Clinical presentation and diagnosis of myocarditis.

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Heart Online First, published on June 24, 2015 as 10.1136/heartjnl-2014-306363 Education in Heart

MYOCARDIAL DISEASE

Clinical presentation and diagnosis of myocarditis Alida L P Caforio,1 Renzo Marcolongo,2 Cristina Basso,3 Sabino Iliceto1 1

Cardiology, Department of Cardiological Thoracic and Vascular Sciences, University of Padua, Padua, Italy 2 Clinical Immunology, Department of Medicine (DIMED), University of Padua, Padua, Italy 3 Cardiovascular Pathology, Department of Cardiological, Thoracic and Vascular Sciences, University of Padua, Padua, Italy Correspondence to Dr Alida L P Caforio, Division of Cardiology, Department of Cardiological, Thoracic and Vascular Sciences, Centro ‘V. Gallucci’, University of PadovaPoliclinico, Via Giustiniani, 2, Padova 35128, Italy; [email protected]

Myocarditis represents a challenging diagnosis, mainly because there is no pathognomonic clinical presentation, and the disease may masquerade as a variety of non-inflammatory myocardial diseases. Thus, in the 1996 WHO/International Society and Federation of Cardiology (WHO/ISFC)1 and in the 2007 European Society of Cardiology (ESC) classifications of cardiomyopathies,2 as well as in the 2013 ESC myocarditis Task Force report,3 the disease is defined histologically as an inflammatory disease of the myocardium diagnosed on endomyocardial biopsy (EMB), based upon histological, immunological, immunohistochemical and molecular findings to detect possible infectious causes.1–6 The term inflammatory cardiomyopathy may be used for histologically confirmed myocarditis in association with cardiac dysfunction (box 1).1 Although EMB remains the diagnostic gold standard for myocarditis and it is the only tool that, at present, provides distinction of its aetiological forms,1–6 it is not widely used. This results in lack of certainty in the epidemiological impact and the natural history of the disease. Myocarditis may resolve spontaneously, recur or become chronic, leading about 1/3 of biopsy-proven cases to dilated cardiomyopathy (DCM), death or heart transplantation.7 Traditionally, when the diagnosis was only based upon the histological Dallas diagnostic criteria, myocarditis was considered to be a relatively rare cause of heart failure and/or of sudden cardiac death.8 9 Nowadays, the use of highly sensitive immunohistochemical and molecular tools applied to EMB10–18 and of cardiovascular MR (CMR) for non-invasive imaging19–21 suggests that we may be indeed facing the tip of an iceberg, with a substantial underestimation of myocarditis frequency and of its causative role in DCM.

AETIOLOGY

To cite: Caforio ALP, Marcolongo R, Basso C, et al. Heart Published Online First: [ please include Day Month Year] doi:10.1136/ heartjnl-2014-306363

Etiopathogenetic agents of myocarditis are shown in table 1. Viral infections are presumed to represent the most common causes in North America and Europe. Viral genomes are detected in the myocardium of a variable proportion of patients using molecular techniques, mainly reverse transcritapse polymerase chain reaction (PCR).7 10–18 20–22 Parvovirus B19 and human herpes virus 6 (HHV6) are becoming, at least in German series, the most frequently detected virus types, and co-infection is found in a sizable proportion of patients.10 13–15 18 21 22 The sensitivity and specificity of EMB for the diagnosis of specific viral infections are unknown and may vary as a function of disease stage, time from onset of clinical symptoms to EMB and variable epidemiology of viral infections in different countries.7 10–18 20–22 Myocarditis is autoimmune if no infectious agents are identified on

Learning objectives 1. How to formulate the clinical suspicion of myocarditis. 2. How to reach the diagnosis of ‘clinically suspected’ and ‘definite (biopsy-proven)’ myocarditis according to the European Society of Cardiology (ESC) 2013 Task Force criteria. 3. How to interpret non-invasive and invasive diagnostic findings in the context of the heterogeneous clinical presentations of suspected myocarditis. 4. How to assess prognosis.

ESC curriculum sections 2.1 History taking and clinical examination 2.2 The ECG 2.3 Non-invasive imaging 2.4 Invasive imaging 2.10 Myocardial diseases EMB and other known causes are excluded (box 1).23 24 Autoimmune myocarditis may occur with exclusive cardiac involvement or in systemic autoimmune disorders, in which it is often associated with a bad prognosis,25–29 particularly in Churg– Strauss syndrome,25 29 Wegener granulomatosis,26 idiopathic inflammatory myopathies,28 systemic lupus erythematosus27 and is managed with intensified immunosuppression.24–29

PATHOGENESIS Viral myocarditis The viral pathogenesis of myocarditis associated with parvovirus B19 and HHV6 is at present poorly understood and a subject of intensive research.10 30 Recently, parvovirus B19 replication intermediates were found in human acute myocarditis with high viral load but not in DCM; co-infection with other cardiotropic viruses was observed more frequently with HHV6.31 Co-infected patients had higher viral parvovirus B19 load compared with monoinfected patients, suggesting that HHV6 had transactivated parvovirus B19.31 These researchers suggest that parvovirus B19 infection of the human heart may cause the development of an endothelial cell-mediated inflammatory disease and that this is related to both viral load and genotype, in brief that parvovirus B19 infection may be pathogenic only in a subset of patients with myocarditis.10 31

