Heart Metab. (2014) 62:8–12OriGinal Article

Definition and etiologyMyocarditis refers to the clinical, imaging, biochemical and histological manifestations of myocardial inflam-mation. The cardinal feature of myocardial inflammation is an abnormally high number of effector lymphocyte subsets and macrophages associated with myocyte damage. The clinical syndromes associated with myocarditis include myopericarditis, sudden death and heart failure resulting from immune-mediated myocar-dial damage. Common findings in myocarditis include stiffening and contractile impairment of the ventricles, conduction system disease and a heightened risk of ventricular arrhythmias, particularly during exercise. The histological definition of myocarditis is clas-sically represented by the Dallas criteria, proposed by a consensus panel of cardiovascular pathologists in 1986 [1]. These criteria define myocarditis as an

inflammatory cellular infiltrate in the heart with or without myocyte necrosis and/or degeneration of adjacent myocytes. In the past two decades immu-nohistochemical criteria that include the increased expression of class II (HLA-DR) antihuman leukocyte antigens and heightened numbers of CD3, CD4, CD8 or CD68-positive inflammatory cells have increased the sensitivity of endomyocardial biopsy (EMB) for the diagnosis of myocarditis [2]. Markers of comple-ment deposition that are commonly seen in humeral allograft rejection have recently been found in patients with cardiomyopathy, suggesting persistent activation of innate immune pathways [3]. Myocarditis may result from a myriad of cardiac infections and noninfectious triggers such including toxins, chest irradiation and rarely even vaccines [4]. In the setting of systemic inflammation myocarditis can

8

Management of myocarditisChantal El Amm1 and Leslie T. Cooper2

1Division of Cardiovascular Diseases, University Hospitals, Cleveland, Ohio, USA2Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA

Correspondence: Leslie T. Cooper, MD, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

Tel: +1 507 284 3680, fax: +1 507 266 0228, e-mail: cooper.leslie@mayo.edu

AbstractMyocarditis refers to inflammation of the myocardium, which can result in chest pain, arrhythmias and dilated cardiomyopathy. The presenting symptoms are non specific and diverse triggers, most com-monly viruses, can lead to the common clinical presentations. The pathogenesis of myocarditis can be simplified into a phase of acute injury resulting in an innate and adaptive immunological response, which downregulates in most patients leading to myocardial recovery. In a minority of cases, extensive scar form the initial injury or persistent inflammation results in chronic dilated cardiomyopathy. Cardiac magnetic resonance imaging is used in the diagnosis, with endomyocardial biopsy being reserved for cases in which the result will significantly alter prognosis or therapy. The management of myocarditis in patients with cardiomyopathy depends on the presence of infection and inflammation; if there is no evidence of either then patients are treated with standard guideline-based heart failure therapy. Emerging therapeutic strategies focus on modulating patient-specific immune reactions. Patients who fail to respond to medical therapy and have advanced heart failure may require mechanical circulatory support or heart transplantation. L Heart Metab; 2014;62:8–12

Keywords: Endomyocardial biopsy; heart failure; myocarditis.

develop in association with autoimmune disorders such as lupus erythematosus, hypersensitivity reactions or idiopathic hypereosinophilic syndrome [5, 6]. The most commonly identified cause of myocarditis is an upper respiratory tract or gastrointestinal virus infection. The most common viruses identified in heart biopsies from patients with acute myocarditis are currently parvovirus B19 and human herpes virus 6 [7]. Because most data on viral cardiomyopathy were gathered from case series in Europe and North America, the prevalence of viral disease as a proportion of heart failure in much of Africa, Asia and South America remains unknown. In specific regions of the developing world, rheumatic carditis after streptococcal A infection and Chagas’ disease from Trypanosoma cruzi remain important causes of myocarditis and heart failure [8].

