The management of myocarditis - European Heart Journal

REVIEW

Frontiers in cardiovascular medicine

The management of myocarditisHeinz-Peter Schultheiss 1,2*, Uwe Kuhl1,2, and Leslie T. Cooper1,2

1Charite Hospital, Berlin, Germany; and 2Mayo Clinic, Rochester, MN, USA

Received 2 January 2011; revised 25 March 2011; accepted 28 April 2011; online publish-ahead-of-print 23 June 2011

Despite considerable advances in our understanding of myocarditis pathogenesis, the clinical management of myocarditis has changedrelatively little in the last few years. This review aims to help bridge the widening gap between recent mechanistic insights, which arelargely derived from animal models, and their potential impact on disease burden. We illustrate the pathogenenic mechanisms that areprime targets for novel therapeutic interventions. Pathway and pathogen-specific molecular diagnostic tests have expanded the role forendomyocardial biopsy. State of the art cardiac magnetic resonance imaging can now provide non-invasive tissue characterization and localizeinflammatory infiltrates but imaging techniques are misleading if infectious agents are involved. We emphasize the gaps in our current clinicalknowledge, particularly with respect to aetiology-based therapy, and suggest opportunities for high impact, translational investigations.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywords Myocarditis pathogenesis † Clinical management

Aetiology of myocarditisAetiologies of myocarditis include a number of infectious and non-infectious agents such as viruses, bacteria, protozoa, fungi, toxins,myocardial involvement in systemic diseases, or physical condition,but often the underlying cause cannot be identified (Table 1).Drugs can induce myocardial inflammation by either direct toxiceffects on heart tissue or by inducing hypersensitivity reactions,which are often associated with an eosinophilic myocarditis.1 Eosi-nophils are also observed in myocardial inflammatory processeswhich are associated with Churg–Strauss or hypereosinophilicsyndromes, vaccination against smallpox or caused by helminthicand parasitic infections. Myocardial involvement may be causedby granulomatous and systemic diseases or (auto)immune pro-cesses with often unknown pathogenetic mechanisms, but allthese aetiologies are far less common than virus-induced myocar-ditis or post-infectious inflammatory cardiomyopathy.2– 4 Apartfrom enteroviruses, which traditionally have been considered themost common agent in myocarditis and dilated cardiomyopathy,distinct RNA- and DNA viruses and virus subtypes have beenidentified with varying degrees of frequency (Table 1).5– 22

Although viral infections can cause serious human diseases, themajority of viral infections are asymptomatic or oligosymptomaticand therefore, such infections are frequently not recognized aspossible causes of delayed onset of heart disease.23 In the past,viral myocarditis and chronic viral heart disease have therefore

more often been a clinically derived diagnosis of exclusion,rather than a specifically proven diagnosis. Beside the temporarychanges of virus epidemics and the geographical differences inthe aetiological profiles of viruses, the presence of myocarditicand non-myocarditic virus variants, the enormous variability ofclinical symptoms of viral heart disease, which may range fromasymptomatic presentation to manifest heart failure, and last butnot least the lack of consequent diagnostic efforts for completevirus analysis have hampered an early identification of afflictedpatients and thus have prevented the generation of validepidemiological data.

Pathogenic mechanismsFor many viruses, the exact cardiac infection site and the under-lying pathogenic mechanisms are unknown. Most information onthe pathophysiology of viral heart disease and post-infectious auto-immune myocarditis in both rodent models and humans is knownfrom enteroviral infections such as coxsackievirus B3. Entero-viruses enter the host through the gastrointestinal or respiratorytract, reside in the reticuloendothelial system as an extracardiacreservoir, and attack heart tissue as a secondary target organ.After enterovirus internalization, the negative strand RNA isreversely transcribed into a positive strand for subsequent virusreplication.22,24 A direct virus-related cytolysis of cardiomyocytes

* Corresponding author. Tel: +49 308 445 2344; Fax: +49 308 445 3565; Email: [email protected]

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: [email protected]

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is already detected before any inflammatory infiltrate develops andappears to be decisive in fulminant cases of myocarditis.25,26

In contrast to enteroviruses, which primarily infect and injurecardiomyocytes, other frequent cardiotropic viruses such as ery-throviruses or human herpesvirus 6 A/B infect the vascular endo-thelial cells (ECs).27– 30 Following primary infection in childhood,erythroviruses, including its genotype 1 (parvovirus B19, B19V),may reside asymptomatically in the bone marrow of a vast majorityof the adult population. The in vivo tropism of B19V infection isregulated by a number of determinants and persistent infectionand replication is mainly restricted to erythroid progenitor cells,but also EC, by the distribution of the primary erythroviral recep-tor, the P antigen, and reported co-receptors-like integrin a5b1and the KU80 protein.31–33 With respect to the heart tissue, ery-throviruses do not infect cardiomyocytes. In biopsy samples ofpatients with fulminant myocarditis or sudden onset heart failure,B19V genomes have been localized in EC of venuoles, smallarteries, or arterioles.27 In chronic inflammatory cardiomyopathy,B19V infection is predominantly detected in ECs of smallcapillaries.28,29

