Scholarly article on topic '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'

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 Academic research paper on "Basic medicine"

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Academic research paper on topic "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"


European Heart Journal (2013) 34, 2636-2648 doi:10.1093/eurheartj/eht210


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

Alida L. P. Caforio1^*, Sabine Pankuweit2^, Eloisa Arbustini3, Cristina Basso4, Juan Gimeno-Blanes5, Stephan B. Felix6, Michael Fu7, Tiina Helio8, Stephane Heymans9, Roland Jahns10, Karin Klingel11, Ales Linhart12, Bernhard Maisch2, William McKenna13, Jens Mogensen14, Yigal M. Pinto15, Arsen Ristic16, Heinz-Peter Schultheiss17, Hubert Seggewiss18, Luigi Tavazzi19, Gaetano Thiene4, Ali Yilmaz20, Philippe Charron21, and Perry M. Elliott13

Maastricht, Maastricht, The Netherlands; Department of Internal Medicine, Medizinische Klinik und Poliklinik I, Cardiology, Wuerzburg, Germany; Department of Molecular Pathology, University Hospital Tubingen, Tubingen, Germany; 122nd Department of Internal Medicine, 1st School of Medicine, Charles University, Prague 2, Czech Republic; 13The Heart Hospital, University College, London, UK; 14Department of Cardiology, Odense University Hospital, Odense, Denmark; 15Department of Cardiology (Heart Failure Research Center), Academic Medical Center, Amsterdam, The Netherlands; 16Department of Cardiology, Clinical Center of Serbia and Belgrade University School of Medicine, Belgrade, Serbia; 17Department of Cardiology and Pneumology, Charite Centrum 11 (Cardiovascular Medicine), Charitee-Universitatsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany; 18Medizinische Klinik 1, Leopoldina Krankenhaus Schweinfurt, Schweinfurt, Germany; 19GVM Care and Research, Maria Cecilia Hospital, Cotignola, RA, Italy; 20Robert-Bosch-Krankenhaus, Stuttgart, Germany; and 21UPMC Univ Paris 6, AP-HP, Hopital Pitiee-Salpeetriere, Centre de Reference Maladies cardiaques hereditaires, Paris, France

Received 14 December 2012; revised 19 April 2013; accepted 23 May 2013; online publish-ahead-of-print 3 July 2013

In this position statement of the ESC Working Group on Myocardial and Pericardial Diseases an expert consensus group reviews the current knowledge on clinical presentation, diagnosis and treatment of myocarditis, and proposes new diagnostic criteria for clinically suspected myocarditis and its distinct biopsy-proven pathogenetic forms. The aims are to bridge the gap between clinical and tissue-based diagnosis, to improve management and provide a common reference point for future registries and multicentre randomised controlled trials of aetiology-driven treatment in inflammatory heart muscle disease.

Keywords Myocarditis • Cardiomyopathy • Diagnosis • Therapy

Division of Cardiology, Department of Cardiological Thoracic and Vascular Sciences, University of Padua, Padova, Italy; Universitätsklinikum Gießen und Marburg GmbH, Standort

Marburg, Klinik fur Kardiologie, Marburg, Germany; Academic Hospital IRCCS Foundation Policlinico, San Matteo, Pavia, Italy; Cardiovascular Pathology, Department of Cardiological

Thoracic and Vascular Sciences, University of Padua, Padova, Italy; Servicio de Cardiologia, Hospital U. Virgen de Arrixaca Ctra. Murcia-Cartagena s/n, El Palmar, Spain; Medizinische

Klinik B, University of Greifswald, Greifswald, Germany; Department of Medicine, Heart Failure Unit, Sahlgrenska Hospital, University of Göteborg, Göteborg, Sweden; 8Division of

Cardiology, Helsinki University Central Hospital, Heart & Lung Centre, Helsinki, Finland; Center for Heart Failure Research, Cardiovascular Research Institute, University Hospital of


Myocarditis is a challenging diagnosis due to the heterogeneity of clinical presentations.1 -3 The actual incidence of myocarditis is also difficult to determine as endomyocardial biopsy (EMB), the diagnostic gold standard,1-3 is used infrequently.2,3 Studies addressing the issue of sudden cardiac death in young people report a highly variable autopsy

prevalence of myocarditis, ranging from 2 to 42% of cases.4,5 Similarly, biopsy-proven myocarditis is reported in 9-16% of adult patients with unexplained non-ischaemic dilated cardiomyopathy (DCM)6,7 and in 46% of children with an identified cause of DCM.8 In patients presenting with mild symptoms and minimal ventricular dysfunction, myocarditis often resolves spontaneously without specific treatment.9 However, in up to 30% of cases, biopsy-proven myocarditis can progress to

^A.L.P.C. and S.P. contributed equally to the document.

* Corresponding author. Division of Cardiology, Department of CardiologicalThoracic and Vascular Sciences, Padua University Medical School, Policlinico Universitario, Via N Giustinani, 2, 35128 Padova, Italy. Tel: +39 (0)498212348, Fax: +39 (0)498211802, Email:

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2013. For permissions please email:

DCM and is associated with a poor prognosis.1 -3,7-9 Prognosis in myocarditis patients also varies according to the underlying aetiology.9 The treatment of many forms of myocarditis is symptomatic,10 but immunohistochemical1-3,9,10,11 -15 and molecular biologicalanalysis of EMB16 as well as autoantibody serum testing is important to identify those patients in whom specific therapy is appropriate.9,17

In this Position Statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases, an expert consensus group has reviewed the current literature on clinical presentation, diagnosis, and treatment of myocarditis and propose new diagnostic criteria for clinically suspected myocarditis. The present article is an opinion statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.


In this document, we recommend use of existing definitions of myocarditis and inflammatory cardiomyopathy (Box 1), but acknowledge that there is some confusion about the terms DCM and inflammatory cardiomyopathy. Dilated cardiomyopathy is a clinical diagnosis based on morphological and functional characterization ofthe leftventricle; inflammatory cardiomyopathy is both a histological and functional diagnosis characterized by myocarditis in association with systolic and/or diastolic cardiac dysfunction; thus inflammatory cardiomyopathy and DCM are not mutually exclusive.


Myocarditis (WHO/ISFC1):

Inflammatory disease of the myocardium diagnosed by established histological*, immunological and immunohistochemical criteria**. *N.B. established histological Dallas criteria12 defined as follows: 'histological evidence of inflammatory infiltrates within the myocardium associated with myocyte degeneration and necrosis of non-ischaemic origin 12'.

**N.B. unspecified immunohistochemical criteria1, we propose an abnormal inflammatory infiltrate to be defined as follows:

'>14 leucocytes/mm2 including up to 4 monocytes/mm2 with the

2 15 1819

presence of CD 3 positive T-lymphocytes > 7 cells/mm '. , , Inflammatory Cardiomyopathy (WHO /ISFC1): Myocarditis in association with cardiac dysfunction. N.B. Inflammatory cardiomyopathy, involved in the pathogenesis of DCM, includes idiopathic, autoimmune and infectious subtypes.1 Dilated Cardiomyopathy (ESC13; WHO /ISFC1): DCM is a clinical diagnosis characterized by dilation and impaired contraction of the left or both ventricles that is not explained by abnormal loading conditions or coronary artery disease.

N.B. DCM includes idiopathic, familial/genetic, viral and/or immune, alcoholic/toxic subtypes.1

The histological diagnosis of myocarditis includes different forms, classified according to the type of inflammatory cell infiltrate: lymphocytic, eosinophilic, polymorphic, giant cell myocarditis, and cardiac sarcoidosis.2,4,12 The taskgroup also recommends the following criteria for subsets of myocarditis or inflammatory cardiomyop-

athy 1,2,9,13,14,16-21

Viral myocarditis

Histological evidence for myocarditis associated with positive viral polymerase chain reaction (PCR) (Table 1).

Autoimmune myocarditis

Histological myocarditis with negative viral PCR, with or without serum cardiac autoantibodies (aabs) (Table 2).

N.B. There are autoimmune diseases (e.g. Hashimoto's thyroiditis) where aabs are mainly biomarkers, autoantibody-mediated forms (e.g. Graves' disease), in which aabs are pathogenic, and cell-mediated autoimmune diseases, which are negative for aabs. In all cases, autoimmune diseases are negative for infectious agents.

Viral and immune myocarditis

Histological myocarditis with positive viral PCR and positive cardiac aabs (Table 2).

N.B. Afollow-up EMB may document persistent viral myocarditis, histological and virological resolution, or persistent virus-negative myocarditis, with or without serum cardiac aabs, e.g. post-infectious autoimmune disease.

Aetiology of myocarditis

Although the aetiology of myocarditis often remains undetermined, a large variety of infectious agents, systemic diseases, drugs, and toxins can cause the disease (Table 1).1 -3,11,16,21 -24 Some causes of myocarditis are now largely historical or occur in very specific scenarios such as sepsis or in immunocompromised patients. Molecular techniques, mainly (reverse transcriptase)(RT)-PCR amplification,9,18,19,22,24 - 34 suggest that viral infections are the most important cause of myocarditis in North America and Europe with genomes of enterovirus, adenovirus, influenza viruses, human herpes virus-6 (HHV-6), Epstein-Barr-virus, cytomegalovirus, hepatitis C virus, and parvovirus B19 reported in the myocardium of patients with myocarditis and DCM. Lymphocytic and giant cell myocarditis are presumed idiopathic or autoimmune if no viruses are identified in EMB and other known causes are excluded (Figure 1).17 Similarly, the diagnosis of idiopathic granulomatous myocarditis (cardiac sarcoidosis) requires negative stains for microorganisms.2 Autoimmune myocarditis may occur with exclusive cardiac involvement or in the context of autoimmune disorders with extra-cardiac manifestations,9,11,17 most frequently in sarcoid-osis (Figure 1), hypereosinophilic syndrome, scleroderma, and systemic lupus erythematosus.


In human myocarditis, there is evidence for viral and autoimmune mechanisms, acting in individuals with or without ageneticpredispos-


ition (familial or sporadic cases, respectively). , , , _ M urine studies of viral myocarditis23,104_107are based mostly on Coxsackievirus B3-infected animals, which exhibit strain-specific susceptibility. Enteroviruses that preferentially enter cardiomyocytes via specific receptors cause severe cytopathic effects due to virus replication in the first 2 weeks post-infection. As a consequence, a humoral and cellular immune response, mainly consisting of macrophages and CD4+ and CD8+ T- lymphocytes, is initiated in resistant

Table 1 Causes of myocarditis/inflammatory cardiomyopathy

1. Infectious myocarditis

Bacterial Staphylococcus, Streptococcus, Pneumococcus, Meningococcus, Gonococcus, Salmonella, Corynebacterium diphtheriae, Haemophilus influenzae,

Mycobacterium (tuberculosis), Mycoplasma pneumoniae, Brucella

Spirochaetal Borrelia (Lyme disease), Leptospira (Weil disease)

Fungal Aspergillus, Actinomyces, Blastomyces, Candida, Coccidioides, Cryptococcus, Histoplasma, Mucormycoses, Nocardia, Sporothrix

Protozoal Trypanosoma cruzi, Toxoplasma gondii, Entamoeba, Leishmania

Parasitic Trichinella spiralis, Echinococcus granulosus, Taenia solium

Rickettsial Coxiella burnetii (Q fever), R. rickettsii (Rocky Mountain spotted fever), R. tsutsugamuschi

Viral RNA viruses: Coxsackieviruses A and B, echoviruses, polioviruses, influenza A and B viruses, respiratory syncytial virus, mumps virus,

measles virus, rubella virus, hepatitis C virus, dengue virus, yellow fever virus, Chikungunya virus, Junin virus, Lassa fever virus, rabies virus, human immunodeficiency virus-1 DNA viruses: adenoviruses, parvovirus B19, cytomegalovirus, human herpes virus-6, Epstein-Barr virus, varicella-zoster virus, herpes simplex virus, variola virus, vaccinia virus

2. Immune-mediated myocarditis

Allergens Tetanus toxoid, vaccines, serum sickness

Drugs: penicillin, cefaclor, colchicine, furosemide, isoniazid, lidocaine, tetracycline, sulfonamides, phenytoin, phenylbutazone, methyldopa, thiazide diuretics, amitriptyline

Alloantigens Heart transplant rejection

Autoantigens Infection-negative lymphocytic, infection-negative giant cell

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, rheumatic heart disease (rheumatic fever)