PathogenesisThe pathogenesis of myocarditis can be simplified into a phase of acute injury, a subsequent innate and adap-tive immunological response and finally a transition either to chronic cardiomyopathy with fibrotic scar or to recovery (Figure 1) [9]. Genetic factors strongly impact susceptibility to and outcome of myocarditis in mice, but specific genes that influence human disease have not been identified [10]. In enteroviruses, variations in the 5′ region of the viral genome influence replication efficiency and virulence [11]. In models of enteroviral myocarditis, virus-mediated acute myocyte damage elicits an innate immune response that includes the recruitment of natural killer cells and proinflammatory cytokines through an inflammasome-mediated pathway [12]. The innate response develops into an antigen-specific immune response, which leads to successful virus clearance. In many cases the immune reaction downregulates and immune homeostasis is restored with no lasting cardiac damage. However, in a minority of cases the virus and/or the inflammatory reaction persists and contributes to cardiomyopathy and a syndrome of

heart failure. Up to 30% of myocarditis cases progress to chronic cardiomyopathy [13]. Autoantigens such as cardiac myosin can mediate this chronic myocardial damage through molecular mimicry with viral antigens [14]. The opportunity for therapeutic intervention in clinical medicine is presently limited to the later phases of this disease model.

ManagementIn 2013 the European Society of Cardiology (ESC) Working Group on Myocardial and Pericardial Diseases published a position statement on the management and therapy of myocarditis [15]. In their paradigm, management of patients who have persistent cardio-myopathy resulting from acute myocarditis depends on the presence or absence of myocardial infection and inflammation. Patients with viral infection may be considered for antiviral therapies. Patients with inflammation and no virus infection may benefit from immunosuppressive or immunomodulatory therapies [16]. Patients with neither evidence of viral genomes nor inflammation and whose ejection fraction is less than 40% should be treated with guideline-based heart failure therapy. An EMB is required to determine whether inflammation or infection is present. The ESC position statement recommends that a standard 12-lead ECG and a transthoracic echo-cardiogram be performed in all patients with clinically suspected myocarditis. Although there are no ECG changes sufficiently specific to diagnose myocarditis, the presence of QRS prolongation is an independent negative predictor of survival [17]. The echocardio-gram is valuable to exclude valvular or pericardial heart disease. Echocardiographic findings predictive of lower transplant-free survival are lower left ven-tricular ejection fraction and impaired right ventricular function [18]. Myocardial damage occurs in about a third of patients with pericarditis [19]. In patients with pericar-ditis, a troponin rise and normal left ventricular function the term “myopericarditis” is used. In patients with pericarditis and more severe myocardial dysfunction, the term “perimyocarditis” has been suggested. The overall likelihood of death or heart failure is quite low in patients with myopericarditis [20]. Non steroidal anti-inflammatory drugs and colchicine are probably safe for the treatment of pericarditis even with elevated troponin if the ejection fraction is normal, but should be avoided in more severe cases with systolic heart failure.

9

AbbreviationsACCF/AHA: American College of Cardiology Foundation/ American Heart Association; DCM: dilated car-diomyopathy; EMB: endomyocardial biopsy; ESC: European Society of Cardiology; 18FDG: [18F]2-fluoro-2-deoxyglucose; MRI: magnetic resonance imaging; PET: positron emission tomography

Heart Metab. (2014) 62:8–12 Chantal El Amm

Management of myocarditis

Avoidance of competitive athletics is recom-mended in all patients with myocarditis and myo-pericarditis for at least 6 months. Return to athletics requires re-evaluation of heart function and an

assessment of arrhythmic risk usually with a Holter monitor and/or an exercise ECG [21]. Cardiac magnetic resonance imaging (MRI) is useful to distinguish ischemic from nonischemic

10

Chantal El Amm Heart Metab. (2014) 62:8–12Management of myocarditis

Fig. 1 Pathogenesis of myocarditis. Th, T helper, reproduced with permission from NEJM [9].