Caforio ALP, et al. Heart 2015;0:1–13. doi:10.1136/heartjnl-2014-306363

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Education in Heart Box 1 Definitions Myocarditis (WHO/International Society and Federation of Cardiology (ISFC), European Society of Cardiology (ESC)1–3 Inflammatory disease of the myocardium diagnosed by established histological*, immunohistochemical** and immunological criteria***. *Established histological Dallas criteria4 defined as follows: “Histological evidence of inflammatory infiltrates within the myocardium associated with myocyte degeneration and necrosis of non-ischaemic origin”. **Immunohistochemical criteria, abnormal inflammatory infiltrate3 5–6defined as follows: “≥14 leucocytes/mm2 including up to 4 monocytes/mm2 with the presence of CD3-positive T lymphocytes ≥7 cells/mm2”. ***Immunological criteria and myocarditis aetiology defined as follows3 (see also figure 3): ▸ Viral: histology (Hx) and immunoHx positive ( pos), PCR pos for ≥virus ▸ Autoimmune: Hx and immunoHx pos; viral PCR negative (neg); with or without pos cardiac autoantibodies (aabs); exclusion of other known inflammatory causes ▸ Viral and immune****: Hx and immunoHx pos; viral PCR pos; cardiac aabs pos ****N.B. a follow-up endomyocardial biopsy may identify persistent viral myocarditis, resolved myocarditis (Hx and virological), or persistent virus-negative myocarditis, for example, postinfectious autoimmune. Inflammatory cardiomyopathy and dilated cardiomyopathy (DCM) (WHO/ISFC, ESC)*****1–3 Myocarditis in association with cardiac dysfunction. *****Involved in the pathogenesis of DCM, includes idiopathic, autoimmune and infectious subtypes. DCM is a clinical diagnosis characterised by dilation and impaired contraction of the left or both ventricles that is not explained by abnormal loading conditions or coronary artery disease. ******DCM includes idiopathic, familial/genetic, viral and/or immune, alcoholic/toxic subtypes. Historically, the best studied animal model has been experimentally induced murine Coxsackievirus B3 myocarditis.30–34 In experimental infection with these viruses, only genetically susceptible mouse strains develop acute severe disease as a result of myocyte necrosis due to virus replication; the likelihood of progression to chronic DCM is also higher in susceptible strains, although the severity of acute disease does not always predict the likelihood of progression. Conversely in resistant animals an immune response, mainly mediated by macrophages and T lymphocytes, eliminates the infectious agent within 2 weeks.

Postinfectious and primarily autoimmune myocarditis In several susceptible mouse strains, enteroviral RNA and inflammation persist in the heart for several weeks, triggering myocardial autoimmune phenomena.30–34 Such mouse strains also develop autoimmune myocarditis (and later on DCM) after immunisation with cardiac myosin, or spontaneously, for example, in the absence of an infectious trigger. In these mice, genetic predisposition is controlled by major histocompatibility complex (MHC) and non-MHC genes,35–44 some associated with 2

type 1 diabetes and other autoimmune diseases.45 46 The MHC is the mouse equivalent of the human leucocyte antigen (HLA) complex, which plays a role in human autoimmune myocarditis.44 47–51 In the last two decades, the involvement of autoimmunity has been documented in a sizable proportion of myocarditis and inflammatory cardiomyopathy patients, particularly those with a DCM phenotype.23 24 35–78 Autoimmune diseases in humans fulfil at least two of the major criteria proposed by Witebsky and Rose.79 80 In keeping with the findings in other conditions, in myocarditis and in autoimmune DCM there may be familial aggregation48–50 and HLA associations.51 81 Other main clinical autoimmune features (box 2) include the findings of mononuclear cell infiltrates, abnormal expression of HLA class II and/or adhesion molecules on cardiac endothelium in the absence of viral genomes (assessed by PCR on EMB) in affected patients and family members,52 53 increased levels of serum cytokines and cardiac autoantibodies (aabs) in patients and family members,7 23 54 55 57–64 67 68 70 72 74–78 and response to immunosuppression or immunomodulation.26–29 53 56 73 A number of cardiac aabs have been found in patients with myocarditis/DCM.7 23 54 55 57–64 67 68 70 72 74–78 A direct pathogenic role by at least some aabs is suggested by (1) demonstration of in vitro functional effects of cardiac aabs isolated from affected patients; (2) induction of the cardiac abnormalities seen in human post-myocarditic DCM by immunisation of animals with defined autoantigens; (3) induction of myocardial pathological changes by transfer of immune components from one experimental animal to another; (4) demonstration of improved cardiac morphology and function by specific removal of aabs by immunoabsorption in animals (box 2). For example, a study suggests that anticardiac myosin aabs induced by immunisation of rats against cardiac myosin crossreact with cardiac membrane beta1-adrenergic receptors and enhance cAMP-dependent protein kinase A activity in myocytes.39 Passive transfer of purified aabs from cardiac myosin-immunised rats results in IgG deposits and increases myocyte apoptosis in the heart, leading to a cardiomyopathic phenotype in recipients.39

CLINICAL PRESENTATIONS IN BIOPSY-PROVEN MYOCARDITIS In myocarditis, cardiac signs and symptoms are heterogeneous and lack specificity, depending on the degree of myocardial inflammation and ventricular dysfunction, and may be subtle; thus, the disease may be unrecognised.3 7–12 16–18 20–22 24 Myocarditis should be suspected in a previously asymptomatic young subject with few coronary artery disease (CAD) risk factors who, days or weeks after a presumed respiratory or gastrointestinal viral syndrome with or without increased systemic inflammatory markers and fever, develops dyspnoea or orthopnoea, or palpitations, or effort intolerance/malaise, or heart failure, or chest pain (which may be pleuritic if concomitant pericarditis