3. Toxic myocarditis Drugs

Heavy metals Miscellaneous Hormones

Amphetamines, anthracyclines, cocaine, cyclophosphamide, ethanol, fluorouracil, lithium, catecholamines, hemetine, interleukin-2,

trastuzumab, clozapine Copper, iron, lead (rare, more commonly cause intramyocyte accumulation)

Scorpion sting, snake, and spider bites, bee and wasp stings, carbon monoxide, inhalants, phosphorus, arsenic, sodium azide Phaeochromocytoma, vitamins: beri-beri

Physical agents Radiation, electric shock

animals (C57BL/6 mice, Sv129 mice) and leads to the elimination of the infectious agent within 2 weeks following infection. In susceptible mouse strains (e.g. A/J, ABY/SnJ, ASW/SnJ, ACA/SnJ, SWR/J, Balb/c), viral RNA and inflammation persist in the heart for several weeks.104-105 There is evidence that in these susceptible mice strains, the ongoing infection and inflammation trigger autoimmune reactions in the heart, most likely as a result of myocyte necrosis and subsequent release of self-antigens previously hidden to the immune system (Figure 2).108 The same genetically predisposed strains of animals develop autoimmune lymphocytic or giant cell myocarditis and later DCM after immunization with cardiac autoantigens (e.g. cardiac myosin) or spontaneously. In common with other autoimmune diseases such as Type 1 diabetes, major histocompatibility complex (MHC) and non-MHC genes appear to be responsible for the predisposition to murine myocarditis.17108-115

It is likely that genetic predisposition is also important for the development of viral116 and/or autoimmune myocarditis and its progression to DCM in humans.35-36,117 Progression from myocarditis to DCM seems to occur predominantly in patients with histologically confirmed persistant (chronic) inflammation18 that cannot eliminate the infective microbialagents32 or have developed pathogenic cardiac autoantibodies directed against myocardial structural, sarcoplasmic, or sarcolemmal proteins. The frequency, cardiac, and disease specificity for such anti-

93637 118 119

bodies in myocarditis/DCM are summarized in Table 2. , , , ,

Clinical presentation

Myocarditis presents in many different ways, ranging from mild symptoms of chest pain and palpitations associated with transient ECG changes to life-threatening cardiogenic shock and ventricular arrhythmia (Table 3). The disease may affect individuals of all ages, although it is most frequent in the young. This diversity of clinical scenarios implies that the diagnosis of myocarditis requires a high level of suspicion early in the course of the disease and the use of appropriate investigations to identify its cause. In all cases of suspected myocarditis, it is mandatory to exclude coronary artery disease and other cardiovascular, e.g. hypertension, or extra-cardiac non-inflammatory diseases that could explain the clinical presentation. Rarely patients with other cardiovascular disorders such as coronary artery disease, cardiomyopathy, and hypertensive heart disease present with a clinical deterioration caused by myocarditis that is mistakenly attributed to the natural history of the preexisting disease. If this is strongly suspected by the clinician, further investigation including EMB may be appropriate.

Myocarditis can be an incidental finding in autopsy studies of individuals who died of non-cardiac death or in myocardial samples obtained for clinical reasons unrelated to the clinical suspicion of myocarditis, for example following valve surgery or in explanted hearts taken from patients that have received inotropic drugs. In these circumstances, the significance of myocardial inflammation must be interpreted cautiously in the light of the clinical scenario.

Table 2 Serum cardiac autoantibodies in autoimmune myocarditis/dilated cardiomyopathy: frequency in myocarditis/ dilated cardiomyopathy, other cardiac disease (OCD) and normals

Cardiac autoantibody (Ab) % aabs positive %antibody Functional effect/clinical References

positive relevance

Myoc DCM OCD Normal

Muscle-specific ASA, 28-59* 9-41* NT 0-25 Myocytolysis 72,77,57,64



AHA 41-56*,A,a 26 -30*,A,a 1 -4 3 Cardiac- and disease-specific early 9a,50a,35a, 36a,118a,52a

AIDA 17*,A,a 16*,A,a 2-4 0 predictors; predict DCM

development in relatives

Anti-Beta1-AR 33 40-51A 13 -55 0-13 Negative predictors, pro-apoptotic and 48,55,61-63,66a,72,74-76,

NT 35*,A,a 16 7 other in vitro effects 78,84,109,88,90,92,93,98

73-96*,A,a 29-95*,A,a 8 0

NT 27-28 10 0

Anti-Beta2-AR NT 30-38A 33 15 Association with idiopathic arrhythmia 53",62,69a,89

NT 13 -14

NT 30-75a 37 18

Anti-muscarinic acetylcholine 11 30-77c 23d-61 8-13 Negative inotropic, muscarinic effects 47d,48c,54,58,59,70,74-

receptor-2 NT 83e Association with atrial arrhythmia 75,88,94,98

Cardiodepressant NT 64 Negative inotropic effects in rat and 56,66A,85-87,91A

(Fg-gamma-receptor 2a) human myocytes in vitro

Anti-Ky channel-interacting protein NT 14A 8 4 Increased cell death in myocytes in vitro

2, KChIP2.6—ELISA)

Anti-Alpha-MHC (cardiac-specific) 17-37*,A,a 20-46*,A,a 4-16 0-2.5 Negative predictors, pro-apoptotic 109,51 a,60a, 118a,140a

Anti-Beta-MHC (muscle-cross 68,95,96


Anti-MLC 1v NT 17A-35 25 0-15 51,67"

Anti-tropomyosin NT 55A 21 NT 67

Anti-non-myofibrillar NT 46*,A,a 17 0 51a

Anti-MHC NT 67A 42 NT 67

Anti-actin NT 71A 21 NT 67

Anti-Troponin I ,T NT 1.7A-20A 0A -18 0-4 Negative predictors 66,68,80

Anti-laminin 73 78 25 -35 6 97

Anti-HSP60,70 NT 10-85A 1 -42 3 67,79

Anti-s.Na/K-ATPase 26* NT 2 Ventricular tachycardia predictors 49

Anti- ANT 91*,A,a 57*,A,a 0 0 Negative inotropic 81 -83a

Anti-M7 13* 31* 10 0 65

Anti-BCKD-E2 100*A 60*A 4 0 46

Legend to Table 2:*P < 0.05 vs. normals; AP < 0.05 vs. OCD.

AFA, anti-fibrillary Ab; AHA, organ-specific and partially organ-specific anti-heart aabs; AIDA, anti-intercalated disks-aabs; ANT, adenine nucleotide translocator; AMLA, anti-myolemmal aabs; AR, adrenergic receptor; ASA, anti-sarcolemmal aabs; IFA, anti-interfibrillary aabs; BCKD, branched chain alpha-ketoacid dehydrogenase dihydrolipoyl transacylase; HSP, heat shock protein; NT, not tested; OCD, other cardiac disease; MHC, myosin heavy chain; MLC1v, myosin light chain 1 ventricular; Myoc, myocarditis. aCardiac and disease-specific for myocarditis/DCM.

bIncrease L-type Ca2+ current; short-term positive inotropic effects; increase in cytoplasmic cAMP, and cAMP/ FRET-activity.

c77% (in Chagas-DCM).

dIn atrial fibrillation patients.

eIn selected ELISA-positive heart failure patients.

Diagnosis of myocarditis

Non-invasive imaging techniques such as cardiac magnetic resonance (CMR) imaging can be useful in making the diagnosis of myocarditis and for monitoring disease progression, but we strongly endorse the

concept that EMB should be the gold standard for the diagnosis of definite myocarditis.1 -3 However, this implies that all patients with suspected myocarditis should undergo an EMB which is not routine practice; moreover, current guidelines recommend EMB only in a limited number of clinical scenarios that do not include some common

CD3+ T cells

CD68+ macrophages

. ■ ip > ■

Acute myocarditis

I. ■ , . >, J, _ ,

!■ ' - ■ ' -

I • - • •• -' ^ : Chronic


Vi & • ■ ;v

* ■ ^v V *

, 1 ' \ Sarcoidosis

A*. ■

Giant ceil myocarditis

/:■-• • <>«r J. \ • . mxw^if^iivtsv.^r.fmurn

Cine-SSFP (diastole) Cine-SSFP (systole) | T2w edema | T1w LGE

«vT ^

r» J //

Figure 1 Upper panel: histopathology and immunopathology of acute lymphocytic myocarditis (first row, x 100), chronic lymphocytic myocarditis (second row, x200), sarcoidosis (third row, x 100), and giant cell myocarditis (fourth row, x200). Left column = haematoxylin-eosin (HE); middle column = staining with anti-CD3 antibody (pan T lymphocyte marker); right column = staining with anti-CD68 antibody (macrophage marker). Lower panel: short-axis (upper line) and long-axis (lower line) CMR images of a young patient with acute myocarditis. In the first two columns, cine-SSFP images are shown in diastole and systole and suggest absence of any wall motion abnormality. In the next column, T2-weighted edema images demonstrate the presence of patchy focal edema in the subepicardium of the inferolateral wall (red arrows). In the last column, T1-weighted LGE images demonstrate presence of subepicardially distributed LGE (red arrows) which is typical for acute myocarditis.

Figure 2 The picture shows the pathogenetic mechanisms involved in myocarditis and progression to dilated cardiomyopathy.

presentations of myocarditis, in particular, pseudo-infarction. In order to improve recognition of myocarditis in clinical practice and to aid selection of patients that require further diagnostic evaluation and treatment, we propose new criteria for clinically suspected myocarditis for which biopsy analysis is recommended (Table 4). These criteria are based upon consensus of experts and require validation in future multicentre registries and randomized trials in patients who have undergone EMB. Medical centres that cannot safely perform EMB or do not have access to state-of-the-art CMR should refer patients with clinically suspected myocarditis to a tertiary referral unit experienced in EMB and CMR, particularly when patients present with haemodynamic instability or life-threatening arrhythmia.

Firstline tests in patients with a clinical presentation consistent with myocarditis

Electrocardiogram (ECG)

Electrocardiogram (ECG) is usually abnormal in myocarditis though

9121 122

ECG signs are neither specific nor sensitive (Table ). , , Some ECG changes are more suggestive of myocarditis than others. For example, ST-T segment elevation in myocarditis is typically concave (rather than convex in myocardial ischaemia)and diffuse without reciprocal changes. A-V block in the presence of mild left ventricular dilatation can be due to various causes (including laminopathy), but it may also be suggestive of Lyme disease, cardiac sarcoidosis, or giant cell myocarditis. In recent studies, QRS prolongation was an independent negative predictor for survival (which could be also due solely to asyn-chrony in left bundle branch block), while Q-waves and repolarization

abnormalities were unrelated to outcome or immunohistological features of inflammation on EMB.122

Recommendation 1. Standard 12-lead electrocardiogram should be performed in all patients with clinically suspected myocarditis.


Echocardiography helps to rule out non-inflammatory cardiac disease such as valve disease and to monitor changes in cardiac chamber size, wall thickness, ventricular function, and pericardial effusions. Global ventricular dysfunction, regional wall motion abnormalities, and diastolic dysfunction with preserved ejection fraction may occur in myocarditis.123,124 Histologically proven myocarditis may resemble dilated, hypertrophic, and restrictive cardiomyopathy and can mimic ischaemic heart disease.124,125 Fulminant myocarditis often presents with a non-dilated, thickened, and hypocontractile left ventricle as the intense inflammatory response results in interstitial oedema and loss of ventricular contractility.123,124 The role of newer imaging techniques such as tissue Doppler or strain-rate imaging in the diagnosis of myocarditis remains to be determined.


2. All patients with clinically suspected myocarditis should undergo a standard trans-thoracic echocardiogram at presentation.