Endothelial cell infection is associated with endothelial dysfunc-tion which predicts long-term disease progression in chronic heartfailure.34 –39 The pathogenetic mechanisms by which B19 exertsendothelial damage are complex and may involve cytotoxicity ofthe non-structural protein 1, transactivation of interleukin-6(IL-6), and tumour necrosis factor a, as well as induction of apop-tosis as shown in vitro.40 –45. Recently, we could show that B19V isreleased from the bone marrow by infected capillary precursorcells and that interferon-b (IFN-b) improves viability of B19Vinfected human ECs.46 Since endothelial dysfunction and respectivesymptoms improved upon IFN-b treatment while both remained

unchanged in non-treated patients providing evidence thatB19-induced damage of ECs is at least partially mediated viadirect virus–cell interaction.46

HHV-6 is a lymphotropic virus with tropism mainly for CD4+and CD8+ T cells, B cells, and natural killer cells. AlthoughHHV-6 is thought of as a lymphotropic virus, it also can infectvascular endothelium.47,48 Several studies have identifiedHHV-6-specific DNA in the vascular endothelium in vivo, andsuggested EC damage by the virus.48 –51 It has been suggestedthat ECs and cardiac myocytes might be an important reservoirfor viral latency and reactivation.47

Similar to the other herpes viruses, HHV-6 becomes frequentlyreactivated by infections or drugs with subacute clinical presenta-tions, especially in acquired or drug-induced immunodeficiencies(e.g. transplant recipients) or in patients with autoimmune dis-orders. It has been suggested that often HHV-6 rather enhancesthe pathogenicity of other viruses than being a pathogen itself. Ina minority of patients (,1%), HHV-6 is integrated into thechromosome of all nucleated cells resulting in lifelong persistenceof HHV-6 which is then passed to 50% of the progenies.

Since distinct cardiac target structures are affected by differentinfectious agents and post-infectious mechanisms, viral myocarditis(viral heart disease) and post-infectious immune myocarditispresent with heterogenic clinical phenotypes. If the contractileapparatus (cardiomyocytes) or interstitial cells and matrixstructures (e.g. dystrophin) are preferentially involved, ventriculardilatation and systolic heart failure with progression towards post-myocarditic dilated cardiomyopathy (DCM) is directly causedby cytolytic viruses or viral proteases.52 Involvement ofvascular tissue (ECs) by other viruses may affect myocardialcontractility indirectly, e.g. as a consequence of endothelial

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Table 1 Causes of myocarditis

Infectious causes Non-infectious causes

RNA viruses: picornaviruses (coxsackie A + B, echovirus, poliovirus,hepatitis virus), orthomyxovirus (influenza), paramyxoviruses(respiratory syncitial virus, mumps), togaviruses (rubella), flaviviruses(dengue fever, yellow fever)

Autoimmune diseases: dematomyositis, inflammatory bowel disease,rheumatoid arthritis, sjogren syndrome, systemic lupus erythematodes,Wegener’s granulomatosis, giant cell myocarditis

DNA viruses: adenovirus (A 1, 2 ,3, and 5), erythrovirus [1 (B19V) and 2],herpesviruses (human herpes virus 6 A/B, cytomegalievirus, Epstein-Barrvirus, varicella-zoster virus), retrovirus (HIV)

Drugs: aminophyllin, amphetamine, anthracyclin, catecholamines,chloramphenicol, cocain cyclophosphamid, doxorubicin, 5-fluoruracil,mesylate, methylsergit, phenytoin, trastuzumab, zidovudine

Bacteria: chlamydia (C. pneumonia/psittacosis) haemophilus influence,legionella, pneumophilia, brucella clostridium, francisella tularensis,neisseria meningitis, mycobacterium (tuberculosis), salmonella,staphylococcus, streptococcus A, S. pneumonia, tularemia, tetanus,syphilis, Vibrio cholera

Hypersensitivity reactions (drugs): azitromycin, benzodiazepines, clozapine,cephalosporins, dapsone, dobutamin, lithium, diuretics, thiazide,methyldopa, mexiletine, Streptomycin, sulfonamides, non-steroidalanti-inflammational drugs, tetanus toxoid, tetracycline, tricyclicantidepressiva