Education in Heart Table 1

Etiopathogenetic agents associated with myocarditis/inflammatory cardiomyopathy

1. Infectious myocarditis Bacterial Haemophilus influenzae, mycobacterium (tuberculosis), Mycoplasma pneumoniae, others (rare)3 Spirochetal Borrelia (Lyme disease), Leptospira (Weil disease) Fungal: uncommon, mainly immunocompromised patients3 Protozoal Trypanosoma cruzi (common in South America), others (rare)3 Parasitic Rare3 Rickettsial Rare3 Viral (common) RNA viruses: coxsackievirus A and B, echovirus, influenza A and B virus, respiratory syncytial virus, HIV-1, others (rare)3 DNA viruses: parvovirus B19 (most common in recent German series), adenovirus (mainly paediatric cases) cytomegalovirus (immunocompromised patients),3 herpes simplex virus, human herpes virus-6, common in recent German series, often in association with parvovirus B19, Epstein–Barr virus, others (rare)3 2. Immune-mediated (infection-negative) myocarditis Allergic Tetanus toxoid, vaccines, serum sickness Drugs: penicillin, cefaclor, colchicine, furosemide, isoniazid, lidocaine, tetracycline, sulfonamides, phenytoin, phenylbutazone, methyldopa, thiazide diuretics, amitriptyline Alloantigenic Heart transplant rejection Autoimmune Idiopathic: infection-negative lymphocytic (common), infection-negative giant cell (rare) Associated with autoimmune or immune-oriented disorders: systemic lupus erythematosus, rheumatoid arthritis, Churg–Strauss syndrome, Kawasaki’s disease, inflammatory bowel disease, scleroderma, polymyositis, myasthenia gravis, insulin-dependent diabetes mellitus, thyrotoxicosis, sarcoidosis, Wegener’s granulomatosis 3. Toxic myocarditis Drugs Amphetamines, anthracyclines, cocaine, cyclophosphamide, ethanol, fluorouracil, lithium, catecholamines, hemetine, interleukin-2, trastuzumab, clozapine Heavy metals Copper, iron, lead Miscellaneous Scorpion sting, snake, and spider bites, bee and wasp stings, carbon monoxide, inhalants, phosphorus, arsenic, sodium azide, Hormones Pheochromocytoma, vitamins: beriberi Physical agents Radiation, electric shock Adapted from Caforio et al.3

Box 2 Fulfilled Rose–Witebsky autoimmune features in myocarditis/ dilated cardiomyopathy Major ▸ Mononuclear cell infiltrates and abnormal human leucocyte antigen (HLA) expression on endomyocardial biopsy in the absence of infectious agents (by PCR) or known inflammatory causes52–53 ▸ Serum autoantibodies in patients and in unaffected family members7 23 54 55 57–64 67–68 70 72 74–78 ▸ Autoantibody and/or autoreactive lymphocytes in situ within the affected tissue74 ▸ Identification and isolation of autoantigen(s) involved37–46 59 65–66 68 71 78 ▸ Disease induced in animals by immunisation with relevant autoantigen,37–40 71 and/or passive transfer of serum, purified autoantibody and/or lymphocytes39 54 65 67–69 ▸ Efficacy of immunosuppressive therapy in patients26–29 53 56 73 Minor A. Common to all autoimmune disorders ▸ Familial aggregation48–50 ▸ HLA association51 81 ▸ Clinical course characterised by exacerbations and remissions3 7 ▸ Autoimmune diseases associated in the same patient or in family members3 7 50 B. Typical of organ-specific autoimmune disorders ▸ Autoantibodies directly against organ-specific autoantigens57–59 ▸ Induction of antibodies induces an organ-specific disease/ phenotype37–40 71 ▸ Transfer of autoantibodies also transfers the disease/ phenotype39 54 66 68 Adapted from Caforio et al.24 Caforio ALP, et al. Heart 2015;0:1–13. doi:10.1136/heartjnl-2014-306363

is present) with or without cardiac troponin I or T (cTNI or cTNT) release and unobstructed coronary arteries at coronary angiography.3 7–12 16–18 20–22 24 82 83 Biopsy-proven myocarditis may also present with arrhythmia, including syncope or aborted sudden death,3 7–12 16–18 20–22 84 subacute or chronic heart failure, or new-onset acute heart failure and/or cardiogenic shock.3 7–12 16–18 20–22 24 Myocarditis may also accompany or cause peripartum cardiomyopathy3 7 or Takotsubo cardiomyopathy.85 Fulminant myocarditis has been described as having viral prodromes within 4 weeks before cardiac symptoms, a distinct onset of unexplained heart failure, haemodynamic compromise and, in general, a good prognosis.86 Since myocarditis can simulate many non-inflammatory pathologies, any other cause (eg, valve heart disease, pericardial constriction, CAD) should be excluded.

ECG AND ECHOCARDIOGRAPHIC FINDINGS IN BIOPSY-PROVEN MYOCARDITIS Similar to the clinical presentation, ECG findings are also not specific or sensitive for myocarditis including all types of ‘idiopathic’ atrial or ventricular tachyarrhythmias or bradyarrhythmias, P-Q segment depression and/or repolarisation abnormalities.3 7–12 16–18 20–22 24 84 Still, some ECG changes are suggestive for myocarditis: ST-T segment elevation is more concave (convex in ischaemia) and diffusely present over the precordial leads, without reciprocal changes. PR-depression is frequently present in pericarditis associated with 3


Education in Heart myocarditis, but is rare in cardiac ischaemia. Q-waves are uncommon in myocarditis. T-wave inversion generally occurs after complete ST-T normalisation in myocarditis, but usually takes place while the ST-segment is still elevated after myocardial infarction. Echocardiography defines morphology and biventricular function, but it is not specific. It may be normal or similar to DCM. Pericardial effusion may be present, as well as segmental wall motion abnormalities.87 88 Apical LV aneurisms suggest Chagas’s disease. In fulminant myocarditis, there may be a slight increase in LV wall thickness and a mildly dilated severely hypokinetic ventricle.87 Echocardiography is helpful in ruling out some non-inflammatory causes of cardiac signs and symptoms or associated conditions, for example, valve disease. In addition, it provides non-invasive morpho-functional imaging at presentation and during follow-up since temporal changes in terms of systolic function, chamber size and thickness may occur very quickly in myocarditis requiring repeat echocardiographies.