3. Trans-thoracic echocardiogram should be repeated during hospitalization if there is any worsening of haemodynamics.

Table 3 Clinical presentations of patients with biopsy-proven inflammatory heart muscle disease

(1) Acute coronary syndrome-like

(a) Acute chest pain

- Frequently starting within 1 -4 weeks of a respiratory or gastrointestinal infection

- Frequently associated with severe and recurrent symptoms

- In the absence of angiographic evidence of CAD

(b) ST/T wave changes

- ST-segment elevation or depression

- T-wave inversions

(c) With or without normal global or regional LV and/or RV dysfunction on echocardiography or CMR

(d) With or without increased TnT/TnI that may have a time course similar to acute myocardial infarction or a prolonged and sustained release over several weeks or months

(2) New onset or worsening heart failure in the absence of CAD and known causes of heart failure

(a) New onset or progressive heart failure over 2 weeks to 3 months

- Dyspnoea

- Peripheral oedema

- Chest discomfort

- Fatigue

(b) Impaired systolic LV and/or RVfunction, with or without an increase in wall thickness, with or without dilated LVand/orRVon echocardiography or CMR

(c) Symptoms possibly started after a respiratory or gastrointestinal infection, or in the peri-partum period

(d) Non-specific ECG signs, bundle branch block, AV-block, and/or ventricular arrhythmias

(3) Chronic heart failure in the absence of CAD and known causes of heart failure (see point 2 above)

(a) Heart failure symptoms (with recurrent exacerbations) of >3 months duration W

(b) Fatigue, palpitation, dyspnoea, atypical chest pain, arrhythmia in an ambulant patient g

(c) Impaired systolic LV and/or RVfunction on echocardiography or CMR suggestive of DCM or non-ischaemic cardiomyopathy 2;

(d) Non-specific ECG signs, sometimes bundle branch block and/or ventricular arrhythmias and/or AV-block y

(4) 'life-threatening condition', in the absence of CAD and known causes of heart failure comprising o

(a) Life-threatening arrhythmias and aborted sudden death a

(b) Cardiogenic shock !d

(c) Severely impaired LV function 5

Nuclear imaging

Data on radionuclide evaluation, including antimyosin antibody imaging, are scarce but suggest that its sensitivity for detecting myocardial inflammation is variable and its specificity low.125-128 Due to their limited availability and risk from radiation exposure, nuclear techniques are not routinely recommended for the diagnosis of myocarditis, with the possible exception of sarcoidosis.

Thallium 201 and technetium 99m scintigraphy have been used to detect cardiac sarcoidosis but lack specificity. Gallium-67 scintigraphy and more recently positron emission tomography using 18 fluorodeoxyglucose are probably more sensitive and may be useful in the acute phase of sarcoidosis and to monitor disease progres-sion.129-132The detection of extracardiac disease can suggest a diagnosis of cardiac sarcoidosis.


4. Nuclear imaging is not routinely recommended in the diagnosis of myocarditis, with the possible exception of suspected cardiac sarcoidosis.

Cardiovascular magnetic resonance (CMR) imaging

Cardiovascular magnetic resonance imaging provides non-invasive tissue characterization ofthe myocardium and can support the diagnosis of myocarditis (Figure ?).133_139 The timing of CMR in suspected myocarditis will depend upon local availability and expertise, but it is reasonable to first perform CMR in clinically stable patients, prior to EMB. It should not be performed in life-


threatening presentations where EMB is urgently indicated. , Cardiovascular magnetic resonance imaging techniques have been evaluated in animal models of myocarditis as well as in

19 20 125 133_139

patients. , , , Based on pre-clinical and clinical studies,

an 'International Consensus Group on CMR Diagnosis of Myocarditis' published detailed recommendations on the indication, implementation, and analysis of appropriate CMR techniques for non-invasive diagnosis of myocarditis (Lake Louise criteria).20 The combined use of three different CMR techniques is suggested (Table 5).134,136-139 One study has demonstrated good correlation between CMR and EMB in troponin-positive patients without coronary artery disease133; however, correlation is worse in patients with a longer history of symptoms and histologically confirmed

Table 4 Diagnostic criteria for clinically suspected myocarditis

Clinical presentations3

Acute chest pain, pericarditic, or pseudo-ischaemic

New-onset (days up to 3 months) or worsening of: dyspnoea at rest or exercise, and/or fatigue, with or without left and/or right heart failure signs Subacute/chronic (>3 months) or worsening of: dyspnoea at rest or exercise, and/or fatigue, with or without left and/or right heart failure signs Palpitation, and/or unexplained arrhythmia symptoms and/or syncope, and/or aborted sudden cardiac death Unexplained cardiogenic shock

Diagnostic criteria

I. ECG/Holter/stress test features

Newly abnormal 12 lead ECG and/or Holter and/or stress testing, any ofthe following: 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 TnT/TnI

III. Functional and structural abnormalities on cardiac imaging (echo/angio/CMR)

New, otherwise unexplained LV and/or RVstructure and function abnormality (including incidentalfinding in apparently asymptomatic subjects): regional wall motion or global systolic or diastolic function abnormality, with or without ventricular dilatation, with or without increased wall thickness, with or without pericardial effusion, with or without endocavitary thrombi

IV. Tissue characterization by CMR

Oedema and/or LGE of classical myocarditic pattern (see text)

Clinically suspected myocarditis if >1 clinical presentation and >1 diagnostic criteria from different categories, in the absence of: (1) angiographically detectable coronary artery disease (coronary stenosis > 50%); (2) known pre-existing cardiovascular disease or extra-cardiac causes that could explain the syndrome (e.g. valve disease, congenital heart disease, hyperthyroidism, etc.) (see text). Suspicion is higher with higher number of fulfilled criteria. aIf the patient is asymptomatic >2 diagnostic criteria should be met.

chronic myocarditis and in addition CMR cannot exclude viral forms of myocarditis.137


5. Cardiovascular magnetic resonance findings consistent with myocarditis should be based on Lake-Louise criteria (Table 5).

6. Cardiovascular magnetic resonance may be considered in clinically stable patients prior to EMB. Cardiovascular magnetic resonance does not replace EMB in the diagnosis of myocarditis and should not delay EMB in life-threatening presentations.


Inflammatory markers

Erythrocyte sedimentation rate and reactive C protein levels are often raised in myocarditis, but they do not confirm the diagnosis and are often increased in acute pericarditis.52

Troponin and BNP levels

While cardiac troponins are more sensitive of myocyte injury in patients with clinically suspected myocarditis than creatine kinase


levels, they are non-specific and when normal do not

exclude myocarditis.142 This also applies to cardiac hormones such as brain natriuretic peptides,143 circulating cytokines,144 markers related to extracellular matrix degradation,145 and new biomarkers such as pentraxin 3, galectin 3, and growth differentiation factor 15.146

Viral antibodies

Positive viral serology does not imply myocardial infection but rather indicates the interaction ofthe peripheral immune system with an infectious agent. Polyclonal stimulation of antibodies (IgM and IgG) may furthermore lead to incorrect diagnosis. Thus, viral serology is of limited utility in the diagnosis of viral myocarditis147 because the prevalence of circulatory IgG antibodies to cardiotropic viruses in the general population is high in the absence of viral heart disease.2,16,23,25,31,105 In addition, infection with non-cardiotropic enteroviruses may cause an antibody response which is indistinguishable from the response to cardiotropic viruses2,16,23,25,31,105 and, in a recent study, there was no correlation between virus serology and EMB findings.147 Circumstances in which serological testing may be helpful include suspected hepatitis C, rickettsial phase 1 and phase 2, Lyme disease in endemic areas, and human immunodeficiency in high-risk patients.

(b) Serum cardiac autoantibodies (aabs)

Aabs to various cardiac and muscle-specific autoantigens are found in myocarditis and in DCM patients (Table 2).9,35,36,46-

98109 118

, , Lack of viral genome on EMB with detectable serum aabs suggests immune-mediated DCM or myocarditis.9,15,16,100 Antibodies of IgG class, which are shown to be cardiac and disease-specific for myocarditis/ DCM, can be used as autoimmune biomarkers for identifying at risk relatives and those patients in whom, in the absence of active infection of the myocardium, immunosuppression and/or immunomodulation may be beneficial.9,15,16,35,36,100,118 Detection of cardiodepressant antibodies in DCM also predicts haemodynamic benefits from

Table 5 Diagnostic cardiac magnetic resonance criteria for myocarditis

In the setting of clinically suspected myocarditis (Tables 3-4), CMRfindings are consistent with myocardial inflammation, ifat least two of the following criteria are present:

(1) Regional or global myocardial signal intensity increase in T2-weighted oedema imagesa

(2) Increased global myocardial early gadolinium enhancement ratio between myocardium and skeletal muscle in gadolinium-enhanced Tl-weighted imagesb

(3) There is at least one focal lesion with non-ischaemic regional distribution in inversion recovery-prepared gadolinium-enhanced Tl-weighted images (late gadolinium enhancement)c

A CMR study is consistent with myocyte injury and/or scar caused by myocardial inflammation if Criterion 3 is present A repeat CMR study between 1 and 2 weeks after the initial CMR study is recommended if

• None of the criteria are present, but the onset of symptoms has been very recent and there is strong clinical evidence for myocardial inflammation

• One of the criteria is present

The presence of LV dysfunction or pericardial effusion provides additional, supportive evidence for myocarditis

Table reprinted with permission from (20).

aGlobal signal intensity (SI) increase has to be quantified by an SI ratio of myocardium over skeletal muscle of >2.0. If the edema is more subendocardial or transmural in combination

with a colocalized ischaemic (including the subendocardial layer) pattern of late gadolinium enhancement, acute myocardial infarction is more likely and should be reported.

bA global SI enhancement ratio of myocardium over skeletal muscle of >4.0 or an absolute myocardial enhancement of >45% is consistent with myocarditis.

cImages should be obtained at least 5 min after gadolinium injection; foci typically exclude the subendocardial layer, are often multifocal, and involve the subepicardium. If the late

gadolinium enhancement pattern clearly indicates myocardial infarction and is colocalized with a transmural regional edema, acute myocardial infarction is more likely and should be


immunoadsorption.85 Some aabs have been described to be negative predictors in myocarditis or DCM ' (Table ). At present, no commercially available cardiac autoantibody tests have been validated against the results obtained in research laboratories; collaborative work among European research antibody laboratories is in progress to overcome this difficulty.37


7. Troponins, erythrocyte sedimentation rate, reactive C protein levels should be assessed in all patients.

8. Routine viral serology testing is not recommended.

9. Serum samples should be assessed, if possible, for cardiac aabs, if one (or more) of the published tests is available (Table 2), according to specific centre expertise. Disease-specific aabs should preferably be tested.

Proposed criteria for clinically suspected myocarditis

In this position statement, we propose new criteria for the diagnosis of clinically suspected myocarditis. These are based on a clinical presentation consistent with the diagnosis (Table 3) and the presence of one or more abnormalities on non-invasive testing (Table 4).

Myocarditis should be suspected in the presence of: 1 or more of the clinical presentations in Table 4, with or without ancillary features (see below), and

1 or more of the diagnostic criteria from different categories (I to IV) in Table 4 or

when the patient is asymptomatic, 2 or more diagnostic criteria from different categories (I to IV).

Ancillary features which support the clinical suspicion of myocarditis

include: o

• Fever >38.0°C at presentation or within the preceding 30 days 8 with or without evidence of a respiratory (chills, headache, m muscle aches, general malaise) or gastrointestinal (decreased appetite, nausea, vomiting, diarrhoea) infection; §

• peri-partum period121; |

• previous clinically suspected or definite myocarditis (according to 9 the criteria set in Table 4); 1

• personal and/or family history of allergic asthma, other types of allergy, extra-cardiac autoimmune disease, toxic agents;

• family history of DCM, myocarditis (according to the present criteria).

Recommendation 10. All patients with clinically suspected myocarditis should be considered for selective coronary angiography and EMB.

Second level investigations in clinically suspected myocarditis

In patients fulfilling the diagnostic criteria for clinically suspected myocarditis, we recommend selective coronary angiography and EMB (Figure 3). This recommendation also applies to patients with an acute coronary syndrome-like presentation (with or without ST segment elevation), increased cardiac troponins, preserved ventricular systolic function with or without features suggestive of myocarditis on CMR (Figure ?).20 At present, there are limited data on the prognostic implications of CMRfindings in this context, and this common scenario was not included in a recently published AHA/ACC/HFSA scientific statement on EMB.120 Therefore, in the absence of robust prospective data (in suspected myocarditis with pseudo-infarct presentation and

Clinically suspected myocarditis

(see Table 4)

Hospital admission for observation

exclude coronary artery disease

Figure 3 The flow chart shows the proposed diagnostic approach for patients with clinically suspected myocarditis according to Table 4.

normal coronary arteries), the definitive diagnosis of myocarditis should still be based on EMB (Figure 3).