Spirocheta: Borrelia recurrentis, leptospira, Treponema pallidum Hypersensitivity reactions (venomes): bee, wasp, black widow spider,scorpion, snakes

Reckettsia: Coxiella burnetii, R. rickettsii/prowazekii Systemic diseases: Churg-Strauss syndrome, collagen diseases, sarcoidosis,Kawasaki disease, scleroderma

Fungi: actinomyces, aspergillus, candida, cryptococcus, histoplasma,nocardia

Others: heart stroke, hypothermia, transplant rejection, radiation injury

Protozoa: Entamoeba histolytica, leishmania, Plasmodium falciparum,Trypanosoma cruzi, Trypanosoma brucei, Toxoplasma gondii

Helmintic: ascaris, Echinococcus granulosus, Schistosoma, Trichinella spiralis,Wuchereria bancrofti

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dysfunction-associated chronic ischaemia with less often early sys-tolic ventricular dysfunction and possibly slower progressiontowards systolic heart failure.36,46,53,54 Often patients with EC

infection complain for symptoms associated with vasospasm andEC-dysfunction despite normal or nearly normal left ventricularfunction. The contribution of the virus loads and effects of different

Figure 1 Distinct phases of myocardial injury in infectious and post-infectious myocarditis. Myocarditis is an inflammatory disease of thecardiac muscle caused by myocardial infiltration of immunocompetent cells following any kind of cardiac injury. Acute myocarditis is often aresult of a viral infection that produces myocardial necrosis and triggers an immune response to eliminate the infectious agent (healed myo-carditis and/or dilated cardiomyopathy). Chronic myocardial injury may be caused by post-infectious immune or autoimmune processes[indlammatory cardiomyopathy (DCMi)], be associated with systemic autoimmune diseases or develop by a persisting virus infection (viralheart disease), which, in the long run, are responsible for persistent or progressive ventricular dysfunction, arrhythmias, and cardiac complaints.The disease often presents as an acute form of dilated cardiomyopathy but due to its broad spectrum of presentation the clinical diagnosis isfrequently misleading. If the underlying infectious or immune-mediated causes of the disease are carefully defined by clinical and biopsy-basedtools, specific immunosuppressive and antiviral treatment options in addition to basic symptomatic therapy may improve prognosis in a numberof patients with acute and chronic disease.

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virus subtypes are still poorly understood.55 Consequently, distinctviruses with different infection sites in cardiac tissue do not onlyexplain the heterogenic and unpredictable course of viral heartdisease with respect to the expression of its phenotype andearly or late clinical presentation but also determine indicationand response to treatment, or prognosis.

Direct cytopathic injury, apoptosis, activation of the innate andadaptive immune system, and cardiac remodelling have all beenimplicated in the pathogenesis of viral myocarditis. It developswith pathologically distinct phases which time depending deter-mine both clinical presentation and indication for symptomaticor specific treatment strategies (Figure 1).3,56

The early phase of viral myocarditis is initiated by infection ofcardiac myocytes, fibroblasts, or ECs through receptor-mediatedendocytosis.57 –59 Acute myocardial injury can result from eitherdirect virus-mediated lytic processes or are caused by the emer-ging antiviral immune response (Figure 1).60,61 In fulminant casesof myocarditis, resulting myocyte necrosis may cause a significantloss of contractile tissue, which is accompanied by rapidly

developing cardiac failure and early death of the host (earlyphase). Cytokines released by macrophages and activation ofnatural killer cells that directly kill virus-infected heart cellsthrough perforin or granzyme-mediated lysis contribute to earlymyocardial lesions and impaired myocardial function.

The activation of antigen-specific immunity mediated by T-cells,B-cells, and antibody production (adaptive immune response)initiates the second phase of virus clearance (Figure 2).62– 64 Therecruitment of leucocytes to sites of infection is crucial to theinflammatory clearance of pathogens. Various molecules maycontrol inflammatory cell trafficking including chemokines, a familyof low-molecular-weight proteins involved in adherence of inflam-matory cells to activated endothelium and leucocyte chemotaxis(Table 2). Chemokines are important for containment of the infec-tious agents but may extend tissue injury, if attracted inflammatorycells produce pathological mediators that injure terminally differen-tiated cardiomyocytes or induce extensive fibrosis (e.g. TGF-b).65

T-regulatory cells are also important in inhibiting the pathogen-esis of acute viral myocarditis and subsequent dilated

Figure 2 Infection of cardiac endothelial cells or cardiac myocytes by virus causes direct cellular damage and subsequently an innate andadaptive immune response, all of which contribute to cardiomyopathy. Cardiomyopathy from viral injury and the subsequent immune reactioncan include diastolic as well as systolic dysfunction.


