis in auto-immune or auto-inflammatory diseases. Autoimmun Rev 16(8):811–816. https://doi.org/10.1016/j.autrev.2017.05.021

    Article  CAS  PubMed  Google Scholar 

  42. Leuschner F, Katus HA, Kaya Z (2009) Autoimmune myocarditis: past, present and future. J Autoimmun 33:282–289. https://doi.org/10.1016/j.aut.2009.07.009

    Article  CAS  PubMed  Google Scholar 

  43. Anzai A, Mindur JE, Halle L, Sano S, Choi JL, He S, McAlpine CS, Chan CT, Kahles F, Valet C, Fenn AM, Nairz M, Rattik S, Iwamoto Y, Fairweather D, Walsh K, Libby P, Nahrendorf M, Swirski FK (2019) Self-reactive CD4+ IL-3+ T cells amplify autoimmune inflammation in myocarditis by inciting monocyte chemotaxis. J Exp Med 216(2):369–383. https://doi.org/10.1084/jem.20180722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tincani A, Rebaioli CB, Taglietti M, Shoenfeld Y (2006) Heart involvement in systemic lupus erythematosus, antiphospholipid syndrome and neonatal lupus. Rheumatology (Oxford) 45(Suppl 4):iv8-13. https://doi.org/10.1093/rheumatology/kel308

    Article  Google Scholar 

  45. Hypersensitivity and toxic myocarditis (2001) In: Burke A, Tavora F (eds) Practical cardiovascular pathology, 1st edn. Lippincott Williams & Wilkins, Philadelphia, chap 23, pp 249–254

    Google Scholar 

  46. Ansari A, Maron BJ, Berntson DG (2003) Drug-induced toxic myocarditis. Tex Heart Inst J 30(1):76–79

    PubMed  PubMed Central  Google Scholar 

  47. Burke AP, Saenger J, Mullick F, Virmani R (1991) Hypersensitivity myocarditis. Arch Pathol Lab Med 115(8):764–769

    CAS  PubMed  Google Scholar 

  48. Berry JG, Atkins KA (2003) Pathology of human myocarditis. In: Cooper LT Jr (ed) Myocarditis: from bench to bedside, 1st edn. Humana Press, Totowa, NJ, chap 14, pp 325–370 ISBN: 1 58829 112 X/03

    Google Scholar 

  49. Cooper LT Jr (2009) Myocarditis. N Engl J Med 360:1526–1538. https://doi.org/10.1056/NEJMra0800028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Billingham ME (1987) Is acute cardiac rejection a model of myocarditis in humans? Eur Heart J 8(Suppl J):19–23

    Article  Google Scholar 

  51. Caforio AL, Calabrese F, Angelini A, Tona F, Vinci A, Bottaro S, Ramondo A, Carturan E, Iliceto S, Thiene G, Daliento L (2007) A prospective study of biopsy-proven myocarditis: prognostic relevance of clinical and aetiopathogenetic features at diagnosis. Eur Heart J 28:1326–1333. https://doi.org/10.1093/eurheartj/ehm076

    Article  PubMed  Google Scholar 

  52. Dennert R, Crijns HJ, Heymans S (2008) Acute viral myocarditis. Eur Heart J 29:2073–2082. https://doi.org/10.1093/eurheartj/ehn296

    Article  PubMed  PubMed Central  Google Scholar 

  53. Caforio AL, Keeling PJ, Zachara E, Mestroni L, Camerini F, Mann JM, Bottazzo GF, McKenna WJ (1994) Evidence from family studies for autoimmunity in dilated cardiomyopathy. Lancet 344:773–777

    Article  CAS  PubMed  Google Scholar 

  54. Li Y, Heuser JS, Cunningham LC, Kosanke SD, Cunningham MW (2006) Mimicry and antibody-mediated cell signaling in autoimmune myocarditis. J Immunol 177:8234–8240

    Article  CAS  PubMed  Google Scholar 

  55. Rose NR (2009) Myocarditis: infection versus autoimmunity. J Clin Immunol 29:730–737. https://doi.org/10.1007/s10875-009-9339-z

    Article  CAS  PubMed  Google Scholar 

  56. Bulkley BH, Roberts WC (1975) The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy. A study of 36 necropsy patients. Am J Med 58:243–264

    Article  CAS  PubMed  Google Scholar 

  57. Wijetunga M, Rockson S (2002) Myocarditis in systemic lupus erythematosus. Am J Med 113:419–423

    Article  PubMed  Google Scholar 

  58. Frustaci A, Gentiloni N, Caldarulo M (1996) Acute myocarditis and left ventricular aneurysm as presentations of systemic lupus erythematosus. Chest 109:282–284

    Article  CAS  PubMed  Google Scholar 

  59. Mueller KA, Mueller II, Eppler D, Zuern CS, Seizer P, Kramer U, Koetter I, Roecken M, Kandolf R, Gawaz M, Geisler T, Henes JC, Klingel K (2015) Clinical and histopathological features of patients with systemic sclerosis undergoing endomyocardial biopsy. PLoS One 1210:e0126707. https://doi.org/10.1371/journal.pone.0126707

    Article  CAS  Google Scholar 

  60. Dalakas MC (2015) Inflammatory muscle diseases. N Engl J Med 372:1734–1747. https://doi.org/10.1056/NEJMc1506827

    Article  CAS  PubMed  Google Scholar 

  61. Josselson A, Bagnall JW, Virmani R (1984) Acute rhematic carditis causing sudden death. Am J Forensic Med Pathol 5:151–154