Heart Metab. (2014) 62:8–12 Chantal El Amm

Management of myocarditis

cardiomyopathy. An expert panel recommended that both T1 and T2-weighted imaging be used to obtain optimal sensitivity and specificity when myocarditis is suspected [22]. When gadolinium contrast imaging is not feasible,T1 mapping is an emerging tool that can be used as a criterion for the detection of acute myocarditis with a reported sensitivity of 91% [23]. Radionucleotide imaging in unexplained cardio-myopathy is limited to several uncommon clinical scenarios. Resting perfusion imaging combined with [18F]2-fluoro-2-deoxyglucose (18FDG) positron emission tomography (PET) can be helpful in the diagnosis of car-diac sarcoidosis. 18FDG uptake is increased in myocar-dial granulomas in regions with a matched decrease in perfusion. In regions of scar from previous inflammation, a matched decrease in 18FDG and perfusion tracers in a non coronary distribution may be seen. Extrathoracic sites of active sarcoidosis and changes in 18FDG uptake following immunosuppression can also be tracked with PET imaging [24]. Mechanical circulatory support with ventricular assist devices or extracorporeal membrane oxygenation support is beneficial as a bridge to transplantation or recovery in adults and children with fulminant myocar-ditis and profound shock [25]. Cardiac transplantation is also an effective therapy for patients with myocarditis who have refractory heart failure, and survival after transplantation is similar to survival in adults for other causes of cardiac transplantation [26]. The outcome following transplantation in children may be worse than for other causes of dilated cardiomyopathy (DCM) if myocarditis is the cause of transplantation [27]. The role of transvenous EMB in the management of cardiomyopathy remains controversial. However, the 2013 position statement from the ESC Working Group on Myocardial and Pericardial Diseases and the 2013 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline for the mana-gement of heart failure disagree on the routine use of EMB in unexplained DCM [15, 28]. Histology and immunohistology are required to confirm inflammation, and viral genome analysis is a common method to infer active viral infection, but when do the data from EMB change prognosis and management? In certain clinical scenarios, unique data from EMB will impact prognosis and therapy. Consensus generally exists that EMB-confirmed sarcoidosis will change management by the use of immunosuppres-sive therapy in most cases. Lymphocytic myocarditis

predicts successful bridging to recovery after left ven-tricular assist device in adults [29] and the long-term risk of allograft rejection in children [27]. Viral genomes on EMB have been associated with increased risks of left ventricular dysfunction, heart transplantation or death [30–31]. The literature regarding the prognostic value of viral genomes to predict heart transplantation or death is mixed [32]. Since the 2013 ACCF/AHA guideline for the management of heart failure was published, a case series from Johns Hopkins Hospital reported results from 851 patients who underwent right ventricular EMB from 2000 to 2009 [33]. Overall, 25.5% of EMB provided a diagnosis and 22.7% of EMB changed the clinical course. The authors concluded that EMB is useful in acute-onset unexplained cardiomyopathy. However, the usefulness of EMB in chronic DCM was low. Recent reports suggest that left ventricular EMB has a greater diagnostic utility than right ventricular EMB in disorders that primarily affect the left ventricle [34, 35].

Future directionsThe MRI patterns of epicardial and/or mid-myocardial signal abnormality can identify nonischemic myocarditis or scar, but neither MRI nor 18FDG PET can identify specific causes and cellular types such as giant cell or eosinophilic myocarditis. However, perfluorocarbons such as 19fluorine can specifically detect macrophages, granulocytes and dendritic cells in murine myocarditis. A recent study by van Heeswijk et al [36] demonstrated that the perfluorocarbon 19fluorine can be detected using 9.4T cardiac MRI in a mouse model of auto- immune myocarditis. Translation of this and similar imaging agents under investigation to the clinical arena should allow for the noninvasive detection of myocarditis in settings where EMB is not readily available. Emerging therapies to prevent the progression of acute myocarditis to chronic DCM may focus on patient-specific immune reactions. For example, T helper type 17 cells are increased and T regulatory cells are decreased in mice with myocarditis [37]. The persistence of this or other immunophenotypes may identify subsets of myocarditis patients who are at risk of chronic heart failure and who may benefit from tailored immunotherapy. Clinical trials of protein A immunoadsorbtion, a cyclic peptide that binds anti-β1-receptor antibodies and specific anticytokine strategy studies are underway or planned [38]. L