Endomyocardial biopsy

Endomyocardial biopsy confirms the diagnosis of myocarditis and identifies the underlying aetiology and the type of inflammation (e.g. giant cell, eosinophilic myocarditis, sarcoidosis) which imply different treatments and prognosis (Figure 1).1 -3,11,14-16 Importantly, EMB is also the basis for safe (infection negative) immunosuppression and antiviral treatment. If EMB is performed by experienced teams, its complication rate is low (0-0.8).9,18,139,148

The recent scientific statement on EMB gave highest levels of recommendations in the life-threatening clinical presentations.120 However, the diagnostic, prognostic, and therapeutic value of EMB was based on the Dallas histopathologic criteria and did not include immunohistochemistry and viral genome analysis (Figure 1). These are established tools which should be used to achieve an aetio-logical diagnosis.914-16 18 1922,26 30-32100,101,103, 133, 137, 138

To optimize diagnostic accuracy and reduce sampling error in focal myocarditis, EMB should be performed early in the course of the disease and multiple specimens should be taken.2 At least three samples, each 1-2 mm in size, should be taken (from the right or from the left ventricle) and immediately fixed in 10% buffered formalin at room temperature for light microscopy; additional samples should be snap frozen in liquid nitrogen and stored at — 80°C or stored in RNA later tubes at room temperature for viral PCR.2,149 With respect to left or right heart biopsy, some patients may clinically present with exclusive left or right heart failure and myocarditis. In such cases, decision for left or right heart biopsy should be made according to the additional clinical information. To increase the diagnostic sensitivity of immunohistochemistry, use of a large panel of monoclonal and polyclonal antibodies (including anti-CD3,T lymphocytes; anti-CD68, macrophages; and anti HLA-DR) is mandatory for the identification and characterization of the inflammatory infiltrate

and for the detection of HLA-DR upregulation on EMB tissue sections as marker of infectious-negative autoimmune myocarditis where immunosuppression may be considered.2,14,15 Other immunofluorescence stains used to define humoral rejection in heart transplant EMB, such as C3d and C4d, have been recently reported as promising markers of immune activation in patients with inflammatory cardiomyopathy; a limitation ofthese stains is that they require frozen material.40 The diagnostic contribution of EMB is enhanced by molecular analysis with DNA-RNA extraction and RT-PCR amplification of viral genome.16 In order to exclude systemic infection, peripheral blood should be investigated in parallel with EMB2,9; quantification of virus load and determination of virus replication may add diagnostic value.22 Suggested primer sets and PCR protocols are detailed in the supplementary material online, appendix. The main technical requirements are as follows:

• RT-PCR detection ofviralDNAor RNA in the heart should always be controlled by amplifying adequate positive samples containing different viral copy numbers as well as negative controls.2 Sequencing of the amplified viral gene product is mandatory in order to identify virus subtypes and recognize contaminations.

• Blood samples should be tested by RT-PCR to detect acute systemic virus infection, and to exclude persistently/latently infected blood cells which might contaminate heart tissue samples but do not indicate virus infection of the myocardium.2

• The detection ofreplicative forms of viral nucleic acids in the heart supports a pathogenic roleofvirusin myocarditis; however, detection of viral mRNA by RT-PCRmay be difficult to establish in EMB due to low amounts of viral mRNA especially in longstanding chronic myocarditis.


11. Tissue obtained from EMB should be analysed using histology, immunohistochemistry, and viral PCR (on heart tissue and a blood sample).

12. At least three myocardial samples, each 1-2 mm in size, should be taken (from the right or from the left ventricle) and immediately fixed in 10% buffered formalin at room temperature for light microscopy; additional samples should be taken, snap frozen in liquid nitrogen, and stored at — 80°C, or stored in RNA later tubes at room temperature, for viral PCR.2,149

13. Endomyocardial biopsy may be repeated if necessary to monitor response to aetiology-directed therapy, or if a sampling error is suspected in a patient with unexplained progression of heart failure.

Clinical management

Outcome and prognosis of myocarditis depends on aetiology, clinical presentation, and disease stage.3,9-11 Acute myocarditis resolves in about 50% of cases in the first 2-4 weeks, but about 25% will develop persistent cardiac dysfunction and 12-25% may acutely deteriorate and either die or progress to end-stage DCM with a need for heart transplantation.1-3,6-9,16,150 Biventricular dysfunction at presentation has been reported as the main predictor of death or

transplantation.1-3,6-9,16,150 Fulminant myocarditis is said to differ from (sub)acute lymphocytic myocarditis in its mode of onset, degree of haemodynamic compromise, and better outcome, but data are relatively scarce in adult patients.150 Fulminant myocarditis of unknown aetiology is more frequent in children and prevalent in neonates with a dismal prognosis.10 Most studies suggest that survival rates in giant-cell myocarditis are markedly worse.3,9,11,34,99

Molecular detection techniques for viral genome in EMBspecimens

918 32 151_153

have provided conflicting prognostic information. , , , Viral persistence in the myocardium has been associated with ventricular dysfunction and viral genome clearance with improvement of ventricular function and a better 10-year prognosis.32,152 In contrast, in a recent report, immunohistological evidence of inflammation but not the presence of viral genome alone was an independent predictor of survival.18 This discrepancy may relate to the variability in the viral epidemiology of different populations and to low numbers of events.

The frequency of specific viruses among patients who recover spontaneously is largely unknown. This may also confer some bias to the published studies on prognosis.9,18,32,151-153 The molecular mechanisms responsible for the reactivation of latent viral infection, the influence of immune activation triggering viral replication in chronic myocarditis, and immune-independent viral pathogenesis in non-inflamed hearts are remaining gaps in the understanding of viral pathogenicity.22

(a) Conventional medical treatment

As large multicentre randomized controlled trials examining distinct pathogenic subsets are not available,10 recommendations are based on the consensus of the expert Task Force. The core principles of treatment in myocarditis are optimal care of arrhythmia and of heart failure and, where supported by evidence, aetiology-targeted therapy.

1. Haemodynamically unstable patients

Patients with haemodynamically unstable heart failure should be managed promptly according to current ESC guidelines for heart failure154 in intensive care units with respiratory and mechanical cardio-pulmonary support facilities. In acute/fulminant cases with cardiogenic shock and severe ventricular dysfunction, ventricular assist devices or extracorporeal membrane oxygenation (ECMO) may be needed to provide a bridge to transplant or to recov-ery.10,155-157 Because of its simplicity and effectiveness, ECMO therapy can rescue this group of patients.156,157


14. Patients with a life-threatening presentation should be sent to specialized units with capability for haemodynamic monitoring, cardiac catheterization, and expertise in EMB.

15. In patients with haemodynamic instability, a mechanical cardio-pulmonary assist device may be needed as a bridge to recovery or to heart transplantation.

16. Cardiac transplantation should be deferred in the acute phase, because recovery may occur, but can be considered for haemodynamically unstable myocarditis patients, including those with giant cell myocarditis, if optimal pharmacological support and mechanical assistance cannot stabilize the patient.

2. Haemodynamically stable patients

When myocarditis is suspected in asymptomatic or mildly symptomatic patients according to the criteria shown in Table 4, admission to hospital and clinical monitoring are recommended until a definite diagnosis is established, since the situation can evolve rapidly and a cardiopulmonary emergency (e.g. severe heart block or life-threatening arrhythmia) is possible and unpredictable, even if systolic function is initially preserved.10 Exercise testing is contraindicated in the acute stage as it can precipitate arrhythmia.

Patients with haemodynamically stable heart failure should be treated with diuretics, angiotensin-converting enzyme inhibitor, or angiotensin receptor blockade and beta-adrenergic blockade. In patients who have persistent heart failure symptoms despite optimal management, additional treatment with aldosterone antagonists should be considered.154 The procedure for weaning of heart failure therapy following recovery of ventricular function is not defined.

Non-steroidal anti-inflammatory drugs, in particular acetylsalicylic acid, are a cornerstone of treatment for acute pericarditis, but have been associated with increased mortality in experimental models of myocarditis.106-108 Clinical data for their administration in myocarditis are inconclusive, and controlled trials are needed.

Recommendations 17. Management of ventricular dysfunction should be in line with current ESC guidelines on heart failure.

3. Arrhythmia

There are no specific recommendations for the management of arrhythmia in myocarditis, and so management should be in line with current ESC guidelines. 157-162 Sinus bradycardia, prolonged QRS duration, increased left ventricular hypokinesis on echocardiography, persistent or fluctuating cardiac troponin levels may precede a life-threatening arrhythmia.10 Temporary pacing may be needed for complete atrio-ventricular block.10 Indication for cardioverter defibrillator implantation (ICD) is controversial, because myocarditis may heal completely. Bridging by a lifevest in patients with myocarditis and severe ventricular arrhythmia (ventricular tachycardia or fibrillation) could solve the transient problem.163


18. ICD implantation should be deferred until resolution of the acute episode.

19. Arrhythmia management outside the acute phase should be in line with current ESC guidelines on arrhythmia and device implantation.

4. Avoidance of exercise

Physical activity should be restricted during the acute phase of myocarditis until the disease has completely resolved.164,165 Athletes should be temporarily excluded from competitive and amateur-leisure time sport activity regardless of age, gender, severity of symptoms, or therapeutic regimen.164,165 After resolution of the clinical presentation (at least 6 months afterthe onsetofthe disease), clinical

reassessment is indicated before the athlete resumes competitive sport.164,165 Pre-participation screening should be performed every 6 months during the follow-up.164,165 Although the duration of restricted physical activity in non-athletes is undefined, based upon expert opinion of this Task Force, it seems reasonable to give similar recommendations.


20. Physical activity should be restricted during the acute phase ofmyocarditisandforat least 6 months in athletes and non-athletes. This recommendation is based upon expert opinion of this Task Force.

(b) Immunomodulatory therapy

Anti-viral therapies

There is still no approved antiviral-therapy for the treatment of enter-oviral infections. Vaccines may be an option in the future.166 Treatment with acyclovir, gancyclovir, and valacyclovir may be considered in patients with herpes virus infection,167 although their efficacy is unproven in myocarditis. Preliminary data on interferonbeta treatment suggest that it eliminates enteroviral and adenoviral genomes in patients with left ventricular dysfunction,168 is associated with improvement in NYHA functional class,169 and, specifically in enteroviral infection, with a better 10-year prognosis.152 In general, we recommend involvement of infectious disease specialists when deciding on the use of specific antiviral therapies.

High dose intravenous immunoglobulin

High dose intravenous immunoglobulin (IVIG) modulates the immune and inflammatory response by a variety of mechanisms and is used in a number of systemic autoimmune diseases.170 Its use has been associated with improved left ventricular ejection fraction in chronic symptomatic heart failure of various causes,171 but IVIG was ineffective in the IMAC controlled trial of recent-onset DCM in which only 15% of patients had biopsy-proven myocarditis of non-specified cause.172 Nevertheless, IVIG has no major side-effects and may be used in myocarditis refractory to conventional heart failure therapy, both viral and autoimmune forms, particularly if autoantibody-mediated.3 In the absence of multi-centre randomized studies in biopsy-proven myocarditis/DCM of viral or autoimmune origin, we do not give recommendations for the use of IVIG.

Immunoadsorption (IA)

Various aabs have been detected in myocarditis and DCM patients and for some a pathogenic role has been proposed (Table 2). Thus, therapeutic strategies used in other auto-immune disorders,173-175 such as neutralization or immunoadsorption (IA) of disease-causing aabs, might offer treatment options for autoimmune myocarditis/ DCM. Small randomized studies with DCM patients have shown that IA induces improvement of LV function and decreases myocardial inflammation76,102; a larger randomized controlled clinical trial is currently underway in Europe. Until these results are available, we do not give recommendations for the use of immunoadsorption.

(c) Immunosuppressive therapy

Most data on safety and efficacy of immunosuppressive regimes in myocarditis have been obtained using steroids alone, azathioprine and steroids, or cyclosporine A, azathioprine and steroids. Information on other drugs is not available. Data from the few randomized clinical trials of immunosuppression in myocarditis and DCM are shown in Table 6. Response to therapy is reported mainly in chronic virus-negative forms, in giant cell myocarditis, and in active myocarditis defined as autoimmune (e.g. virus-negative and autoantibody positive). Conversely, immunosuppression had a neutral effect in the Myocarditis Treatment Trial, where patients had myocarditis of unknown aetiology.6

It is necessary to identify possible drugs causing hypersensitivity reactions, particularly in patients with hypereosinophilia10; the inducing drug (Table 1) should not be reintroduced after recovery.10

Recently, a single-centre controlled trial suggested a beneficial effect of combined steroid and azathioprine therapy in virus-negative myocarditis.101 These data need to be confirmed in multicentre studies.