NUCLEAR AND CMRI Overall, 111indium antimyosin antibody and gallium-67 nuclear imaging are rarely used (limited availability of tracers, poor spatial resolution, radiation issues, low diagnostic accuracy), although the recent development of novel (molecular) nuclear tracers appears promising at least in animal models.89 90 One exception is represented by gallium-67 scintigraphy and positron emission tomography (PET) with fluorodeoxyglucose in the acute phase and in the follow-up of cardiac sarcoidosis.90 CMRI defines morphology and biventricular function of the heart and provides tissue characterisation.3 19–22 91 The “International Consensus Group on CMR Diagnosis of Myocarditis” suggested the combined use of three different CMR techniques, the so-called Lake Louise criteria.19 Myocardial oedema is assessed on T2-weighted CMR images, hyperaemia/capillary leak on myocardial early gadolinium enhancement ratio and necrosis/fibrosis on late gadolinium enhancement (LGE). LGE is typically subepicardial, localised in inferolateral and less frequently in anteroseptal LV segments, and may be focal or diffuse in distribution. The best overall diagnostic accuracy (78%) is found by the combination of all three tissue-based CMR parameters, but correlative data with EMB are still based on low numbers. CMR does not differentiate specific inflammatory cells (eg, lymphocytes, giant cells) or viral from non-viral myocarditis.3 19–22 91 According to the 2013 ESC Task Force, in clinically stable patients, CMR, if available, can strengthen the clinical suspicion of myocarditis before EMB; in life-threatening presentations, EMB should not be postponed.3 92 93 CMR could replace EMB in the follow-up of diagnosed patients when there is no evidence of viral infection on EMB; on the opposite, if the first EMB is in keeping with viral myocarditis, a second EMB should be required to check the viral clearance from the myocardium.3 4

DIAGNOSTIC ROLE OF BIOMARKERS Inflammatory markers Erythrocyte sedimentation rate and C reactive protein levels are not raised in the majority of patients with biopsy-proven myocarditis; conversely, these are often increased in acute pericarditis.3 7

Troponin and brain natriuretic peptides Cardiac troponins do not differentiate ischaemic from inflammatory myocyte injury, may be raised in several other conditions and when normal do not exclude myocarditis.3 7 17 Similar limitations probably apply to cardiac hormones such as brain natriuretic peptides, circulating cytokines, markers related to extracellular matrix degradation and new biomarkers such as pentraxin 3, galectin 3 and growth differentiation factor 15.3

Viral serology Positive viral serology does not imply active myocardial infection. The prevalence of circulatory IgG antibodies to cardiotropic viruses in the general population is high in the absence of viral heart disease.30 34 94 In addition, infection with noncardiotropic enteroviruses may cause an antibody response that is indistinguishable from the response to cardiotropic viruses,30 34 94 and in a recent study, there was no correlation between virus serology and EMB findings.95 Thus, viral serology is not recommended by the ESC 2013 Task Force, except for hepatitis C, rickettsial phase 1 and phase 2, Lyme disease in endemic areas as well as HIV serologies in high-risk patients and in certain populations at high prevalence of infection.3

Serum cardiac aabs In patients with myocarditis/idiopathic DCM and of their symptom-free relatives, circulating heartreactive aabs are directed against multiple antigens, some of which are strictly expressed in the myocardium (eg, organ-specific for the heart), others expressed in heart and skeletal muscle (eg, musclespecific), as shown in figure 1.7 23 54 55 57–64 67–68 70 72 74–78 Distinct aabs have also different prevalence in disease and normal controls (eg, the organ-specific and cross-reactive 1 type of antiheart aabs shown figure 1 are disease-specific for myocarditis/DCM, some of the muscle aabs are not).7 23 54 55 57–64 67–68 70 72 74–78 Aabs of IgG class, which are shown to be cardiac and diseasespecific for myocarditis/DCM, can be used as autoimmune markers for identifying patients in whom immunosuppression and/or immunomodulation therapy may be beneficial and their relatives at risk.3 7 24 47–49 57–59 Some aabs may have a functional role and thus have an impact on the patients’ prognosis.39 47 54 55 60 63–64 66–68 75–78 The ESC Task Force recommended to assess sera with clinically suspected or definite myocarditis for cardiac aabs, using one (or more) of the published tests, according to specific centre expertise, preferably disease-specific aabs.3



Education in Heart CLINICALLY SUSPECTED MYOCARDITIS: THE 2013 TASK FORCE CRITERIA To aid the clinician in the identification of myocarditis, the ESC Myocarditis Task Force has introduced new rigorous criteria for clinically suspected myocarditis using the combination of a plausible clinical presentation and of diagnostic criteria from different categories, as well as exclusion of known non-inflammatory causes, for example, CAD, that could explain the syndrome.3 (figures 2 and 3, key points 1–2). These criteria were proposed to better

refine the clinical and non-invasive diagnosis of myocarditis also in centres that do not routinely perform EMB.