    Article  CAS  PubMed  Google Scholar 

  62. Litovsky SH, Burke AP, Virmani R (1996) Giant cell myocarditis: an entity distinct from sarcoidosis characterized by multiphasic myocyte destruction by cytotoxic T cells and histiocytic giant cells. Mod Pathol 9(12):1126–1134

    CAS  PubMed  Google Scholar 

  63. Cooper LT Jr (2006) Acute heart failure due to fulminant and giant cell myocarditis. Herz 31(8):767–770. https://doi.org/10.1007/s00059-006-2917-

    Article  PubMed  Google Scholar 

  64. Cooper LT Jr, Berry GJ, Shabetai R (1997) Idiopathic giant-cell myocarditis--natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators. N Engl J Med 336(26):1860–1866. https://doi.org/10.1056/NEJM199706263362603

    Article  PubMed  Google Scholar 

  65. Cooper LT Jr (2005) Giant cell and granulomatous myocarditis. Heart Fail Clin 1(3):431–437. https://doi.org/10.1016/j.hfc.2005.06.004

    Article  PubMed  Google Scholar 

  66. Bonham CA, Strek ME, Patterson KC (2016) From granuloma to fibrosis: sarcoidosis associated pulmonary fibrosis. Curr Opin Pulm Med 22(5):484–491. https://doi.org/10.1097/MCP.0000000000000301

    Article  PubMed  PubMed Central  Google Scholar 

  67. Dubrey SW, Bell A, Mittal TK (2007) Sarcoid heart disease. Postgrad Med J 83(984):618–623. https://doi.org/10.1136/pgmj.2007.060608

    Article  PubMed  PubMed Central  Google Scholar 

  68. Bernstein M, Konzelman FW, Sidlick DM (1929) Boeck’s sarcoid: report of a case with visceral involvement. Arch Intern Med 44:721–734

    Article  Google Scholar 

  69. Kandolin R, Lehtonen J, Airaksinen J, Vihinen T, Miettinen H, Ylitalo K, Kaikkonen K, Tuohinen S, Haataja P, Kerola T, Kokkonen J, Pelkonen M, Pietilä-Effati P, Utrianen S, Kupari M (2015) Cardiac sarcoidosis: epidemiology, characteristics, and outcome over 25 years in a nationwide study. Circulation 131(7):624–632. https://doi.org/10.1161/CIRCULATIONAHA.114.011522

    Article  PubMed  Google Scholar 

  70. Sohn DW, Park JB, Lee SP, Kim HK, Kim YJ (2018) Viewpoints in the diagnosis and treatment of cardiac sarcoidosis: proposed modification of current guidelines. Clin Cardiol 41(10):1386–1394. https://doi.org/10.1002/clc.23060

    Article  PubMed  PubMed Central  Google Scholar 

  71. Luk A, Metawee M, Ahn E, Gustafsson F, Ross H, Butany J (2009) Do clinical diagnoses correlate with pathological diagnoses in cardiac transplant patients? The importance of endomyocardial biopsy. Can J Cardiol 25(2):e48–e54

    Article  PubMed  PubMed Central  Google Scholar 

  72. Johns CJ, Michele TM (1999) The clinical management of sarcoidosis. A 50-year experience at the Johns Hopkins Hospital. Medicine (Baltimore) 78(2):65–111

    Article  CAS  Google Scholar 

  73. Ginsberg F, Parrillo JE (2005) Eosinophilic myocarditis. Heart Failure Clin 1:419–429. https://doi.org/10.1016/j.hfc.2005.06.013

    Article  Google Scholar 

  74. Al Ali AM, Straatman LP, Allard MF, Ignaszewski AP (2006) Eosinophilic myocarditis: case series and review of literature. Can J Cardiol 22:1233–1237

    Article  PubMed  PubMed Central  Google Scholar 

  75. Cooper LT Jr (2017) Eosinophilic myocarditis as a cause of acute cardiac syndromes: the importance of awareness. J Am Coll Cardiol 70(19):2376–2377. https://doi.org/10.1016/j.jacc.2017.09.022

    Article  PubMed  PubMed Central  Google Scholar 

  76. Brambatti M, Matassini MV, Adler ED, Klingel K, Camici PG, Ammirati E (2017) Eosinophilic myocarditis: characteristics, treatment, and outcomes. J Am Coll Cardiol 19:2363–2375. https://doi.org/10.1016/j.jacc.2017.09.023

    Article  Google Scholar 

  77. Fenoglio JJ Jr, McAllister HA Jr, Mullick FG (1981) Drug related myocarditis. I. Hypersensitivity myocarditis. Hum Pathol 12:900–907

    Article  PubMed  Google Scholar 

  78. Kanai-Yoshizawa S, Sugiyama Kato T, Mancini D, Marboe CC (2013) Hypersensitivity myocarditis and outcome after heart transplantation. J Heart Lung Transplant 32:553–559. https://doi.org/10.1016/j.healun.2013.01.1052

    Article  PubMed  Google Scholar 

  79. Takkenberg JJ, Czer LS, Fishbein MC, Luthringer DJ, Quartel AW, Mirocha J, Queral CA, Blanche C, Trento A (2004) Eosinophilic myocarditis in patients awaiting heart transplantation. Crit Care Med 32(3):714–721

    Article  PubMed  Google Scholar 

  80. Janík M, Hejna P (2017) Necrotizing eosinophilic myocarditis. Forensic Sci Med Pathol 13:255–258. https://doi.org/10.1007/s12024-017-9841-1