11

REFERENCES

1. Aretz H, Billingham M, Edwards W, Factor S, Fallon J, Fenoglio J et al (1986) Myocarditis. A histopathologic definition and classification. Am J Cardiovasc Pathol 1:3–14

2. Herskowitz A, Ahmed-Ansari A, Neumann DA, Beschorner WE, Rose NR, Soule LM et al (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

3. She RC, Hammond EH (2010) Utility of immunofluorescence and electron microscopy in endomyocardial biopsies from patients with unexplained heart failure. Cardiovasc Pathol 19:e99–105

4. Blauwet LA, Cooper LT (2010) Myocarditis. Progr Cardiovasc Dis 52:274–288

5. Appenzeller S, Pineau CA, Clarke AE (2011) Acute lupus myocarditis: clinical features and outcome. Lupus 20:981–988

6. Bleeker J, Syed F, Cooper L, Weiler C, Teffer IA, Pardanan IA (2012) Treatment-refractory idiopathic hypereosinophilic syndrome: pitfalls and progress with use of novel drugs. Am J Hematol 87:703–706

7. Schultheiss H-P, Kuhl U, Cooper LT (2011) The management of myocarditis. Eur Heart J 32:2616–2625

8. Marijon E, Ou P, Celermajer D, Ferreira B, Mocumbi A, Jani D et al (2007) Prevalence of rheumatic heart disease detected by echocardiographic screening. N Engl J Med 357:470–476

9. Cooper LT Jr (2009) Myocarditis. N Engl J Med 360:1526–153810. Cihakova D, Sharma RB, Fairweather D, Afanasyeva M, Rose

NR (2004) Animal models for autoimmune myocarditis and autoimmune thyroiditis. Methods Mol Med 102:175–193

11. Chapman NM, Kim KS (2008) Persistent coxsackievirus infec-tion: Enterovirus persistence in chronic myocarditis and dilated cardiomyopathy. Curr Topics Microbiol Immunol 323:275–292

12. Abston ED, Coronado MJ, Bucek A, Bedja D, Shin J, Kim JB et al (2012) Th2 regulation of viral myocarditis in mice: different roles for TLR3 versus TRIF in progression to chronic disease. Clin Dev Immunol 2012:129486

13. Kindermann I, Barth C, Mahfoud F, Ukena C, Lenski M, Yilmaz A et al (2012) Update on myocarditis. J Am Coll Cardiol 59:779–792

14. 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

15. Caforio A, Pankuweit S, Arbustini E, Basso C, Gimeno-Blanes J, Felix S et al (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 J Published first online: 3 July 2013. doi:10.1093/eurheartj/eht210

16. Frustaci A, Russo MA, Chimenti C. Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study. Eur Heart J. 2009 Aug;30(16):1995-2002

17. Ukena C, Mahfoud F, Kindermann I, Kandolf R, Kindermann M, Bohm M (2011) Prognostic electrocardiographic parameters in patients with suspected myocarditis. Eur J Heart Fail 13:398–405

18. Magnani JW, Danik HJ, Dec GW Jr, DiSalvo TG (2006) Survival in biopsy-proven myocarditis: a long-term retrospective analysis of the histopathologic, clinical, and hemodynamic predictors. Am Heart J 151:463–470

19. Imazio M, Cooper LT. Management of myopericarditis. Expert Rev Cardiovasc Ther. 2013 Feb;11(2):193-201

20. Imazio M, Brucato A, Barbieri A, Ferroni F, Maestroni S, Ligabue G et al (2013) Good prognosis for pericarditis with and without myocardial involvement: results from a multicenter, prospective cohort study. Ciculation 128:42–49

21. Maron BJ, Ackerman MJ, Nishimura RA, Pyeritz RE, Towbin JA, Udelson JE (2005) Task force 4: HCM and other cardio-myopathies, mitral valve prolapse, myocarditis, and Marfan

syndrome. J Am Coll Cardiol 45:1340–134522. Friedrich MG, Sechtem U, Schulz-Menger J, Holmvang G,