The 2013 ESC Task Force criteria of clinically suspected myocarditis: key point 1 ▸ Clinically suspected myocarditis is defined by the presence of >1 clinical presentation (with or without ancillary findings) and >1 diagnostic criteria from different categories, in the absence of

Figure 1 Antiheart aabs (AHA) patterns by indirect immunofluorescence test. Organ-specific AHA and antinuclear aabs (ANA) pattern. (A) On human heart tissue: cytoplasmic diffuse staining of cardiac myocytes (organ-specific AHA pattern) and diffuse staining of the nuclei (non-organ-specific ANA pattern) (×200); (B) (×400) on human skeletal muscle tissue: negative for AHA, positive for ANA. Partially organ-specific (or cross-reactive 1) AHA pattern. (C) On human heart tissue: strongly positive fine striational pattern (×400); (D) on human skeletal muscle: weak positive fine striational pattern (×400). Entirely cross-reactive (or cross-reactive 2) AHA pattern. (E) On human heart tissue: strong positive striational pattern (×400); (F) on human skeletal muscle: strongly positive (×400). Negative AHA control serum pattern. (G) On human heart tissue: negative (×400); (H) on human skeletal muscle: negative (×400). Caforio ALP, et al. Heart 2015;0:1–13. doi:10.1136/heartjnl-2014-306363

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Education in Heart – Angiographically detectable CAD (coronary stenosis ≥50%). – Known pre-existing cardiovascular disease or extra-cardiac causes that could explain the syndrome (eg, valve disease, congenital heart disease). Suspicion is higher with higher number of fulfilled criteria. – If the patient is asymptomatic, >2 diagnostic criteria should be met. ▸ Medical history should focus on – Family history of DCM, other cardiomyopathy, sudden cardiac death, autoimmune disease. – Patients’ history: recent (days to 2 weeks) upper respiratory or gastrointestinal suspected viral syndrome, allergy, other autoimmune diseases, previous clinically suspected or proven myocarditis, heavy alcohol intake, assumption of drugs and toxic substances (eg, cocaine), vaccines, travel to places where specific cardiotropic infection is possible or endemic (eg, Brazil, Argentina and Chile for Chagas’s disease), proximity with domestic animals, conventional coronary risk factors, etc. The aim is search as well as exclude possible treatable causes (eg, drug-related toxicity or hypersensitivity).

The 2013 ESC Task Force criteria of clinically suspected myocarditis: key point 2 ▸ Clinical presentations3 include ≥1 of the following: – Acute coronary syndrome-like, with or without normal global or regional LV and/or RV dysfunction on echocardiography or CMR, with or without increased troponin (Tn)T/TnI (that may have a time course similar to acute myocardial infarction or a

prolonged and sustained release over several weeks or months). – New onset or worsening heart failure in the absence of CAD and known causes of heart failure. – Chronic heart failure, with heart failure symptoms (with recurrent exacerbations) of >3 months duration, in the absence of CAD and known causes of heart failure. – Life-threatening condition (including lifethreatening arrhythmias and aborted sudden death, cardiogenic shock, severely impaired LV function), in the absence of CAD and known causes of heart failure. ▸ Diagnostic criteria3 include ≥1 of the following features from categories I to IV: I. Electrocardiogram (ECG)/Holter/stress test features – Newly abnormal 12-lead ECG and/or Holter and/or stress testing, any of the following (see also figure 2): I to III degree atrioventricular block, or bundle branch block, ST/T-wave change (ST elevation or non-ST elevation, T-wave inversion), sinus arrest, ventricular tachycardia or fibrillation and asystole, atrial fibrillation, reduced R-wave height, intraventricular conduction delay (widened QRS complex), abnormal Q waves, low voltage, frequent premature beats, supraventricular tachycardia. II. Myocardiocytolysis markers (elevated cardiac troponins). III. Functional and structural abnormalities on cardiac imaging (echo/angio/CMR) – New, otherwise unexplained LV and/or RV structure and function abnormality

Figure 2 Clinical presentations and diagnostic European Society of Cardiology 2013 Task Force criteria for clinically suspected myocarditis. CMR, cardiac MR; LGE, late gadolinium enhancement. 6



Education in Heart (including incidental finding in apparently asymptomatic subjects): any of those in figure 2. IV. Tissue characterisation by CMR – Oedema and/or LGE of classical myocarditic pattern (according to Lake Louise criteria).19

DIAGNOSIS OF DEFINITE (BIOPSY-PROVEN) MYOCARDITIS BY ESC 2013 TASK FORCE CRITERIA In patients fulfilling the diagnostic criteria for clinically suspected myocarditis, the ESC Myocarditis Task Force recommends selective coronary angiography and EMB, including conventional histology, as well as immunohistochemistry and PCR detection of infectious agents3 6 (box 1). To increase the diagnostic sensitivity of histology, immunohistochemistry using a panel of monoclonal and polyclonal antibodies, including anti-CD3, T lymphocytes; anti-CD68, macrophages; and anti HLA-DR, is recommended for the identification and characterisation of the inflammatory infiltrate and for the detection of HLA-DR upregulation on EMB tissue sections as marker of infectiousnegative autoimmune myocarditis where immunosuppression may be considered.3 6 Other immunofluorescence stains used to define humoral rejection in heart transplant EMB, such as C3d and C4d, may provide additional markers of immune activation in patients with inflammatory cardiomyopathy; a limitation of these stains is that they require frozen material.3 6 This recommendation also applies to patients with an acute coronary syndrome-like presentation, not included in the

American Heart Association/American College of Cardiology/Heart Failure Society of America scientific statement on EMB9 . The Task Force gave this recommendation based upon the following considerations (see also key point 3): (a) If EMB is performed by experienced teams, its complication rate is low and similar to that of standard coronary angiography (0–0.8).3 73 92 93 (b) EMB confirms the diagnosis of myocarditis, and at present it is the only tool to identify the underlying aetiology and the type of inflammation that imply different treatments and prognosis3 6 7 18 24 94 (figures 3 and 4). (c) EMB is the basis for safe (infection negative) immunosuppression.3 73

Diagnosis of definite (biopsy-proven) myocarditis: key point 3 ▸ EMB, including conventional histology (Dallas criteria), as well as immunohistochemistry and PCR detection of infectious agents is the gold standard for diagnosis of myocarditis. ▸ Absence of infectious agents identifies immunemediated myocarditis, either primary or postinfectious, if an infectious agent had been identified on a previous EMB, and is the basis for safe (infection negative) immunosuppression. ▸ EMB is essential to identify specific myocarditis types (eg, giant cell, eosinophilic, sarcoidosis), which imply different treatments and prognosis. ▸ EMB provides differential diagnosis from diseases that may mimic myocarditis (arrhythmogenic RV cardiomyopathy, Takotsubo cardiomyopathy, peripartum cardiomyopathy, infiltrative/storage disorders, cardiac masses).