    Article  PubMed  Google Scholar 

  81. deMello DE, Liapis H, Jureidini S, Nouri S, Kephart GM, Gleich GJ (1990) Cardiac localization of eosinophil granule major basic protein in acute necrotizing myocarditis. N Engl J Med 22:1542–1545. https://doi.org/10.1056/NEJM199011293232207

    Article  Google Scholar 

  82. Getz MA, Subramanian R, Logemann T, Ballantyne F (1991) Acute necrotizing eosinophilic myocarditis as a manifestation of severe hypersensitivity myocarditis. Antemortem diagnosis and successful treatment. Ann Intern Med 115(3):201–202

    Article  CAS  PubMed  Google Scholar 

  83. Yusuf SW, Sharma J, Durand JB, Banchs J (2012) Endocarditis and myocarditis: a brief review. Expert Rev Cardiovasc Ther 10(9):1153–1164. https://doi.org/10.1586/erc.12.107

    Article  CAS  PubMed  Google Scholar 

  84. Berry GJ, Burke MM, Andersen C, Bruneval P, Fedrigo M, Fishbein MC, Goddard M, Hammond EH, Leone O, Marboe C, Miller D, Neil D, Rassl D, Revelo MP, Rice A, Rene Rodriguez E, Stewart S, Tan CD, Winters GL, West L, Mehra MR, Angelini A (2013) The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation. J Heart Lung Transplant 32(12):1147–1162. https://doi.org/10.1016/j.healun.2013.08.011

    Article  PubMed  Google Scholar 

  85. Fedrigo M, Leone O, Burke MM, Rice A, Toquet C, Vernerey D, Frigo AC, Guillemain R, Pattier S, Smith J, Lota A, Potena L, Bontadini A, Ceccarelli C, Poli F, Feltrin G, Gerosa G, Manzan E, Thiene G, Bruneval P, Angelini A, Duong Van Huyen JP (2015) Inflammatory cell burden and phenotype in endomyocardial biopsies with antibody-mediated rejection (AMR): a multicenter pilot study from the AECVP. Am J Transplant 15(2):526–534. https://doi.org/10.1111/ajt.12976

    Article  CAS  PubMed  Google Scholar 

  86. Leone O, Potena L, Foà A, Zuckermann A (2016) Donor selection criteria: clinical and pathological insights. In: Leone O, Angelini A, Bruneval P, Potena L (eds) , vol 7. Springer International Publishing Switzerland, Chap, pp 115–136. https://doi.org/10.1007/978-3-319-46386-5

    Chapter  Google Scholar 

  87. Berman M, Ali A, Ashley E, Freed D, Clarke K, Tsui S, Parameshwar J, Large S (2010) Is stress cardiomyopathy the underlying cause of ventricular dysfunction associated with brain death? J Heart Lung Transplant 29:957–965. https://doi.org/10.1016/j.healun.2010.04.008

    Article  PubMed  Google Scholar 

  88. Guglin M (2015) How to increase the utilization of donor hearts? Heart Fail Rev 20:95–105. https://doi.org/10.1007/s10741-014-9434-y

    Article  PubMed  Google Scholar 

  89. Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, Sullivan RJ, Damrongwatanasuk R, Chen CL, Gupta D, Kirchberger MC, Awadalla M, Hassan MZO, Moslehi JJ, Shah SP, Ganatra S, Thavendiranathan P, Lawrence DP, Groarke JD, Neilan TG (2018) Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol 71:1755–1764. https://doi.org/10.1016/j.Jacc.2018.02.037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Varricchi G, Galdiero MR, Marone G, Criscuolo G, Triassi M, Bonaduce D, Marone G, Tocchetti CG (2017) Cardiotoxicity of immune checkpoint inhibitors. ESMO Open 2(4):e000247. https://doi.org/10.1136/esmoopen-2017-000247

    Article  PubMed  PubMed Central  Google Scholar 

  91. Leone O, Veinot JP, Angelini A, Baandrup UT, Basso C, Berry G, Bruneval P, Burke M, Butany J, Calabrese F, d’Amati G, Edwards WD, Fallon JT, Fishbein MC, Gallagher PJ, Halushka MK, McManus B, Pucci A, Rodriguez ER, Saffitz JE, Sheppard MN, Steenbergen C, Stone JR, Tan C, Thiene G, van der Wal AC, Winters GL (2012) 2011 Consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology. Cardiovasc Pathol 21:245–274. https://doi.org/10.1016/j.carpath.2011.10.001

    Article  PubMed  Google Scholar 

  92. Leone O, Rapezzi C, Sinagra G, Angelini A, Arbustini E, Bartoloni G, Basso C, Caforio AL, Calabrese F, Coccolo F, d’Amati G, Maresi E, Milanesi O, Nodari S, Oliva F, Perkan A, Prandstraller D, Pucci A, Ramondo A, Silvestri F, Valente M, Thiene G (2009) Consensus document on endomyocardial biopsy of the Associazione per la Patologia Cardiovascolare Italiana. G Ital Cardiol 10:3S–50S

    Google Scholar 

  93. Aretz HT, Billingham ME, Edwards WD, Factor SM, Fallon JT, Fenoglio JJ Jr, Olsen EG, Schoen FJ (1987) Myocarditis: a histopathologic definition and classification. Am J Cardiovasc Pathol 1:3–14