21. Immunosuppression should be started only after ruling out active infection on EMB by PCR.

22. Based on experience with non-cardiac autoimmune o disease, the task group recommends consideration of im- o munosuppression in proven autoimmune (e.g. infection- f negative) forms of myocarditis, with no contraindications 3 to immunosuppression, including giant cell myocarditis, u cardiac sarcoidosis, and myocarditis associated with n known extra-cardiac autoimmune disease.10,99 J

23. Steroid therapy is indicated in cardiac sarcoidosis in the 2

presence of ventricular dysfunction and/or arrhythmia 5

and in some forms of infection-negative eosinophilic or toxic myocarditis with heart failure and/or arrhythmia.

24. Immunosuppression may be considered, on an individual basis, in infection-negative lymphocytic myocarditis refractory to standard therapy in patients with no contraindications to immunosuppression.

25. Follow-up EMB may be required to guide the intensity and the length of immunosuppression.

(d) Follow-up

Myocarditis patients can have partial or full clinical recovery; some may relapse many years after the first episode. Relapses should be managed similarly to the index episode. In patients who do not resolve, disease may continue subclinically and lead to DCM.

The myocarditis patient with pseudo-infact presentation, normal coronary arteries, and preserved ventricular function should be discharged when cardiac enzymes have come into the normal range, and offered long-term non-invasive cardiological follow-up. In the event of prolonged (weeks or even months) documented increase of cardiac enzymes, and/or progressive reduction in left and/or right ventricular function, the patient should be readmitted to hospital to perform EMB.

Table 6 Controlled immusuppression trials in myocarditis and dilated cardiomyopathy

Year Type


Primary endpoint



Prednisone trial 1989 Randomized

for DCM

Giant cell myocarditis treatment trial

controlled trial (RCT):

prednisone (PDN) 1995 RCT: PDN and

cyclosporine or azathioprine 2008 Prospective: PDN and

cyclosporine 2003 Prospective: PDN and


RCT: PDN and azathioprine

2009 RCT: PDN and azathioprine

'Reactive' DCM (n = 60) Either higher LV ejection

fraction (LVEF) at 3 months 'Nonreactive DCM)' or lower LV end-diastolic

(n = 42) dimension and better

exercise tolerance

Acute biopsy-proven myocarditis (unknown aetiology) Giant cell myocarditis (autoimmune)

Active myocarditis and chronic heart failure (aetiology known in retrospect) Inflammatory DCM (unknown aetiology, increased HLA espression on EMB) Inflammatory

virus-negative DCM

LVEF at 6 months

Survival at 1 year

LVEF at 1 year

LVEF at 3 months, sustained at 2 years

LVEF at 6 months







Favourable in Frustaci100

virus-negative aabs-positive autoimmune forms Favourable Wojnicz103



Persistently elevated troponin T values could be due to heterophile antibodies interfering with the assay. Performing a troponin I could clarify whether persistent enzyme elevations are due to an analytic error or cardiac pathology. Similarly, chronic skeletal muscle disease could be associated with persistently elevated low level cardiac troponins.


26. All patients with myocarditis should be followed, with clinical assessment, ECG, and echocardiography.

27. Long-term follow-up for patients that have experienced myocarditis is recommended.


This position statement reviews current knowledge, and proposes new diagnostic criteriafor clinically suspected myocarditis and its distinct biopsy-proven pathogenetic forms. The aims are to bridge the gap between clinical and tissue-based diagnosis, to improve management and provide a common reference point for future registries and multicentre randomized controlled trials of aetiology-driven treatment in inflammatory heart muscle disease.

Supplementary material

Supplementary material is available at European Heart Journal online. Conflict of interest: none declared.


1. Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, O'ConnellJ, Olsen E, Thiene G, Goodwin J, Gyarfas I, Martin I, Nordet P. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation 1996;93:841 _842.

2. Leone O, Veinot JP, Angelini A, Baandrup UT, Basso C, Berry G, Bruneval P, Burke M, ButanyJ, 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. 2011 Consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Societyfor Cardiovascular Pathology. Cardiovasc Pathol 2012;21:245 _ 274.

3. Kindermann I, Barth C, Mahfoud F, Ukena C, Lenski M, Yilmaz A, Klingel K, Kandolf R, Sechtem U, Cooper LT, Bohm M. Update on myocarditis. J Am Coll Cardiol 2012;59:779_ 792.

4. Gore I, Saphir O. Myocarditis; a classification of 1402 cases. Am Heart J 1947;34: 827_830.

5. Basso C, Calabrese F, Corrado D, Thiene G. Postmortem diagnosis of sudden cardiac death victims. Cardiovasc Res 2001;50:290_300.

6. Mason JW, O'ConnellJB, Herskowitz A, Rose NR, McManus BM, Billingham ME, Moon TE. A clinical trial of immunosuppressive therapy for myocarditis: The Myocarditis Treatment Trial Investigators. N Engl J Med 1995;333:269_275.

7. Felker GM, Hu W, HareJW, Hruban RH, Baughman KL, Kasper EK. The spectrum of dilated cardiomyopathy. The Johns Hopkins experience in 1278 patients. Medicine 1999;78:270_283.

8. TowbinJA, Lowe AM, Colan SD, Sleeper LA, Orav EJ, Clunie S, MessereJ, Cox GF, Lurie PR, Hsu D, Canter C, WilkinsonJD, Lipshultz SE. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA 2006;296:1867_1876.

9. Caforio AL, Calabrese F, Angelini A, Tona F, Vinci A, Bottaro S, Ramondo A, Carturan E, Iliceto S, Thiene G, Daliento L. A prospective study of biopsy-proven myocarditis: prognostic relevance of clinical and aetiopathogenetic features at diagnosis. Eur Heart J 2007;28:1326_1333.

10. Japanese Circulation Society (JCS) Joint Working Group. Guidelines for diagnosis and treatment of myocarditis (JCS 2009). CircJ 2011 ;75:734_743.

11. Sagar S, Liu PP, Cooper LT. Myocarditis. Lancet 2012;379:738 _747.

12. Aretz HT, Billingham ME, Edwards WD, Factor SM, Fallon JT, Fenoglio JJ Jr, Olsen EG, Schoen FJ. Myocarditis: a histopathologic definition and classification. Am J Cardiol Pathol 1985;1:1 _10.

13. Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, Dubourg O, Kuhl U, Maisch B, McKenna WJ, Monserrat L, Pankuweit S, Rapezzi C,

Seferovic P, Tavazzi L, Keren A. Classification of the cardiomyopathies: a position statement from the European Society of Cardiology working group on myocardial and pericardial disease. Eur Heart J 2007;29:270-276.

14. Maisch B, Bultmann B, Factor S, Grone H-J, Hufnagel G, Kawamura K, Kühl U, Olsen EJ, Pankuweit S, Virmani R, McKenna W, Richardson PJ, Thiene G, Schultheiss HP,Sekiguchi M.World Heart Federation consensus conferences's definition of inflammatory cardiomyopathy (myocarditis): report from two expert committees on histology and viral cardiomyopathy. Heartbeat 1999;4:3-4.

15. Maisch B, Richter A, Sandmoller A, Portig I, Pankuweit S; BMBF-Heart Failure Network. Inflammatory dilated cardiomyopathy (DCMI). Herz 2005;30:535-544.

16. Dennert R, Crijns HJ, Heymans S. Acute viral myocarditis. Eur Heart J 2008;29: 2073-2082.

17. Rose NR. Myocarditis: infection versus autoimmunity. J Clin Immunol 2009;29: 730-737.

18. Kindermann I, Kindermann M, Kandolf R, Klingel K, Bultmann B, Muller T, LindingerA, Boühm M. Predictors ofoutcome in patients with suspected myocarditis. Circulation 2008;118:639-648.

19. MahrholdtH,GoedeckeC, Wagner A, MeinhardtG, Athanasiadis A, Vogelsberg H, Fritz P, Klingel K, Kandolf R, Sechtem U. Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology. Circulation 2004;109:1250-1258.

20. Friedrich MG, Sechtem U, Schulz-Menger J, Holmvang G, Alakija P, Cooper LT, White JA, Abdel-Aty H, Gutberlet M, Prasad S, Aletras A, LaissyJP, Paterson I, Filipchuk NG, Kumar A, Pauschinger M, Liu P; International Consensus Group on Cardiovascular Magnetic Resonance in Myocarditis. Cardiovascular magnetic resonance in myocarditis: A JACC White Paper. J Am Coll Cardiol 2009;53:1475-1487.

21. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Young JB; American Heart Association; Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology InterdisciplinaryWorkingGroups;CouncilonEpidemiologyandPrevention.Con-temporary definitions and classification of cardiomyopathies. An American Heart Association Scientific statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; quality of Care and Outcome research and Functional Genomics and Translational Biology Interdisciplinary Working Groups: and Council on Epidemiology and Prevention. Circulation 2006;113: 1807-1816.

22. Bock CT, Klingel K, Kandolf R. Human parvovirus B19-associated myocarditis. N Engl J Med 2010;362:1248-1249.

23. Liu P, MartinoT, Opavsky MA, Penninger J. Viral myocarditis: balance between viral infection and immune response. Can J Cardiol 1996;12:935-943.

24. Cambridge G, MacArthur CG, Waterson AP, Goodwin JF, Oakley CM. Antibodies to Coxsackieviruses in congestive cardiomyopathy. Br Heart J 1979;41:692-696.

25. Baboonian C, Treasure T. Meta-analysis of the association of enteroviruses with human heart disease. Heart 1997;78:539-543.

26. Schultheiss HP, Kuhl U, Cooper LT. The management of myocarditis. Eur Heart J 2011; advanced e-pubJune 23; doi:10.1093/eurheartj/ehr165.

27. Maisch B, Schoünian U, Crombach M, Wendl I, Bethge C, Herzum M, Klein HH. Cytomegalovirus associated inflammatory heart muscle disease. Scan J Infect Dis 1993;88:135-148.

28. Martin AB, Webber S, Fricker FJ, Jaffe R, Demmler G, Kearney D, Zhang YH, BodurthaJ, Gelb B, Ni J. Acute myocarditis, rapid diagnosis by PCR in children. Circulation 1994;90:330-339.

29. Matsumori A, Matoba Y, Sasayama S. Dilated cardiomyopathy associated with hepatitis C infection. Circulation 1995;92:2519-2525.

30. Pankuweit S, Moll R, Baandrup U, Portig I, Hufnagel G, Maisch B. Prevalence of Parvovirus B 19 genome in endomyocardial biopsy specimen. Hum Pathol 2003; 34:80-86.

31. Kuühl U, Pauschinger M, Noutsias M, Seeberg B, Bock T, Lassner D, Poller W, Kandolf R, Schultheiss HP. High prevalence of viral genomes and multiple viral infections in the myocardium of adults with 'Idiopathic' left ventricular dysfunction. Circulation 2005;111:887-893.

32. Kuhl U, Pauschinger M, Seeberg B, Lassner D, Noutsias M, PollerW, Schultheiss HP. Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation 2005;112:1965-1970.

33. Bowles NE, Ni J, Kearney DL, Pauschinger M, Schultheiss HP, McCarthy R, Hare J, Bricker JT, Bowles KR, Towbin JA. 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 2003;42:466-472.

34. MagnaniJW, Danik HJ, Dec GWJr, DiSalvoTG. Survival in biopsy-proven myocarditis: a long-term retrospective analysis of the histopathological, clinical, and hemodynamic predictors. Am Heart J 2006;151:463-470.

35. Caforio ALP, Keeling PJ,Zachara E, Mestroni L, Camerini F, Mann JM, Bottazzo GF, McKenna WJ. Evidence from family studies for autoimmunity in dilated cardiomyopathy. Lancet 1994;344:773-777.

36. Caforio AL, Mahon NG, Baig MK, Tona F, Murphy RT, Elliott PM, McKenna WJ. Prospective familial assessment in dilated cardiomyopathy. Cardiac autoantibodies predict disease development in asymptomatic relatives. Circulation 2007;115:76-83.

37. Deubner N, Berliner D, Schlipp A, Gelbrich G, Caforio AL, Felix SB, Fu M, Katus H, Angermann CE, Lohse MJ, Ertl G, Stork S, Jahns R. Etiology, Titre-Course, and Survival-Study Group. Cardiac betal-adrenoceptor autoantibodies in human heart disease: rationale and design of the Etiology, Titre-Course, and Survival (ETiCS) Study. Eur J Heart Fail 2010;12:753-762.