Alakija P, Cooper LT et al. Cardiovascular magnetic resonance in myocarditis: a JACC White Paper. J Am Coll Cardiol. 2009 Apr 28;53(17):1475-1487

23. Ferreira ND, Bettencourt N, Rocha J, Leite D, Carvalho M, Teixeira M, Ribeiro VG. Diagnosis of acute myopericarditis by delayed-enhancement multidetector computed tomography. J Am Coll Cardiol. 2012 Aug 28;60(9):868

24. McArdle B, Leung E, Ohira H, Cocker M, deKemp R, DaSilva J et al (2013) The role of F(18)-fluorodeoxyglucose positron emission tomography in guiding diagnosis and management in patients with known or suspected cardiac sarcoidosis. J Nucl Cardiol 20:297–306

25. Wilmot I, Morales DLS, Price JF, Rossano JW, Kim JJ, Decker JA et al (2011) Effectiveness of mechanical circulatory support in children with acute fulminant and persistent myocarditis. J Cardiac Fail 17:487–494

26. Moloney ED, Egan JJ, Kelly P, Wood AE, Cooper LT Jr (2005) Transplantation for myocarditis: a controversy revisited. J Heart Lung Transplant 24:1103–1110

27. Pietra BA, Kantor PF, Bartlett HL, Chin C, Canter CE, Larsen RL et al (2012) Early predictors of survival to and after heart transplantation in children with dilated cardiomyopathy. Circulation 126:1079–1086

28. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Oct 15;62(16):e147-239

29. Boehmer JP, Starling RC, Cooper LT, Torre-Amione G, Wittstein I, Dec GW (2012) Left ventricular assist device support and myocardial recovery in recent onset cardiomyopathy. J Cardiac Fail 18:755–761

30. Caforio A, Calabrese F, Angelini A, Tona F, Vinci A, Bottaro S et al (2007) A prospective study of biopsy-proven myocarditis: prognostic relevance of clinical and aetiopathogenetic features at diagnosis. Eur Heart J 28:1326–1333

31. Kuhl U, Pauschinger M, Seeberg B, Lassner D, Noutsias M, Poller W et al (2005) Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation 112:1965–1970

32. Kindermann I, Kindermann M, Kandolf R, Klingel K, Bultmann B, Muller T et al (2008) Predictors of outcome in patients with suspected myocarditis. Circulation 118:639–648

33. Bennett MK, Gilotra NA, Harrington C, Rao S, Dunn JM, Freitag TB et al. Evaluation of the role of endomyocardial biopsy in 851 patients with unexplained heart failure from 2000-2009. Circ Heart Fail. 2013 Jul;6(4):676-84

34. Chimenti C, Frustaci A. Contribution and risks of left ventricular endomyocardial biopsy in patients with cardiomyopathies: a retrospective study over a 28-year period. Circulation. 2013 Oct 1;128(14):1531-15v41

35. Yilmaz A, Kindermann I, Kindermann M, Mahfoud F, Ukena C, Athanasiadis A et al (2010) Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complica-tion rate and diagnostic performance. Circulation 122:900–909

36. van Heeswijk RB, De Blois J, Kania G, Gonzales C, Blyszczuk P, Stuber M, Eriksson U, Schwitter J (2013) Selective in vivo visualization of immune-cell infiltration in a mouse model of autoimmune myocarditis by fluorine-19 cardiac magnetic resonance.Circ. Cardiovascular imaging. 6(2):277-84

37. Xie Y, Chen R, Zhang X, Chen P, Liu X, Xie Y et al (2011) The role of Th17 cells and regulatory T cells in coxsackievirus b3-induced myocarditis. Virology 421:78–84

38. Munch G, Boivin-Jahns V, Holthoff HP, Adler K, Lappo M, Truol S et al (2012) Administration of the cyclic peptide cor-1 in humans (phase i study): ex vivo measurements of anti-beta1-adrenergic receptor antibody neutralization and of immune parameters. Eur J Heart Fail 14:1230–1239

12

Chantal El Amm Heart Metab. (2014) 62:8–12Management of myocarditis