    CAS  PubMed  Google Scholar 

  94. Stewart S, Winters GL, Fishbein MC, Tazelaar HD, Kobashigawa J, Abrams J, Andersen CB, Angelini A, Berry GJ, Burke MM, Demetris AJ, Hammond E, Itescu S, Marboe CC, McManus B, Reed EF, Reinsmoen NL, Rodriguez ER, Rose AG, Rose M, Suciu-Focia N, Zeevi A, Billingham ME (2005) Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 24(11):1710–1720. https://doi.org/10.1016/j.healun.2005.03.019

    Article  PubMed  Google Scholar 

  95. Baughman KL (2006) Diagnosis of myocarditis—death of Dallas criteria. Circulation 113:593–595. https://doi.org/10.1161/CIRCULATIONAHA.105.589663

    Article  PubMed  Google Scholar 

  96. Carturan E, Basso C, Thiene G (2014) Molecular pathobiology of myocarditis. In: Willis MS, Homesteir JW, Stone JR (eds) Cellular and molecular pathobiology of cardiovascular disease, vol 8, 1st edn. Elsevier Inc, chap, Amsterdam, pp 135–159 ISBN: 978-0-12-405206-2

    Chapter  Google Scholar 

  97. Linder J, Cassling RS, Rogler WC, Wilson JE, Markin RS, Sears TD, McManus BM (1985) Immunohistochemical characterization of lymphocytes in uninflamed ventricular myocardium. Implications for myocarditis. Arch Pathol Lab Med 109:917–920

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  99. Kindermann I, Kindermann M, Kandolf R, Klingel K, Bültmann B, Müller T, Lindinger A, Böhm M (2008) Predictors of outcome in patients with suspected myocarditis. Circulation 118:639–648. https://doi.org/10.1161/CIRCULATIONAHA.108.769489

    Article  PubMed  Google Scholar 

  100. Edwards WD, Holmes DR, Reeders GS (1982) Diagnosis of active lymphocytic myocarditis by endomyocardial biopsy: quantitative criteria for light microscopy. Mayo Clin Proc 57:419–425

    CAS  PubMed  Google Scholar 

  101. Edwards WD (1984) Myocarditis and endomyocardial biopsy. Cardiol Clin 2:647–656

    Article  CAS  PubMed  Google Scholar 

  102. Edwards WD (1985) Current problems in establishing quantitative histopathologic criteria for the diagnosis of lymphocytic myocarditis by endomyocardial biopsy. Heart Vessel 1:138–142

    Article  CAS  Google Scholar 

  103. Holzinger S, Schöllhammer A, Imhof M, Reinwald C, Kramer G, Zuckermann A, Wolner E, Steiner G (1995) Phenotypic patterns of mononuclear cells in dilated cardiomyopathy. Circulation 92:2876

    Article  CAS  PubMed  Google Scholar 

  104. Maisch B, Bultmann B, Factor S (1998) Dilated cardiomyopathy with inflammation or chronic myocarditis: variability and consensus in the diagnosis. Eur Heart J 19(suppl):647 (P3625)

    Google Scholar 

  105. Maisch B, Hufnagel G, Schönian U, Hengstenberg C, for the ESETCID investigators (1995) The European study of epidemiology and treatment of cardiac inflammatory disease. Eur Heart J 16(suppl O):173–175

    Article  PubMed  Google Scholar 

  106. Schnitt SJ, Ciano PS, Schoen FJ (1987) Quantitation of lymphocytes in endomyocardial biopsies: use and limitations of antibodies to leukocyte common antigen. Hum Pathol 18:796–800

    Article  CAS  PubMed  Google Scholar 

  107. Tazelaar HD, Billingham ME (1987) Myocardial lymphocytes. Fact, fancy or myocarditis? Am J Cardiovasc Pathol 1:47–50

    CAS  PubMed  Google Scholar 

  108. Angelini A, Crosato M, Boffa GM, Calabrese F, Calzolari V, Chioin R, Daliento L, Thiene G (2002) Active versus borderline myocarditis: clinicopathological correlates and prognostic implications. Heart 87:2010–2015

    Article  Google Scholar 

  109. Angelini A, Calzolari V, Calabrese F, Boffa GM, Maddalena F, Chioin R, Thiene G (2000) Myocarditis mimicking acute myocardial infarction: role of endomyocardial biopsy in the differential diagnosis. Heart 84:245–250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Schultheiss HP (1993) Dilated cardiomyopathy—a chronic myocarditis? New aspects on diagnosis and therapy. Z Kardiol 82(Suppl 4):25–32

    PubMed  Google Scholar 

  111. Herskowitz A, Ahmed-Ansari A, Neumann DA, Beschorner WE, Rose NR, Soule LM, Burek CL, Sell KW, Baughman KL (1990) Induction of major histocompatibility complex antigens within the myocardium of patients with active myocarditis: a nonhistologic marker of myocarditis. J Am Coll Cardiol 15:624–632

    Article  CAS  PubMed  Google Scholar 

  112. Siskin M, Rao S, Rapkiewicz A, Bangalore S, Garshick M (2017) A case of cardiogenic shock secondary to complement-mediated myopericarditis from influenza B infection. Can J Cardiol 33:1335.e1-e3. https://doi.org/10.1016/j.cjca.2017.06.006

    Article  Google Scholar 

  113. Hanson PJ, Seidman MA (2017) Diagnosing myocarditis in the absence of leukocyte infiltration: a complementary approach. Can J Cardiol 33(10):1223–1224. https://doi.org/10.1016/j.cjca.2017.07.006