38. Baughman KL. Diagnosis of myocarditis: death of Dallas criteria. Circulation 2006; 113:593-595.

39. Wojnicz R, Nowalany-Kozielska E, Wodniecki J, Szczurek-Katanski K, Nozynski J, Zembala M, Rozek MM. Immunohistological diagnosis of myocarditis. Potential role of sarcolemmal induction of the MHC and ICAM-1 in the detection of autoimmune mediated myocyte injury. Eur Heart J 1998;19:1564-1572.

40. She RC, Hammond EH. Utility of immunofluorescence and electron microscopy in endomyocardial biopsies from patients with unexplained heart failure. Cardiovasc Pathol 2010;19:e99-e105.

41. Mahon NG, Madden BP, Caforio ALP, Elliott PM, Haven AJ, Keogh BE, Davies MJ, McKenna WJ. Immunohistochemical evidence of myocardial disease in apparently healthy relatives of patients with dilated cardiomyopathy.J Am Coll Cardiol 2002;39: 455-462.

42. Jin B, Ni H,Geshang Q, Li Y,Shen W,Shi H. HLA-DR4 antigen and idiopathic dilated cardiomyopathy susceptibility: a meta-analysis involving 11,761 subjects. Tissue Antigens 2011;77:107-111.

43. Okazaki T,Tanaka Y, Nishio R, MitsuiyeT, Mizoguchi A, Wang J, Ishida M, Hiai H, Matsumori A, Minato N, HonjoT. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med 2003;9: 1477-1483.

44. Eriksson U, Ricci R, Hunziker L, Kurrer MO, Oudit GY, Watts TH, Sonderegger I, Bachmaier K, Kopf M, Penninger JM. Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity. Nat Med 2003;9:1484-1490.

45. Goser S, Andrassy M, Buss SJ, Leuschner F, VolzCH, Ottl R, Zittrich S, Blaudeck N, | Hardt SE, Pfitzer G, Rose NR, Katus HA, KayaZ. Cardiac troponin I but not cardiac a troponin T induces severe autoimmune inflammation in the myocardium. Circula- 3 tion 2006;114:1693-1702. °

46. Ansari AA, Neckelmann N, Villinger F, Leung P, Danner DJ, Brar SS, Zhao S, 3 Gravanis MB, Mayne A, Gershwin ME, Herskowitz A. Epitope mapping of the 1 branched chain alpha-ketoacid dehydrogenase dihydrolipoyl transacylase 0 (BCKD-E2) protein that reacts with sera from patients with idiopathic dilated car- a diomyopathy. J Immunol 1994;153:4754 -4765. 9

47. Baba A, YoshikawaT, Fukuda Y, SugiyamaT, Shimada M, Akaishi M, Tsuchimoto K, 0 Ogawa S, Fu M. Autoantibodies against M2-muscarinic acetylcholine receptors: 5 new upstream targets in atrial fibrillation in patients with dilated cardiomyopathy.

Eur Heart J 2004;25:1108 -1115.

48. Borda ES, Sterin-Borda L. Antiadrenergic and muscarinic receptor antibodies in Chagas' cardiomyopathy. Int J Cardiol 1996;54:149-156.

49. Baba A, Yoshikawa T, Ogawa S. Autoantibodies produced against sarcolemmal Na-K-ATPase: possible upstream targets of arrhythmias and sudden death in patients with dilated cardiomyopathy. JAm Coll Cardiol 2002;40:1153-1159.

50. Caforio ALP, Bonifacio E, Stewart JT, Neglia D, Parodi O, Bottazzo GF, McKenna WJ. Novel organ-specific circulating cardiac autoantibodies in dilated cardiomyopathy. JAm Coll Cardiol 1990;15:1527-1534.

51. Caforio ALP, Grazzini M, Mann JM, Keeling PJ, Bottazzo GF, McKenna WJ, Schiaffino S. Identification of alpha and beta cardiac myosin heavy chain isoforms as major autoantigens in dilated cardiomyopathy. Circulation 1992;85:1734-1742.

52. Caforio ALP, Brucato A, Doria A, Brambilla G, Angelini A, Ghirardello A, Bottaro S, Tona F, Betterle C, Daliento L, Thiene G, Iliceto S. Anti-heart and anti-intercalated disk autoantibodies: evidence for autoimmunity in idiopathic recurrent acute pericarditis. Heart 2010;96:779-784.

53. Chiale PA, Rosenbaum MB, Elizari MV, Hjalmarson A, Magnusson Y, Wallukat G, HoebekeJ. High prevalence of antibodies against beta 1- and beta2-adrenoceptors in patients with primary electrical cardiac abnormalities. J Am Coll Cardiol 1995;26: 864-869.

54. Chiale PA, Ferrari I. Autoantibodies in Chagas' cardiomyopathy and arrhythmias. Autoimmunity 2001 ;34:205-210.

55. Christ T, Wettwer E, Dobrev D, Adolph E, Knaut M, Wallukat G, Ravens U. Autoantibodies against the beta1 adrenoceptor from patients with dilated cardiomyop-athy prolong action potential duration and enhance contractility in isolated cardiomyocytes. J Mol Cell Cardiol 2001;33:1515-1525.

56. Felix SB, Staudt A, Landsberger M, Grosse Y, Stangl V, Spielhagen T, Wallukat G, Wernecke KD, Baumann G, Stangl K. Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption. JAm Coll Cardiol 2002;39:646-652.

57. FletcherGF,WengerNK.Autoimmunestudiesinpatientswithprimarymyocardial disease. Circulation 1968;37:1032-1035.

58. Fu LX, Magnusson Y, Bergh CH, Liljeqvist JA, Waagstein F, Hjalmarson A, Hoebeke J. Localization of a functional autoimmune epitope on the muscarinic acetylcholine receptor-2 in patients with idiopathic dilated cardiomyopathy. J Clin Invest 1993;91:1964 _ 1968.

59. Fu ML. Characterization of anti-heart M2 muscarinic receptor antibodies—a combined clinical and experimental study. Mol Cell Biochem 1996;163-164:343_347.

60. Goldman JH, Keeling PJ, Warraich RS, Baig MK, Redwood SR, Dalla Libera L, Sanderson JE, Caforio ALP, McKenna WJ. Autoimmunity to alpha myosin in a subset of patients with idiopathic dilated cardiomyopathy. Br Heart J 1995;74: 598_603.

61. Iwata M, Yoshikawa T, Baba A, Anzai T, Mitamura H, Ogawa S. Autoantibodies against the second extracellular loop of beta1-adrenergic receptors predict ventricular tachycardia and sudden death in patients with idiopathic dilated cardiomy-opathy. J Am Coll Cardiol 2001;37:418_424.

62. Jahns R, Boivin V, Siegmund C, Inselmann G, Lohse MJ, Boege F. Autoantibodies activating human beta1-adrenergic receptors are associated with reduced cardiac function in chronic heart failure. Circulation 1999;99:649_654.

63. Jahns R, Boivin V, Krapf T, Wallukat G, Boege F, Lohse MJ. Modulation of beta1-adrenoceptor activity by domain-specific antibodies and heart failure-associated autoantibodies. J Am Coll Cardiol 2000;36:1280_1287.

64. Kirsner AB, Hess EV, Fowler NO. Immunologic findings in idiopathic cardiomyop-athy: a prospective serial study. Am Heart J 1973;86:625_630.

65. Klein R, Maisch B, Kochsiek K, Berg PA. Demonstration of organ specific antibodies against heart mitochondria (anti-M7) in sera from patients with some forms of heart diseases. Clin Exp Immunol 1984;58:283_292.

66. Landsberger M, Staudt A, Choudhury S,Trimpert C, Herda LR, Klingel K, Kandolf R, Schultheiss HP, Kroemer HK, Volker U, Felix SB. Potential role of antibodies against cardiac Kv channel-interacting protein 2 in dilated cardiomyopathy. Am Heart J 2008;156:92_99.

67. Latif N, Baker CS, Dunn MJ, Rose ML, Brady P, Yacoub MH. Frequency and speci-ficityofantiheartantibodiesinpatientswithdilatedcardiomyopathydetectedusing SDS-PAGE and western blotting. J Am Coll Cardiol 1993;22:1378_1384.

68. Leuschner F, Li J, Goser S, Reinhardt L, Ottl R, Bride P, Zehelein J, Pfitzer G, Remppis A, Giannitsis E, Katus HA, Kaya Z. Absence of auto-antibodies against cardiac troponin I predicts improvement of left ventricular function after acute myocardial infarction. Eur Heart J 2008;29:1949_1955.

69. Limas CJ, Limas C. Beta-receptor antibodies and genetics in dilated cardiomyopathy. Eur Heart J 1991;12(Suppl. D):175_177.

70. Liu HR, Zhao RR, Zhi JM, Wu BW, Fu ML. Screening of serum autoantibodies to cardiac beta1-adrenoceptors and M2-muscarinic acetylcholine receptors in 408 healthy subjects of varying ages. Autoimmunity 1999;29:43_51.

71. Magnusson Y, Wallukat G, Waagstein F, Hjalmarson A, HoebekeJ. Autoimmunity in idiopathic dilated cardiomyopathy. Characterization of antibodies against the beta 1-adrenoceptorwithpositivechronotropiceffect.Circulation1994;89:2760_2767.

72. Maisch B, Deeg P, Liebau G, Kochsiek K. Diagnostic relevance of humoral and cyto-toxic immune reactions in primary and secondary dilated cardiomyopathy. Am J Cardiol 1983;52:1072_1078.

73. Maisch B, Deeg P, Liebau G, Kochsiek K. Diagnostic relevance ofhumoral and cellmediated immune reactions in patients with viral myocarditis. Clin Exp Immun 1983; 48:533_545.

74. Matsui S, Fu ML, Shimizu M, Fukuoka T, Teraoka K, Takekoshi N, Murakami E, Hjalmarson A. Dilated cardiomyopathy defines serum autoantibodies against G-protein-coupled cardiovascular receptors. Autoimmunity 1995;21:85_88.

75. Matsui S, Fu M. Characteristic distribution of circulating autoantibodies against G-protein coupled cardiovascular receptors in patients with idiopathic dilated and hypertrophic cardiomyopathy. Int J Cardiol 1996;54:143_147.

76. Mobini R, Staudt A, Felix SB, Baumann G, Wallukat G, Deinum J, Svensson H, Hjalmarson A, Fu M. Hemodynamic improvement and removal of autoantibodies against beta1-adrenergic receptor by immunoadsorption therapy in dilated cardio-myopathy. J Autoimmun 2003;20:345_350.

77. Neumann DA, BurekCL, Baughman KL, Rose NR, HerskowitzA. Circulating heart-reactiveantibodiesinpatientswithmyocarditisorcardiomyopathy.JAmCollCardiol 1990;16:839_846.

78. NikolaevVO, Boivin V, Stork S, Angermann CE, Ertl G, Lohse MJ, Jahns R. A novel fluorescence method forthe rapid detection of functional beta1-adrenergic receptor autoantibodies in heart failure. J Am Coll Cardiol 2007;50:423_431.

79. Portig I, PankuweitS, Maisch B. Antibodies against stress proteins in sera of patients with dilated cardiomyopathy. J Mol Cell Cardiol 1997;29:2245_2251.

80. Shmilovich H, Danon A, Binah O, Roth A, Chen G, Wexler D, Keren G, George J. Autoantibodies to cardiac troponin I in patients with idiopathic dilated and ischemic cardiomyopathy. Int J Cardiol 2007;117:198_203.

81. Schultheiss HP, Bolte HD. Immunological analysis of auto-antibodies against the adenine nucleotide translocator in dilated cardiomyopathy. J Mol Cell Cardiol 1985;17:603_617.

82. Schultheiss HP, Kuhl U, Schwimmbeck P, Strauer BE. Biomolecular changes in dilated cardiomyopathy. In BaroldiG,Camerini F, Goodwin JF(eds), Advances in Cardiomyopathies. Berlin: Springer Verlag; 1990, 221 _234.

83. Schulze K, Becker BF, Schauer R, Schultheiss HP. Antibodies to ADP-ATP carrier— an autoantigen in myocarditis and dilated cardiomyopathy—impair cardiac function. Circulation 1990;81:959_969.

84. Staudt Y, Mobini R, Fu M, Felix SB, Kuhn JP, Staudt A. Beta1-adrenoceptor antibodies induce apoptosis in adult isolated cardiomyocytes. Eur J Pharmacol 2003; 466:1 _ 6.

85. Staudt A, Staudt Y, Dorr M, Bohm M, Knebel F, Hummel A, Wunderle L,Tiburcy M, Wernecke KD, Baumann G, Felix SB. Potential role of humoral immunity in cardiac dysfunction of patients suffering from dilated cardiomyopathy. J Am Coll Cardiol 2004;44:829_836.