Figure 3 Diagnostic work-up and aetiology-based management in myocarditis according to the European Society of Cardiology 2013 Task Force criteria. Aab, cardiac autoantibody, EMB, endomyocardial biopsy. Caforio ALP, et al. Heart 2015;0:1–13. doi:10.1136/heartjnl-2014-306363

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Education in Heart advanced heart block or to transient lifethreatening myocardial dysfunction.96 Advanced heart block may require temporary pacing; it resolves within 1 week in most cases. Tripanozoma cruzi (Chagas’s disease), a common cause of myocarditis/DCM in South America, with a suggested postinfectious autoimmune component, has an acute phase of mild febrile course and a prolonged (up to 30 years) symptom-free latent phase.97 Systolic and diastolic heart failure, ventricular aneurisms, arrhythmias and cardiac autonomic dysfunction may be present. Toxoplasma gondii associated and fungal myocarditis has been mostly observed among seronegative cardiac transplant recipients of seropositive donors and in other immunodeficient populations with multiple opportunistic infections, particularly HIV.24

Giant cell myocarditis, sarcoidosis and myocarditis in extra-cardiac autoimmune disease Giant cell myocarditis, the prototype of autoimmune myocarditis, is a rare but devastating disease, presents as other forms of myocarditis, but is characterised by a rapid and severe downhill course, despite optimal medical care.3 6 7 9 17 56 84 It may be associated with a variety of autoimmune disorders and may recur in the native heart following recovery and in the donor heart following transplantation with up to 25% rate of recurrence; relapse in both conditions usually responds to intensified immunosuppression.3 6 7 9 17 56 84 Sarcoidosis, a systemic granulomatous disease of unknown aetiology and suspected immune origin, may present initially or predominantly with myocardial involvement, mimicking arrhythmogenic cardiomyopathy; ventricular septum and conduction system involvement can lead to bradyarrhythmia or tachyarrhythmia and sudden cardiac death.9 90 Myocarditis in connective tissue diseases, and in other immune-mediated systemic diseases (box 1), includes a range of clinical expressions, from conduction diseases to DCM.25–29

Myocarditis in rheumatic heart disease Figure 4 Pathological example of lymphocytic myocarditis (A), eosinophilic (B) and giant cell myocarditis (C) on endomyocardial biopsy. (H&E stain; inset in (A) CD3 stain, lymphocytic marker) (modified from Basso et al94). ▸ If EMB is performed in experienced centres, its complication rate is similar to that of standard coronary angiography. ▸ EMB may be taken from the right or from the LV according to centre and operator preference and expertise. Antiplatelet or anticoagulation strategy for LV EMB may be different among centres.

CLINICAL PRESENTATION OF SPECIFIC FORMS OF MYOCARDITIS Non-viral, infectious myocarditis The spirochete Borrelia burgdorferi causes Lyme disease, which can result in a broad spectrum of presentations, from asymptomatic, first-degree to 8

Although rheumatic fever (RF) remains a leading cause of acquired cardiopathy on a global scale, well-conducted recent studies on biopsy-proven acute or chronic rheumatic myocarditis are lacking because RF is rare in Europe and the USA; most of the literature on this subject date back to the 1950s. It is unclear whether or not myocarditis in RF can be defined as infectious or postinfectious autoimmune according to the 2013 Task Force criteria. The histological finding of Aschoff bodies is the hallmark of rheumatic inflammation in the heart.3 6 24 Rheumatic myocarditis is thought to be a component of acute rheumatic carditis, which also includes pericarditis and valvulitis. In acute rheumatic heart disease, histological analyses have shown the presence of dense valvular mainly CD4+ inflammatory cell infiltrates and Aschoff nodules in the myocardium.3 6 24 In addition, CD4+ and CD8+ infiltrating T-cell clones



Education in Heart recognised streptococcal M peptides and cardiac tissue proteins, suggesting that molecular mimicry may be the mechanism responsible for postinfectious autoimmunity to heart structures.3 6 24 However, in acute rheumatic myocarditis, histopathology reveals no necrosis and for this feature there are authors who have questioned that rheumatic myocarditis exists.6 24 Because acute rheumatic myocarditis is frequently asymptomatic, its diagnosis is difficult and requires a high-suspicion rate.3 6 24 98 Rheumatic patients with acute myocarditis often present mild symptoms such as tachycardia or mild worsening of heart failure, frequently attributed to worsening of the valvular heart disease or another cause of decompensation, such as volume or salt overload. The diagnosis of acute rheumatic myocarditis requires the use of multiple imaging techniques. An echocardiography can reveal mild to moderate pericardial effusion (rarely pericardial effusion or even pericardial tamponade). Transoesophageal echocardiography can sometimes show small multiple vegetations on the edge of native valves, representing the rheumatic verrucae that characterise the acute phase of the disease. The 12-lead ECG may reveal a first-degree atrioventricular heart block, which is a sign of myocarditis, but this is not very sensitive. Imaging techniques that highlight inflammation in the heart may be useful, for example, gallium-67 myocardium scintigraphy.3 6 24 98 A good correlation has been shown between a positive scintigraphy and EMB for the diagnosis of active rheumatic myocarditis. PET-CT is currently being evaluated and appears to have a better sensitivity than the gallium scan.3 6 24 98 In conclusion, acute rheumatic myocarditis is a difficult diagnosis that should be considered in any patient, including patients who have just undergone valve surgery, with rheumatic valvular heart disease who present with a sudden worsening of heart failure symptoms or rapid-onset ventricular dysfunction, particularly if the patient is not on secondary prophylaxis for RF.