    Article  PubMed  Google Scholar 

  114. Calabrese F, Carturan E, Thiene G (2010) Cardiac infections: focus on molecular diagnosis. Cardiovasc Pathol 19(3):171–182. https://doi.org/10.1016/j.carpath.2009.09.010

    Article  PubMed  Google Scholar 

  115. Martin AB, Webber S, Fricker FJ, Jaffe R, Demmler G, Kearney D, Zhang YU, Bodurtha J, Gelb B, Ni J et al (1994) Acute myocarditis. Rapid diagnosis by PCR in children. Circulation 90:330–339

    Article  CAS  PubMed  Google Scholar 

  116. Severini GM, Mestroni L, Falaschi A, Camerini F, Giacca M (1993) Nested polymerase chain reaction for high-sensitivity detection of enteroviral RNA in biological samples. J Clin Microbiol 31:1345–1349

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Calabrese F, Thiene G (2003) Myocarditis and inflammatory cardiomyopathy: microbiological and molecular biological aspects. Cardiovasc Res 60:11–25

    Article  CAS  PubMed  Google Scholar 

  118. Frustaci A, Calabrese F, Chimenti C, Pieroni M, Thiene G, Maseri A (2002) Lone hepatitis C virus myocarditis resposive to immunosuppressive therapy. Chest 122:1348–1356

    Article  PubMed  Google Scholar 

  119. Modrow S (2006) Parvovirus B19: the causative agent of dilated cardiomyopathy or a harmless passenger of the human myocard? Ernst Schering Res Found Workshop 55:63–82

    Article  Google Scholar 

  120. Lam KM, Oldenburg N, Ma K, Gaylore V, Mikhail GW, Strouhal PD, Middeldorp JM, Banner N, Yacoub M (1998) Significance of reverse transcription polymerase chain reaction in the detection of human cytomegalovirus gene transcripts in thoracic organ transplant recipients. J Heart Lung Transplant 17:555–565

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  122. Okabe M, Fukuda K, Arakawa K, Kikuchi M (1997) Chronic variant of myocarditis associated with hepatitis C virus infection. Circulation 96:22–24

    Article  CAS  PubMed  Google Scholar 

  123. Ruppert V, Maisch B (2012) Molecular signatures and the study of gene expression profiles in inflammatory heart diseases. Herz 37(6):619–626. https://doi.org/10.1007/s00059-012-3662-5

    Article  CAS  PubMed  Google Scholar 

  124. Shai RM (2006) Microarray tools for deciphering complex diseases. Front Biosci 11:1414–1424

    Article  CAS  PubMed  Google Scholar 

  125. Pham MX, Teuteberg JJ, Kfoury AG, Starling RC, Deng MC, Cappola TP, Kao A, Anderson AS, Cotts WG, Ewald GA, Baran DA, Bogaev RC, Elashoff B, Baron H, Yee J, Valantine HA (2010) Gene-expression profiling for rejection surveillance after cardiac transplantation. N Engl J Med 362:1890–1900. https://doi.org/10.1056/NEJMoa0912965

    Article  CAS  PubMed  Google Scholar 

  126. Halloran PF, Potena L, Van Huyen JD, Bruneval P, Leone O, Kim DH, Jouven X, Reeve J, Loupy A (2017) Building a tissue-based molecular diagnostic system in heart transplant rejection: the heart molecular microscope diagnostic (MMDx) system. J Heart Lung Transplant 36(11):1192–1200. https://doi.org/10.1016/j.healun.2017.05.029

    Article  PubMed  Google Scholar 

  127. Heidecker B, Kittleson MM, Kasper EK, Wittstein IS, Champion HC, Russell SD, Hruban RH, Rodriguez RE, Baughman KL, Hare JM (2011) Transcriptomic biomarkers for the accurate diagnosis of myocarditis. Circulation 123(11):1174–1184. https://doi.org/10.1161/CIRCULATIONAHA.110.002857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Potena L, Agostini V, Borgese L, Rinaldi E, Giovannini L, Reeve J, Parkes M, Masetti M, Russo A, Leone O, Halloran P (2019) Clinical and pathological insights of myocardial molecular profiling: time to revise ISHLT grading system? J Heart Lung Transplant 38(4S):S86–S87

    Article  Google Scholar 

  129. Billingham ME (1989) Acute myocarditis: is sampling error a contraindication for diagnostic biopsies? J Am Coll Cardiol 14:921–922

    Article  CAS  PubMed  Google Scholar 

  130. Baandrup U, Florio RA, Olsen EG (1982) Do endomyocardial biopsies represent the morphology of the rest of the myocardium? A quantitative light microscopic study of single v. multiple biopsies with the King's bioptome. Eur Heart J 3:171–178

    Article  CAS  PubMed  Google Scholar 

  131. Hauck AJ, Kearney DL, Edwards WD (1989) Evaluation of postmortem endomyocardial biopsy specimens from 38 patients with lymphocytic myocarditis: implications for role of sampling error. Mayo Clin Proc 64:1235–1245

    Article  CAS  PubMed  Google Scholar 

  132. Chow LH, Radio SJ, Sears TD, McManus BM (1989) Insensitivity of right ventricular endomyocardial biopsy in the diagnosis of myocarditis. J Am Coll Cardiol 14:915–920

    Article  CAS  PubMed  Google Scholar 

  133. Shields RC, Tazelaar HD, Berry GJ, Cooper LT Jr (2002) The role of right ventricular endomyocardial biopsy for idiopathic giant cell myocarditis. J Card Fail 8(2):74–78