86. Staudt A, Eichler P,TrimpertC, Felix SB, GreinacherA. Fc(gamma) receptors IIa on cardiomyocytes and their potential functional relevance in dilated cardiomyopathy. J Am Coll Cardiol 2007;49:1684_1692.

87. Staudt A, Herda LR, Trimpert C, Lubenow L, Landsberger M, Dorr M, Hummel A, Eckerle LG, Beug D, Muller C, Hoffmann W, Weitmann K, Klingel K, Kandolf R, Kroemer HK, GreinacherA, Felix SB. Fcgamma-receptor IIa polymorphism and the role of immunoadsorption in cardiac dysfunction in patients with dilated cardiomyopathy. Clin Pharmacol Ther 2010;87:452_458.

88. Stavrakis S, Kem DC, Patterson E, Lozano P, Huang S, Szabo B, Cunningham MW, Lazzara R, Yu X. Opposing cardiac effects of autoantibody activation of beta-adrenergic and M2 muscarinic receptors in cardiac-related diseases. Int J Cardiol 2011;148:331 _336.

89. Sterin-Borda L, Perez Leiros C, Wald M, Cremaschi G, Borda E. Antibodies to beta 1 and beta 2 adrenoreceptors in Chagas' disease. Clin Exp Immunol 1988;74:349_354.

90. Stork S, Boivin V, Horf R, Hein L, Lohse MJ, Angermann CE, Jahns R. Stimulating autoantibodies directed against the cardiac beta1-adrenergic receptor predict increased mortality in idiopathic cardiomyopathy. Am Heart J 2006;152:697_704.

91. Trimpert C, Herda LR, Eckerle LG, Pohle S, Muller C, Landsberger M, Felix SB, Staudt A. Immunoadsorption in dilated cardiomyopathy: long-term reduction of cardiodepressant antibodies. EurJ Clin Invest 2010;40:685_691. |

92. Wallukat G, Morwinski M, Kowal K, Förster A, Boewer V, Wollenberger A. Auto- a antibodies against the beta-adrenergic receptor in human myocarditis and dilated § cardiomyopathy: beta-adrenergic agonism without desensitization. Eur Heart J o 1991;12(Suppl. D):178_181. §

93. Wallukat G, Wollenberger A, Morwinski R, Pitschner HF. Anti-beta S

1-adrenoceptor autoantibodies with chronotropic activity from the serum of patients with dilated cardiomyopathy: mapping of epitopes in the first and second extracellular loops. J Mol Cell Cardiol 1995;27:397_406.

94. Wallukat G, Nissen E, Morwinski R, MullerJ. Autoantibodies against the beta- and to muscarinic receptors in cardiomyopathy. Herz 2000;25:261 _266.

95. Warraich RS, Noutsias M, KazakI, Seeberg B, Dunn MJ, Schultheiss HP, Yacoub MH, Kuhl U. Immunoglobulin G3 cardiac myosin autoantibodies correlate with left ventricular dysfunction in patients with dilated cardiomyopathy: immunoglobulin G3 and clinical correlates. Am Heart J 2002;143:1076_1084.

96. Warraich RS, Griffiths E, Falconar A, Pabbathi V, Bell C, Angelini G, Suleiman MS, Yacoub MH. Human cardiac myosin autoantibodies impair myocyte contractility: a cause-and-effect relationship. FASEBJ 2006;20:651 _660.

97. Wolff PG, Kuhl U, Schultheiss HP. Laminin distribution and autoantibodiestolaminin in dilated cardiomyopathy and myocarditis. Am Heart J 1989;117:1303_1309.

98. Zhang L, Hu D, Li J, Wu Y, Liu X, Yang X. Autoantibodies against the myocardial beta1-adrenergic and M2-muscarinic receptors in patients with congestive heart failure. Chin Med j (Engl) 2002;115:1127_1131.

99. Cooper LTJr, Menon S, Deng M, Mullin GM, Starling R, Jaski B, Bourge R, Dec GW, Hare J, Kao A, Leier C, Wagoner L, Zucker M, Skopecki H, Murali S, Mendez J, Caforio AL, Rodeheffer R, Mason JW, Ballman KV, Gersh BJ, Tazelaar HD, Edwards WD. Usefulness of immunosuppression for giant cell myocarditis. Am J Cardiol 2008;102:1535_1539.

100. Frustaci A, Chimenti C, Calabrese F, Pieroni M, Thiene G, Maseri A. Immunosuppressive therapy for active lymphocytic myocarditis: virological and immunologic profile of responders versus nonresponders. Circulation 2003;107:857_863.

101. 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;30:1995_2002.

102. Felix SB, Staudt A, Dorffel WV, Stangl V, Merkel K, Pohl M, Docke WD, Morgera S, Neumayer HH, Wernecke KD, Wallukat G, Stangl K, Baumann G. Hemodynamic effects of immunoadsorption and subsequent immunoglobulin substitution in dilated cardiomyopathy: three month results from a randomized trial. J Am Coll Cardiol 2000;35:1590_1598.

103. WojniczR,Nowalany-KozielskaE,WojciechowskaC,GlanowskaG,Wilczewski P, NiklewskiT,ZembalaM,PolonskiL,RozekMM,WodnieckiJ.Randomized,placebo controlledstudyforimmunosuppressivetreatmentofinflammatorydilatedcardio-myopathy. Two-year follow-up results. Circulation 2001;104:39_45.

104. HuberSA, GaunttCJ,Sakkinen P. Enteroviruses and myocarditis: viral pathogenesis through replication, cytokine induction, and immunopathogenicity. Adv Virus Res 1999;51:35-68.

105. Klingel K, Hohenadl C, Canu A, Albrecht M, Seemann M, MallG, Kandolf R. Ongoing enterovirus-induced myocarditis is associated with persistent heart muscle infection: quantitative analysis of virus replication, tissue damage, and inflammation. Proc Natl Acad Sci USA 1992;89:314-318.

106. Liu PP, Mason JW. Advances in the understanding of myocarditis. Circulation 2001; 104:1076-1082.

107. Woodruff JF. Viral myocarditis. A review. Am J Pathol 1980;101:425-484.

108. Malkiel S, Kuan AP, Diamond B. Autoimmunity in heart disease: mechanisms and genetic susceptibility. Mol Med Today 1996;2:336-342.

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

110. Neu N, Rose NR, Beisel KW, Herskowitz A, Gurri-Glass G, Craig SW. Cardiac myosin induces myocarditis in genetically predisposed mice. J Immunol 1987;139: 3630-3636.

111. Kodama M, Hanawa H, Saeki M, Hosono H, Inomata T, Suzuki K, Shibata A. Rat dilated cardiomyopathy after autoimmune giant cell myocarditis. Circ Res 1994; 75:278-284.

112. TanejaV, Behrens M, Cooper LT, Yamada S, Kita H, Redfield MM,Terzic A, David C. Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice. J Mol Cell Cardiol 2007;42:1054-1064.

113. Elliott JF, Liu J, Yuan ZN, Bautista-Lopez N, Wallbank SL, Suzuki K, Rayner D, Nation P, Robertson MA, Liu G, Kavanagh KM. Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic lAbeta knockout NOD mice. Proc Natl Acad Sci USA 2003;100:13447-13452.

114. Satoh M, Shimoda Y, Maesawa C, Akatsu T, Ishikawa Y, Minami Y, Hiramori K, Nakamura M. MyD88 signaling controls autoimmune myocarditis induction. Circulation 2006;113:258-265.

115. Guler ML, Ligons DL, Wang Y, Bianco M, Broman KW, Rose NR. Two autoimmune diabetes loci influencing T cell apoptosis control susceptibility to experimental autoimmune myocarditis. J Immunol 2005;174:2167-2173.

116. Lim JK, Glass WG, McDermott DH, Murphy PM. CCR5: no longer a 'good for nothing' gene-chemokine control of West Nile virus infection. Trends Immunol 2006;27:308-312.

117. MaekawaY,Ouzounian, Opavsky MA, Liu PP. Connecting the missing link between dilated cardiomyopathy and viral myocarditis: virus, cytoskeleton, and innate immunity. Circulation 2007;115:5-8.

118. Caforio AL, Goldman JH, Haven AJ, Baig KM, Libera LD, McKenna WJ. Circulating cardiac autoantibodies as markers of autoimmunity in clinical and biopsy-proven myocarditis. The Myocarditis Treatment Trial Investigators. Eur Heart J 1997;18: 270-275.

119. Jahns R, Boivin V, Lohse MJ. Beta1-adrenergic receptor function, autoimmunity, and pathogenesis of dilated cardiomyopathy. Trends Cardiovasc Med 2006;16:20-24.

120. Cooper LT, Baughman KL, Feldman AM, Frustaci A,Jessup M, Kuhl U, Levine GN, Narula J, Starling RC,TowbinJ,Virmani R.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. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. J Am Coll Cardiol 2007;50:1914-1931.

121. Bultmann BD, Klingel K, Nabauer M, Wallwiener D, Kandolf R. High prevalence of viral genomes and inflammation in peripartum cardiomyopathy. Am J Obstet Gynecol 2005;193:363-365.

122. UkenaC, Mahfoud F, Kindermann I, Kandolf R, Kindermann M, Bohm M. Prognostic electrocardiographic parameters in patients with suspected myocarditis. Eur J Heart Fail 2011;13:398-405.

123. Felker GM, Boehmer JP, Hruban RH, Hutchins GM, Kasper EK, Baughman KL, Hare JM. Echocardiographic findings in fulminant and acute myocarditis. J Am Coll Cardiol 2000;36:227-232.

124. Pinamonti B, Alberti E, Cigalotto A, Dreas L, Salvi A, Silvestri F, Camerini F. Echocardiography findings in myocarditis. Am J Cardiol 1988;62:285-291.

125. Yilmaz A, Klingel K, Kandolf R, Sechtem U. Imaging in inflammatory heart disease: from the past to current clinical practice. Hellenic J Cardiol 2009;50:449-460.

126. O'ConnellJB, Henkin RE, Robinson JA, Subramanian R, Scanlon PJ, Gunnar RM. Gallium-67 imaging in patients with dilated cardiomyopathy and biopsy-proven myocarditis. Circulation 1984;70:58-62.

127. Dec GW, Palacios I, Yasuda T, FallonJT, Khaw BA, Strauss HW, Haber E. Antimyo-sin antibody cardiac imaging: its role in the diagnosis of myocarditis. JAm Coll Cardiol 1990;16:97-104.

128. Ardehali H, Qasim A, CappolaT, Howard D, Hruban R, HareJM, Baughman KL, Kasper EK. Endomyocardial biopsy plays a role in diagnosing patients with unexplained cardiomyopathy. Am HeartJ 2004;147:919-923.

129. Tellier P, Paycha F, Antony I, Nitenberg A, Valeyre D, Foult JM, Battesti JP. Reversibility by dipyridamole ofthallium-201 myocardial scan defects in patients with sar-coidosis. Am JMed1988;85:189-193.

130. Fields CL, Ossorio MA, Roy TM, Denny DM, Varga DW. Thallium-201 scintigraphy in the diagnosis and management of myocardial sarcoidosis. South Med J 1990;83: 339-342.

131. Le Guludec D, Menad F, Faraggi M, Weinmann P, Battesti JP, Valeyre D. Myocardial sarcoidosis. Clinical value oftechnetium-99 m sestamibi tomoscintigraphy. Chest 1994;106:1675-1682.

132. Ohira H, Tsujino I, Yoshinaga K. (1)F-Fluoro-2-deoxyglucose positron emission tomography in cardiac sarcoidosis. EurjNudMedMol Imaging2011;38:1773-1783.

133. Baccouche H, Mahrholdt H, Meinhardt G, Merher R, Voehringer M, Hill S, Klingel K, KandolfR,SechtemU,YilmazA.Diagnosticsynergyofnon-invasivecardiovascular magnetic resonance and invasive endomyocardial biopsy in troponin-positive patients without coronary artery disease. Eur Heart J 2009;30:2869-2879.

134. Abdel-Aty H, Boye P, Zagrosek A, Wassmuth R, Kumar A, Messroghli D, Bock P, Dietz R, Friedrich MG, Schulz-Menger J. Diagnostic performance of cardiovascular magnetic resonance in patients with suspected acute myocarditis: comparison of different approaches. JAm Coll Cardiol 2005;45:1815-1822.