Toxic and hypersensitivity myocarditis Hypersensitivity myocarditis, probably the most common form of drug-induced cardiac toxicity, is unpredictable and not related to drug dosage. Non-specific skin rash, malaise, fever and eosinophilia may suggest the diagnosis, but are absent in many cases.6 24 On the other hand, a direct cardiac toxicity is dose-dependent, may be reversible and is often potentiated by other antineoplastic treatments, such as radiotherapy.

Paediatric myocarditis Myocarditis is considered a frequent cause of a new-onset DCM phenotype in children, with small studies reporting high rates of recovery of LV function. Most published data are either retrospective or observational and often based on administration registries. In addition, diagnosis is biopsy-proven in a minority of patients. In a recent multiinstitutional paediatric registry from the USA, children with biopsy-confirmed or probable Caforio ALP, et al. Heart 2015;0:1–13. doi:10.1136/heartjnl-2014-306363

myocarditis had similar proportions of death, transplantation and echocardiographic normalisation 3 years after presentation and better outcomes than those of children with idiopathic DCM.99 In children with myocarditis who had impaired LV ejection at presentation, rates of echocardiographic normalisation were greater in those without LV dilation and in those with greater septal wall thickness at presentation99 A nation-wide survey in Japan collected 169 clinically suspected cases, with an incidence of 43.5 cases/year and 0.26 cases/ 100 000.100 Major clinical presentations at onset were congestive heart failure, refractory arrhythmia and syncope in 70, 37 and 17 patients, respectively, 64 cases were fulminant, 89 acute and 8 chronic. Mechanical support seemed effective and lifesaving. Survival was 73%, and two-thirds of survivors had no sequelae. An EMB was performed in only 33% of cases; therefore, aetiology-specific markers could not be defined.100 In another survey from the USA, 514 cases of clinically suspected acute myocarditis were identified from April 2006 to March 2011 using the Pediatric Health Information System database.101 Ninety-seven patients (18.9%) received extracorporeal membrane oxygenation (ECMO), 22 (4.3%) received ventricular assist device (VAD), 21 (4.1%) underwent heart transplantation and 37 (7.2%) died. Of the 104 patients who received ECMO or VAD, 17 (16.3%) had heart transplantation, 25 (24%) died and 62 (59.6%) showed recovery of myocardial function. Although ECMO, VAD and vasoactive medications were independently associated with increased mortality/transplantation, it was concluded that ECMO or VAD may be successful strategies in supporting patients until resolution of cardiac dysfunction or as a bridge to transplant because 76% of this highrisk cohort were successfully bridged to transplant or recovery. Again EMB was performed in a minority.101 One study suggested that a routine performance of EMB in critically ill children with DCM is useful to identify those with myocarditis who do not need heart transplantation.102 More prospective data are needed to clarify the prognostic impact of aetiology and disease stage in paediatric myocarditis.

SUMMARY AND CONCLUSION The ESC 2013 Task Force consensus document recommends a systematic consideration of EMB in patients with stringent criteria for clinically suspected myocarditis that combine clinical presentation and non-invasive diagnostic features.3 However, EMB should not be limited to standard histology (Dallas criteria), but include immunohistochemistry, and molecular analysis for infectious agents and should be performed by experienced teams. The rationale for suggesting such in-depth diagnostic effort is the availability of a wide range of immunosuppressive17 24 56 73 and immunomodulatory therapeutic options3 17 24 77 for infectionnegative patients, which, in principle, as seen in extra-cardiac autoimmune disease, and in the available clinical studies, could be beneficial to stop or 9


Education in Heart evidence-based data from multicentre randomised controlled trials in the majority of patients with infection-negative biopsy-proven myocarditis are needed to define indications, efficacy on morbidity and mortality, drug regimens and length of treatment. In addition, the same diagnostic work-up will make it feasible to test future antiviral treatments in infection-positive patients.104 105

Key messages ▸ Clinically suspected myocarditis, according to the European Society of Cardiology (ESC) 2013 Task Force criteria, is defined by the presence of >1 clinical presentation (with or without ancillary findings) and >1 diagnostic criteria from different categories, in the absence of: – Angiographically detectable coronary artery disease (coronary stenosis ≥50%). – Known pre-existing cardiovascular disease or extra-cardiac causes that could explain the syndrome (eg, valve disease, congenital heart disease). Suspicion is higher with higher number of fulfilled criteria. – If the patient is asymptomatic, >2 diagnostic criteria should be met. ▸ The ESC 2013 Task Force document recommends consideration of endomyocardial biopsy (EMB) in all cases of clinically suspected myocarditis. ▸ The diagnosis of definite myocarditis according to the ESC 2013 Task Force criteria is based upon EMB confirmation, including conventional histology (Dallas criteria), as well as immunohistochemistry and PCR detection of infectious agents. ▸ Absence of infectious agents identifies immune-mediated myocarditis, either primary or post-infectious if an infectious agent had been identified on a previous EMB, and is the basis for safe (infection negative) immunosuppression. ▸ EMB is essential to identify specific myocarditis types (eg, giant cell, eosinophilic, sarcoidosis), which imply different treatments and prognosis. ▸ EMB provides differential diagnosis from diseases that may mimic myocarditis (arrhythmogenic RV cardiomyopathy, Takotsubo cardiomyopathy, peripartum cardiomyopathy, infiltrative/storage disorders, cardiac masses). ▸ The 2013 ESC Task Force consensus document gives specific guidance for aetiology-directed treatment in the diverse etiopathogenetic subsets of definite myocarditis, particularly in relation to immune-mediated forms.