    Article  PubMed  Google Scholar 

  134. Sekiguchi M, Hiroe M, Take M, Hirosawa K (1980) Clinical and histopathological profile of sarcaoidosis of the heart and acute idiopathic myocarditis. Jpn Circ J 44:264–273

    Article  CAS  PubMed  Google Scholar 

  135. Narula J, Khaw BA, Dec GW, Palacios IF, Newell JB, Southern JF, Fallon JT, Strauss HW, Haber E, Yasuda T (1996) Diagnostic accuracy of antimyosin scintigraphy in suspected myocarditis. J Nucl Cardiol 3:371–381

    Article  CAS  PubMed  Google Scholar 

  136. Hauck AJ, Kearney DL, Edwards WD (1989) Evaluation of postmortem endomyocardial biopsy specimens from 38 hearts of patients with lymphocytic myocarditis: implications for role of sampling error. Mayo Clin Proc 64:1235–1245

    Article  CAS  PubMed  Google Scholar 

  137. Dec GW, Fallon JT, Southern JF, Palacios I (1990) “Borderline” myocarditis: an indication for repeat endomyocardial biopsy. JACC 15:283–289

    Article  CAS  PubMed  Google Scholar 

  138. Burke AP, Farb A, Robinowitz M, Virmani R (1991) Serial sectioning and multiple level examination of endomyocardial biopsies for the diagnosis of myocarditis. Mod Pathol 4:690–693

    CAS  PubMed  Google Scholar 

  139. Thiene G, Veinot JP, Angelini A, Baandrup UT, Basso C, Bruneval P, Buja LM, Butany J, d'Amati G, de Gouveia RH, Fallon JT, Fishbein MC, Gallagher PJ, Kholova I, Leone O, McManus B, Rodriguez ER, Schoen FJ, Sheppard MN, Stone JR, van der Wal AC, Winters GL, Association for European Cardiovascular Pathology and Society for Cardiovascular Pathology Task Force on Training in Cardiovascular Pathology (2010) AECVP and SCVP 2009 recommendations for training in cardiovascular pathology. Cardiovasc Pathol 19(3):129–135. https://doi.org/10.1016/j.carpath.2009.12.001

    Article  PubMed  Google Scholar 

  140. Yilmaz A, Kindermann I, Kindermann M, Mahfoud F, Ukena C, Athanasiadis A, Hill S, Mahrholdt H, Voehringer M, Schieber M, Klingel K, Kandolf R, Böhm M, Sechtem U (2010) Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance. Circulation 122:900–909. https://doi.org/10.1161/CIRCULATIONAHA.109.924167

    Article  PubMed  Google Scholar 

  141. Chimenti C, Frustaci A (2013) Contribution and risks of left ventricular endomyocardial biopsy in patients with cardiomyopathies: a retrospective study over a 28-year period. Circulation 128:1531–1541. https://doi.org/10.1161/CIRCULATIONAHA.13.001414

    Article  PubMed  Google Scholar 

  142. Escher F, Lassner D, Kühl U, Gross U, Westermann D, Poller W, Skurk C, Weitmann K, Hoffmann W, Tschöpe C, Schultheiss HP (2014) Analysis of endomyocardial biopsies in suspected myocarditis—diagnostic value of left versus right ventricular biopsy. Int J Cardiol 177:76–78. https://doi.org/10.1016/j.ijcard.2014.09.071

    Article  CAS  PubMed  Google Scholar 

  143. Baccouche H, Mahrholdt H, Meinhardt G, Merher R, Voehringer M, Hill S, Klingel K, Kandolf R, Sechtem U, Yilmaz A (2009) Diagnostic synergy of non-invasive cardiovascular magnetic resonance and invasive endomyocardial biopsy in troponin-positive patients without coronary artery disease. Eur Heart J 30:2869–2879. https://doi.org/10.1093/eurheartj/ehp328

    Article  CAS  PubMed  Google Scholar 

  144. De Cobelli F, Pieroni M, Esposito A, Chimenti C, Belloni E, Mellone R, Canu T, Perseghin G, Gaudio C, Maseri A, Frustaci A, Del Maschio A (2006) Delayed gadolinium-enhanced cardiac magnetic resonance in patients with chronic myocarditis presenting with heart failure or recurrent arrhythmias. J Am Coll Cardiol 47:1649–1654. https://doi.org/10.1016/j.jacc.2005.11.067

    Article  PubMed  Google Scholar 

  145. Mahrholdt H, Goedecke C, Wagner A, Meinhardt G, Athanasiadis A, Vogelsberg H, Fritz P, Klingel K, Kandolf R, Sechtem U (2004) Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology. Circulation 109(10):1250–1258. https://doi.org/10.1161/01.CIR.0000118493.13323.81

    Article  PubMed  Google Scholar 

  146. Gutberlet M, Spors B, Thoma T, Bertram H, Denecke T, Felix R, Noutsias M, Schultheiss HP, Kühl U (2008) Suspected chronic myocarditis at cardiac MR: diagnostic accuracy and association with immunohistologically detected inflammation and viral persistence. Radiology 246:401–409. https://doi.org/10.1148/radiol.2461062179

    Article  PubMed  Google Scholar 

  147. Dec GW Jr, Palacios IF, Fallon JT, Aretz HT, Mills J, Lee DC, Jhonson RA (1985) Active myocarditis in the spectrum of acute dilated cardiomyopathies. N Engl J Med 312:885–890. https://doi.org/10.1056/NEJM198504043121404