135. Aletras AH, Kellman P, Derbyshire JA, Arai AE. ACUT2E TSE-SSFP: a hybrid method for T2-weighted imaging of edema in the heart. Magn Reson Med 2008; 59:229-235.

136. Friedrich MG, Strohm O, Schulz-MengerJ, Marciniak H, Luft FC, Dietz R. Contrast media-enhanced magnetic resonance imaging visualizes myocardial changes in the course of viral myocarditis. Circulation 1998;97:1802-1809.

137. Gutberlet M, Spors B, Thoma T, Bertram H, Denecke T, Felix R, Noutsias M, Schultheiss HP, Kuhl U. Suspected chronic myocarditis at cardiac MR: diagnostic accuracy and association with immunohistologically detected inflammation and viral persistence. Radiology 2008;246:401 -409.

138. Yilmaz A, Mahrholdt H, Athanasiadis A, Vogelsberg H, Meinhardt G, Voehringer M, Kispert EM, Deluigi C, Baccouche H, Spodarev E, Klingel K, Kandolf R, Sechtem U. Coronary vasospasm as the underlying cause for chest pain in patients with PVB19 myocarditis. Heart 2008;94:1456-1463.

139. Yilmaz A, Kindermann I, Kindermann M, Mahfoud F, UkenaC, Athanasiadis A, Hill S, Mahrholdt H, Voehringer M, Schieber M, Klingel K, Kandolf R, Bohm M, Sechtem U. Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance. Circulation 2010;122: 900-909.

140. Lauer B, Schannwell M, Kuhl U, Strauer BE, Schultheiss HP. Antimyosin autoanti-bodies are associated with deterioration of systolic and diastolic left ventricular function in patients with chronic myocarditis. J Am Coll Cardiol 2000;35:1106-1110.

141. Lauer B, Niederau C, Kuhl U, Schannwell M, Pauschinger M, Strauer BE, SchultheissHP.CardiactroponinTinpatientswithclinicallysuspectedmyocarditis. JAm Coll Cardiol 1997;30:1354-1359.

142. HeymansS. Myocarditis and heart failure: need for better diagnostic, predictive, and therapeutic tools. EurHeartJ2007;28:1279-1280.

143. Jensen J, Ma LP, Fu ML, Svaninger D, Lundberg PA, Hammarsten O. Inflammation increases NT-proBNP and the NT-proBNP/BNP ratio. Clin Res Cardiol 2010;99: 445-452.

144. Deswal A, Petersen NJ, Feldman AM, YoungJB, White BG, Mann DL. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation 2001;103:2055-2059.

145. Deardorff R, Spinale F. Cytokines and matrix metalloproteinases as potential bio-markers in chronic heart failure. Biomark Med 2009;3:513-523.

146. Emdin M, Vittorini S, PassinoC,Clerico A. Old and new biomarkers of heart failure. Eur J Heart Fail 2009;11:331-335.

147. Mahfoud F, Gartner B, Kindermann M, Ukena C, Gadomski K, Klingel K, Kandolf R, Bohm M, Kindermann I. Virus serology in patients with suspected myocarditis: utility or futility?. Eur Heart J 2011;32:897-903.

148. Holzmann M, Nicko A, Kuhl U, Noutsias M, Poller W, Hoffmann W, Morguet A, Witzenbichler B, Tschope C, Schultheiss HP, Pauschinger M. 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;118:1722-1728.

149. Parrillo JE, Aretz HT, Palacios I, Fallon JT, Block PC. The results of transvenous endomyocardial biopsy can frequently be used to diagnose myocardial diseases in patients with idiopathic heart failure. Endomyocardial biopsies in 100 consecutive patients revealed a substantial incidence of myocarditis. Circulation 1984;69: 93-101.

150. McCarthy RE 3rd, Boehmer JP, Hruban RH, Hutchins GM, Kasper EK, HareJM, Baughman KL. Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N Engl J Med 2000;342:690-695.

151. Mahrholdt H, Wagner A, Deluigi CC, Kispert E, Hager S, Meinhardt G, Vogelsberg H, Fritz P, Dippon J, Bock CT, Klingel K, Kandolf R, Sechtem U. Presentation, patterns of myocardial damage, and clinical course of viral myocarditis. Circulation 2006;114:1581 _1590.

152. Kuhl U, Lassner D, von Schlippenbach J, Poller W, Schultheiss HP. Interferon-beta improves survival in Enterovirus-associated cardiomyopathy. J Am Coll Cardiol 2012; 60:1295_1296.

153. Grun S,Schumm J, Greulich S, Wagner A, Schneider S, Bruder O, Kispert E-M, Hill S, Ong P, Klingel K, Kandolf R, Sechtem U, Mahrholdt H. Long-term follow-up of biopsy-proven viral myocarditis. Predictors of mortality and incomplete recovery. J Am Coll Cardiol 2012;59:1604_1615.

154. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Boehm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Kober L, Lip GYH, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Roennevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A.; ESC committee for practice guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA). Eur Heart] 2012;33:1787_1847.

155. Mirabel M, Luyt CE, Leprince P, Trouillet JL, Leger P, Pavie A, Chastre J, Combes A. Outcomes, long-term quality of life, and psychologic assessment of fulminant myo-carditispatientsrescuedbymechanicalcirculatorysupport.CritCareMed2011;39: 1029_1035.

156. Chen YS, Wang MJ, Chou NK, Han YY, Chiu IS, Lin FY, Chu SH, Ko WJ. Rescue for acute myocarditis with shock by extracorporeal membrane oxygenation. Ann Thorac Surg 1999;68:2220_2224.

157. Hsu KH, Chi NH, Yu HY, Wang CH, Huang SC, Wang SS, Ko WJ, Chen YS. Extracorporeal membranous oxygenation support for acute fulminant myocarditis: analysis of a single center's experience. Eur J CardiothoracSurg 2011;e-pub, 18 February. doi:10.1016/j.ejcts.2010.12.050.

158. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL, Smith SC Jr, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B.; American College of Cardiology/American Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association and the Heart Rhythm Society. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death—executive summary: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Eur Heart J 2006;27: 2099_2140.

159. Vardas PE, Auricchio A, Blanc JJ, Daubert JC, Drexler H, Ector H, Gasparini M, Linde C, Morgado FB, Oto A, Sutton R, Trusz-Gluza M.; European Society of Cardiology; European Heart Rhythm Association. Guidelines for cardiac pacing and cardiac resynchronization therapy: The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in collaboration with the European Heart Rhythm Association. Eur Heart J 2007;28:2256_2295.

160. Dickstein K, Vardas PE, Auricchio A, Daubert JC, Linde C, McMurray J, Ponikowski P, Priori SG, Sutton R, van Veldhuisen DJ; ESC Committee for Practice Guidelines (CPG), Vahanian A, Auricchio A, BaxJ, Ceconi C, Dean V, Filippatos G, Funck-Brentano C, Hobbs R, Kearney P, McDonagh T, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas P, Widimsky P; Document Reviewers, Tendera M, Anker SD, Blanc JJ, Gasparini M, Hoes AW, Israel CW, Kalarus Z, Merkely B, Swedberg K, Camm AJ. 2010 Focused Update of ESC Guidelines on device therapy in heart failure: an update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC guidelines for cardiac and resynchronization therapy. Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association. Eur Heart J 2010;31:2677_2687.

161. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, Hindricks G, Kirchhof P; ESC Committee for Practice Guidelines (CPG), BaxJJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S; Document Reviewers, Vardas P, Al-Attar N, Alfieri O, Angelini A, Blomstrom-Lundqvist C, Colonna P, De Sutter J, Ernst S, Goette A, Gorenek B, Hatala R, Heidbuchel H, Heldal M, Kristensen SD, Kolh P, Le Heuzey JY,

Mavrakis H, Mont L, Filardi PP, Ponikowski P, Prendergast B, Rutten FH, Schotten U, Van Gelder IC, Verbeugt FW. 2012 focused update ofthe ESC Guidelines for the management of atrial fibrillation: an update ofthe 2010 ESC Guidelines for the management of atrialfibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719-2747.

162. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le HeuzeyJY, Ponikowski P, Rutten FH. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation ofthe European Society of Cardiology (ESC). Eur Heart J 2010; 31:2369-2429.

163. Prochnau D, Surber R, Kuehnert H, Heinke M, Klein HU, Figulla HR. Successful use of a wearable cardioverter-defibrillator in myocarditis with normal ejection fraction. Clin Res Cardiol 2010;99:129-131.

164. Basso C, Carturan E, Corrado D, Thiene G. Myocarditis and dilated cardiomyop-athy in athletes: diagnosis, management and recommendations for sport activity. Cardiol Clin 2007;25:423-429.

165. PellicciaA, Fagard R, Bj0rnstad HH, Anastassakis A, Arbustini E, Assanelli D, Biffi A, Borjesson M, Carre F, Corrado D, Delise P, Dorwarth U, Hirth A, Heidbuchel H, Hoffmann E, Mellwig KP, Panhuyzen-Goedkoop N, Pisani A, Solberg EE, van-Buuren F, Vanhees L, Blomstrom-Lundqvist C, Deligiannis A, Dugmore D, Glikson M, Hoff PI, Hoffmann A, Hoffmann E, Horstkotte D, Nordrehaug JE, Oudhof J, McKenna WJ, Penco M, Priori S, Reybrouck T, Senden J, Spataro A, Thiene G; Study Group of Sports Cardiology ofthe Working Group of Cardiac Rehabilitation and Exercise Physiology; Working Group of Myocardial and Pericardial Diseases ofthe European Society of Cardiology. Recommendations for competitive sports participation in athletes with cardiovascular disease: a consensus document from the Study Group of Sports Cardiology ofthe Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2005;26: 1422-1445.

166. MartinoTA, Liu P,Sole MJ. Viral infection and the pathogenesis of dilated cardiomyopathy. Circ Res 1994;74:182-188.

167. Krueger GR, Ablashi DV. Human herpesvirus-6: a short review of its biological behaviour. Intervirology 2003;46:257-269.

168. Kuhl U, Pauschinger M, Schwimmbeck PL, Seeberg B, Lober C, Noutsias M, Poller W, Schultheiss HP. 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 -2798.

169. Schultheiss HP.: The Effect of Subcutaneous Treatment with Interferon-Beta-1b Over 24 Weeks on Safety, Virus Elimination and Clinical Outcome in Patients with Chronic Viral Cardiomyopathy. Paper presented at: American Heart Association Scientific Sessions; November 11,2008; New Orleans, LA.

170. Orange JS, Hossny EM, Weiler CR, Ballow M, Berger M, Bonilla FA, Buckley R, Chinen J, El-Gamal Y, Mazer BD, Nelson RP Jr, Patel DD, Secord E, Sorensen RU, Wasserman RL, Cunningham-Rundles C.; Primary Immunodeficiency Committee ofthe American Academy of Allergy, Asthma and Immunology. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol 2006;117(4 suppl):S525-S553.

171. Gullestad L, Aass H, Fjeld JG, Wikeby L, Andreassen AK, Ihlen H, Simonsen S, KjekshusJ, Nitter-Hauge S, Ueland T, Lien E, Fr0land SS, Aukrust P. Immunomodu-lating therapy with intravenous immunoglobulin in patients with chronic heart failure. Circulation 2001;103:220-225.

172. 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. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation 2001;103:2254-2259.

173. Tzartos SJ, Bitzopoulou K, Gavra IM, Kordas G, Jacobson L, Kostelidou K, Lagoumintzis G, Lazos O, Poulas K, Sideris S, Sotiriadis A, Trakas N, Zisimopoulou P. Antigen-specific apheresis of pathogenic autoantibodies from myasthenia gravis sera. Ann N YAcad Sci 2008;1132:291 -299.

174. Bygren P, Freiburghaus C, Lindholm T, Simonsen O,Thysell H, Wieslander J. Goodpasture's syndrome treated with staphylococcal protein A immunoadsorption. Lancet 1985;2:1295-1296.

175. Palmer A, Gjorstrup P, Severn A, Welsh K, Taube D. Treatment of systemic lupus erythematodes by extracorporeal immunoadsorption. Lancet 1988;2:272.

176. Parrillo JE, Cunnion RE, Epstein SE, Parker MM, Suffredini AF, Brenner M, Schaer GL, Palmeri ST, Cannon RO, Alling D, Wittes JT, Ferrans VJ, Rodriguez RE, Fauci AS. A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy. N Engl J Med 1989;321:1061 -1068.