Acknowledgements CB is supported by the Registry for Cardiocerebro-vascular pathology, Veneto Region, Venice, Italy. Contributors Substantial contributions to the conception or design of the work, or the acquisition, analysis or interpretation of data: RM and CB. Drafting the work or revising it critically for important intellectual content and final approval of the version published: RM CB and SI. Competing interests None declared. Provenance and peer review Commissioned; externally peer reviewed.

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control the chronic cardiac tissue injury mediated by the immune system leading to irreversible fibrosis and burned out DCM. For some specific forms of myocarditis, immunosuppression is established,25–29 3 6 7 9 17 56 84 90 103 but more

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You can get CPD/CME credits for Education in Heart Education in Heart articles are accredited by both the UK Royal College of Physicians (London) and the European Board for Accreditation in Cardiology—you need to answer the accompanying multiple choice questions (MCQs). To access the questions, click on BMJ Learning: Take this module on BMJ Learning from the content box at the top right and bottom left of the online article. For more information please go to: http://heart.bmj.com/misc/education.dtl ▸ RCP credits: Log your activity in your CPD diary online (http://www. rcplondon.ac.uk/members/CPDdiary/index.asp)—pass mark is 80%. ▸ EBAC credits: Print out and retain the BMJ Learning certificate once you have completed the MCQs—pass mark is 60%. EBAC/ EACCME Credits can now be converted to AMA PRA Category 1 CME Credits and are recognised by all National Accreditation Authorities in Europe (http://www.ebac-cme. org/newsite/?hit=men02). Please note: The MCQs are hosted on BMJ Learning—the best available learning website for medical professionals from the BMJ Group. If prompted, subscribers must sign into Heart with their journal’s username and password. All users must also complete a one-time registration on BMJ Learning and subsequently log in (with a BMJ Learning username and password) on every visit. 10

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invasive endomyocardial biopsy in troponin-positive patients without coronary artery disease. Eur Heart J 2009;30:2869–79. Important study describing the higher yield of etiological diagnosis in patients with myocardial infarction and normal coronary arteries using both CMR and endomyocardial biopsy. Yilmaz A, Kindermann I, Kindermann M, et al. Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance. Circulation 2010;122:900–9. Holzmann M, Nicko A, Kühl U, et al. Complication rate of right ventricular endomyocardial biopsy via the femoral approach: a retrospective and prospective study analyzing 3048 diagnostic procedures over an 11-year period. Circulation 2008;118:1722–8. Basso C, Calabrese F, Angelini A, et al. Classification and histological, immunohistochemical, and molecular diagnosis of inflammatory myocardial disease. Heart Fail Rev 2013;18:673–81. Mahfoud F, Gärtner B, Kindermann M, et al. Virus serology in patients with suspected myocarditis: utility or futility? Eur Heart J 2011;32:897–03. Important study reporting the lack of correlation between viral serology and biopsy-proven viral myocarditis. This study has had an impact on the recommendations by the ESC Task Force (ref 3) in relation to application of viral serology in clinically suspected myocarditis. It is not recommended any more in all patients, but only in selected cases (see text). Costello JM, Alexander ME, Greco KM, et al. Lyme carditis in children: presentation, predictive factors, and clinical course. Pediatrics 2009;123:e835–41. Marin-Neto JA, Cuhna-Neto E, Maciel BC, et al. Pathogenesis of chronic Chagas heart disease. Circulation 2007;115:1109–23. Spina GS, Sampaio RO, Branco CE, et al. Incidental histological diagnosis of acute rheumatic myocarditis: case report and review of the literature. Front Pediatr 2014;2:126. Foerster SR, Canter CE, Cinar A, et al. Ventricular remodeling and survival are more favorable for myocarditis than for idiopathic dilated cardiomyopathy in childhood an outcomes study from the Pediatric Cardiomyopathy Registry. Circ Heart Fail 2010;3:689–97. Saji T, Matsuura H, Hasegawa K, et al. Comparison of the clinical presentation, treatment, and outcome of fulminant and acute myocarditis in children. Circ J 2012;76:1222–8. Ghelani SJ, Spaeder MC, Pastor W, et al. Demographics, trends, and outcomes in pediatric acute myocarditis in the United States, 2006 to 2011. Circ Cardiovasc Qual Outcomes 2012;5:622–7. Hill KD, Atkinson JB, Doyle TP, et al. Routine performance of endomyocardial biopsy decreases the incidence of orthotopic heart transplant for myocarditis. J Heart Lung Transplant 2009;28:1261–6. Japanese Circulation Society ( JCS) Joint Working group. Guidelines for diagnosis and treatment of myocarditis. Circ J 2011;75:734–43. One of the few recent Cardiology Society guidelines for myocarditis, issued by the Japanese Circulation Society. Martino TA, Liu P, Sole MJ. Viral infection and the pathogenesis of dilated cardiomyopathy. Circ Res 1994;74:182–8. Kuhl U, Pauschinger M, Schwimmbeck PL, et al. Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 2003;107:2793–8. Single centre experience on the application of interferon-beta treatment for biopsy-proven enteroviral persistence in inflammatory cardiomyopathy, describing virus clearance and improvement of left ventricular function.

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Clinical presentation and diagnosis of myocarditis Alida L P Caforio, Renzo Marcolongo, Cristina Basso and Sabino Iliceto Heart published online June 24, 2015

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