    Article  PubMed  Google Scholar 

  148. Casella M, Pizzamiglio F, Dello Russo A, Carbucicchio C, Al-Mohani G, Russo E, Notarstefano P, Pieroni M, D’Amati G, Sommariva E, Giovannardi M, Carnevali A, Riva S, Fassini G, Tundo F, Santangeli P, Di Biase L, Bolognese L, Natale A, Tondo C (2015) Feasibility of combined unipolar and bipolar voltage maps to improve sensitivity of endomyocardial biopsy. Circ Arrhythm Electrophysiol 8:625–632. https://doi.org/10.1161/CIRCEP.114.002216

    Article  PubMed  Google Scholar 

  149. Pieroni M, Dello Russo A, Marzo F, Pelargonio G, Casella M, Bellocci F, Crea F (2009) High prevalence of myocarditis mimicking arrhythmogenic right ventricular cardiomyopathy differential diagnosis by electroanatomic mapping-guided endomyocardial biopsy. J Am Coll Cardiol 53:681–689. https://doi.org/10.1016/j.jacc.2008.11.017

    Article  PubMed  Google Scholar 

  150. Friedrich MG, Sechtem U, Schulz-Menger J, Holmvang G, Alakija P, Cooper LT, White JA, Abdel-Aty H, Gutberlet M, Prasad S, Aletras A, Laissy JP, Paterson I, Filipchuk NG, Kumar A, Pauschinger M, Liu P (2009) Cardiovascular magnetic resonance in myocarditis: a JACC White Paper. J Am Coll Cardiol 53:1475–1487. https://doi.org/10.1016/j.Jcmg.2016.09.010

    Article  PubMed  PubMed Central  Google Scholar 

  151. Francone M, Chimenti C, Galea N, Scopelliti F, Verardo R, Galea R, Carbone I, Catalano C, Fedele F, Frustaci A (2014) CMR sensitivity varies with clinical presentation and extent of cell necrosis in biopsy-proven acute myocarditis. JACC Cardiovasc Imaging 7:254–263. https://doi.org/10.1016/j.jcmg.2013.10.011

    Article  PubMed  Google Scholar 

  152. Ferreira VM, Schulz-Menger J, Holmvang G, Kramer CM, Carbone I, Sechtem U, Kindermann I, Gutberlet M, Cooper LT, Liu P, Friedrich MG (2018) Cardiovascular magnetic resonance in nonischemic myocardial inflammation: expert recommendations. J Am Coll Cardiol 72:3158–3176. https://doi.org/10.1016/j.jacc.2018.09.072

    Article  PubMed  Google Scholar 

  153. Cooper LT, Baughman KL, Feldman AM, Frustaci A, Jessup M, Kühl U, Levine GN, Narula J, Starling RC, Towbin J, Virmani R, American Heart Association, American College of Cardiology; European Society of Cardiology; Heart Failure Society of America; Heart Failure Association of the European Society of Cardiology (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. https://doi.org/10.1016/j.iacc.2007.09.008

    Article  PubMed  Google Scholar 

  154. Peretto G, Sala S, De Luca G, Campochiaro C, Sartorelli S, Cappelletti AM, Rizzo S, Palmisano A, Esposito A, Margonato A, Tresoldi M, Thiene G, Basso C, Dagna L, Della Bella P (2018) Impact of systemic immune-mediated diseases on clinical features and prognosis of patients with biopsy-proved myocarditis. Int J Cardiol S0167-5273(18):35834–0. https://doi.org/10.1016/j.ijcard.2018.11.104

    Article  Google Scholar 

  155. Dello Russo A, Casella M, Pieroni M, Pelargonio G, Bartoletti S, Santangeli P, Zucchetti M, Innocenti E, Di Biase L, Carbucicchio C, Bellocci F, Fiorentini C, Natale A, Tondo C (2012) Drug-refractory ventricular tachycardias following myocarditis: endocardial and epicardial radiofrequency catheter ablation. Circ Arrhythm Electrophysiol 5:492–498. https://doi.org/10.1161/circep.111.965012

    Article  Google Scholar 

  156. Pieroni M, De Santis M, Zizzo G, Bosello S, Smaldone C, Campioni M, De Luca G, Laria A, Meduri A, Bellocci F, Bonomo L, Crea F, Ferraccioli G (2014) Recognizing and treating myocarditis in recent-onset systemic sclerosis heart disease: potential utility of immunosuppressive therapy in cardiac damage progression. Semin Arthritis Rheum 43:526–535. https://doi.org/10.1016/J,semarthrit.2013.07.006

    Article  PubMed  Google Scholar 

  157. 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 30:1995–2002. https://doi.org/10.1093/eurheart/ehp249

    Article  CAS  PubMed  Google Scholar 

  158. Merken J, Hazebroek M, Van Paassen P, Verdonschot J, Van Empel V, Knackstedt C, Abdul Hamid M, Seiler M, Kolb J, Hoermann P, Ensinger C, Brunner-La Rocca HP, Poelzl G, Heymans S (2018) Immunosuppressive therapy improves both short- and long-term prognosis in patients with virus-negative nonfulminant inflammatory cardiomyopathy. Circ Heart Fail 11:e004228. https://doi.org/10.1161/CIRCHEARTFAILURE.117.004228

    Article  CAS  PubMed  Google Scholar 

  159. 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 104:39–45

    Article  CAS  PubMed  Google Scholar 

  160. Kühl U, Pauschinger M, Schwimmbeck PL, Seeberg B, Lober C, Noutsias M, Poller W, Schultheiss HP (2003) Interferon-β _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. https://doi.org/10.1161/01.CIR.0000072766.67150.51

    Article  CAS  PubMed  Google Scholar 

  161. McNamara DM, Holubkov R, Starling RC, Dec GW, Loh E, Torre-Amione G, Gass A, Janosko K, Tokarczyk T, Kessler P, Mann DL, Feldman AM (2001) Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation 103:2254–2259

    Article  CAS  PubMed  Google Scholar 

  162. Kandolin R, Lehtonen J, Salmenkivi K, Räisänen-Sokolowski A, Lommi J, Kupari M (2013) Diagnosis, treatment, and outcome of giant-cell myocarditis in the era of combined immunosuppression. Circ Heart Fail 6:15–22. https://doi.org/10.1161/CITCHEARTFAILURE.112.969261

    Article  CAS  PubMed  Google Scholar 

  163. Tan JL, Fong HK, Birati EY, Han Y (2019) Cardiac sarcoidosis. Am J Cardiol 123:513–522. https://doi.org/10.1016/J.amjcard.2018.10.021

    Article  PubMed  Google Scholar 

  164. Trachtenberg BH, Hare JM (2017) Inflammatory cardiomyopathic syndromes. Circ Res 121:803–818. https://doi.org/10.1161/CIRCRESAHA.117.310221

    Article  CAS  PubMed  Google Scholar 

  165. Calabrese F, Basso C, Carturan E, Valente M, Thiene G (2006) Arrhythmogenic right ventricular cardiomyopathy/dysplasia: is there a role for viruses? Cardiovasc Pathol 15:11–17. https://doi.org/10.1016/j.carpath.2005.10.004

    Article  PubMed  Google Scholar 

  166. Protonotarios A, Wicks E, Ashworth M, Stephenson E, Guttmann O, Savvatis K, Sekhri N, Mohiddin SA, Syrris P, Menezes L, Elliott P (2018) Prevalence of 18F-fluorodeoxyglucose positron emission tomography abnormalities in patients with arrhythmogenic right ventricular cardiomyopathy. Int J Cardiol 26:S0167–5273(18)34604–7. https://doi.org/10.1016/j,ijcard.2018.10.083

    Article  Google Scholar 

  167. Siegismund CS, Escher F, Lassner D, Kühl U, Gross U, Fruhwald F, Wenzel P, Münzel T, Frey N, Linke RP, Schultheiss HP (2018) Intramyocardial inflammation predicts adverse outcome in patients with cardiac AL amyloidosis. Eur J Heart Fail 20:751–757. https://doi.org/10.1002/ejhf.1039

    Article  CAS  PubMed  Google Scholar 

  168. Nordin S, Kozor R, Medina-Menacho K, Abdel-Gadir A, Baig S, Sado DM, Lobascio I, Murphy E, Lachmann RH, Mehta A, Edwards NC, Ramaswami U, Steeds RP, Hughes D, Moon JC (2018) Proposed stages of myocardial phenotype development in Fabry disease. JACC Cardiovasc Imaging:S1936-878X(18)30307-3. https://doi.org/10.1016/j.jcmg.2018.03.020

  169. Pieroni M, Notarstefano P, Oliva A, Campuzano O, Santangeli P, Coll M, Nesti M, Carnevali A, Fraticelli A, Iglesias A, Grassi S, Brugada R, Bolognese L (2018) Electroanatomic and pathologic right ventricular outflow tract abnormalities in patients with Brugada syndrome. J Am Coll Cardiol 72:2747–2757. https://doi.org/10.1016/j,jacc.2018.09.037

    Article  PubMed  Google Scholar 

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Acknowledgments

Iacopo Olivotto was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement no. 777204: ‘SILICOFCM - In Silico trials for drug tracing the effects of sarcomeric protein mutations leading to familial cardiomyopathy’; by the Italian Ministry of Health (Left ventricular hypertrophy in aortic valve disease and hypertrophic cardiomyopathy: genetic basis, biophysical correlates and viral therapy models (RF-2013-02356787), and NET-2011-02347173 (Mechanisms and treatment of coronary microvascular dysfunction in patients with genetic or secondary left ventricular hypertrophy).

Contributions

All individuals listed as co-authors of the manuscript (Ornella Leone, Maurizio Pieroni, Claudio Rapezzi and Iacopo Olivotto) gave substantial contributions to the conception or design of the work and to drafting the work or revising it critically for important intellectual content. All co-authors (Ornella Leone, Maurizio Pieroni, Claudio Rapezzi and Iacopo Olivotto) gave final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work be appropriately investigated and resolved.

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Authors and Affiliations

  1. Cardiovascular Pathology Unit, Department of Pathology, Sant’Orsola-Malpighi University Hospital, Via G. Massarenti 9, 40138, Bologna, Italy

    Ornella Leone

  2. Cardiovascular Department, San Donato Hospital, Arezzo, Italy

    Maurizio Pieroni

  3. Cardiology, Department of Experimental Diagnostic and Specialty Medicine, Alma Mater Studiorum-University of Bologna, Bologna, Italy

    Claudio Rapezzi

  4. Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy

    Iacopo Olivotto

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  1. Ornella Leone
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  2. Maurizio Pieroni
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  4. Iacopo Olivotto
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Correspondence to Ornella Leone.

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Leone, O., Pieroni, M., Rapezzi, C. et al. The spectrum of myocarditis: from pathology to the clinics. Virchows Arch 475, 279–301 (2019). https://doi.org/10.1007/s00428-019-02615-8

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