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cardiomyopathy. Adoptive transfer of T-regulatory cells protectsmice from coxsackievirus B3 (CVB3)-induced myocarditisthrough the transforming growth factor b-coxsackie-adenovirusreceptor pathway and thus suppresses the immune response tocardiac tissue.66 Coxsackievirus B3 causes severe myocarditis inBALB/c mice. BALB/c mice receiving CD4(+) CD25(+) T regulat-ory cells from gd(+) T-cell-depleted donors developed signifi-cantly less myocarditis and CD4(+) Th1 cell responsescompared with mice receiving equal numbers of CD4(+)CD25(+) cells from infected gd (+) T-cell-sufficient animals.This study showed that gd (+) cells promote CD4(+)IFN-g(+) acute and memory responses by limiting FoxP3(+) Tregulatory cell activation.67 Finally, male BALB/c mice infectedwith CVB3 develop more severe acute inflammation in the heartcompared with females due to fewer T regulatory cells andTim-3(+) M2 macrophages.68

Negative immune modulation, an important property of anintact immune system to prevent excessive tissue damage by anoverwhelming immune response, normally occurs rapidly aftersuccessful elimination of the infectious pathogens. Under certaincircumstances, chronic immune stimulation and autoimmunitymay result from incompletely cleared virus infection or in responseto the virus- and immune-mediated chronic tissue damage,respectively. Both cellular and humeral inflammatory processesmay contribute to the progression of chronic myocardialinjury.69 The underlying pathological processes are not well

understood but in chronic inflammatory cardiomyopathy, sub-groups of patients may benefit from immunosuppression.

If viral infection and autoimmune processes have resolved, themagnitude of the remaining tissue damage determines the furthercourse of the disease.70 This late phase of post-infectious diseaseis distinguished by cardiac remodelling, progressive dilitation, andchronic heart failure. Aetiology-specific treatment is probably notuseful but only standard heart failure medication and/or devicesmay prevent or delay progression and improve prognosis.

Genetic predisposition is a likely factor in some cases of myocar-ditis, although direct evidence in human disease is lacking. Inmurine models of myocarditis, genetic predisposition to Th1,Th2, and Th17 cytokine responses influence the severity andtime course of viral infection (reviewed in Rose 2009).71 Similarly,truncations in the 5′ untranslated region of the Coxsackie B virusgenome can lower viral replication rate and lead to chronic infec-tion.72 Few genomic studies in human disease have been per-formed in part due to relatively small patient cohorts and lack oflarge multi-centre biobanks linked to well-characterized clinicalphenotypes with outcome data.

Autoimmune myocarditis, exemplified by giant cell myocarditis,usually occurs without an identified trigger such as a viral infection;although vial infection can amplify naturally occurring autoantibodiesand autoreactive T cells. The time course of cytokine and chemokineexpression following experimental autoimmune myocarditis in theLewis rat is similar to the pattern observed in models of severe

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Table 2 Potential pathogenesis-directed therapies depend on the phase of myocarditis. At all phases, guideline basedtreatments appropriate to the clinical scenario are indicated

Phase of disease Proposed mechanism and infectious agents Potential therapy

Symptomatic heart failure medication

Acute myocarditis (early phase) Direct cytopathic injury Antiviral agents?Innate immune system activation (macrophages,

NK-cells, and cytokines)Antiviral agents? intravenous immune

globulin?

Post-infectious (auto)immunity Adaptive immune response (T-cells, B-cells,antibody production)

Immune modulationSteroidsImmunoadsorptionIntravenous immune globulinMuronomab-CD3

Chronic viral cardiomyopathy Enterovirus Interferon-bAdenovirus Interferon-bErythro-/parvovirus Intravenous immune globulin (acute infection)

Type I interferons (chronic infection)

Human herpesvirus 6 Val-/GanciclovirCytomegalovirus Val-/ganciclovir

FoscanetCidovir

Ebstein-Barr virus Val-/ganciclovirFoscanetCidovovir

Herpes simplex virus AciclovirVaricella AciclovirRespiratory syntitial virus RibavirinHepatitis C virus Pegylated Interferon-a + ribavirinHIV Anti-retrovirals


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enteroviral myocarditis (Figure 3)73 The early rise in pro-inflammatorycytokines such as Il-2 and IFN-g, is followed by regulatory cytokinessuch as IL-10 and profibrotic cytokines like TGF-b1.65,74–76

However, in other models of autoimmune and viral myocarditisgender, hormone milieu, and the nature of the initial innateimmune response impact the severity and time course of subsequentinflammation and cardiomyopathy.77,78 In naıve BABL/c mice organ-specific, IL-17-mediated autoimmunity and heart failure is inducedby self-antigen loaded activated dendritic cells (DCs) that primeMYHC-a-specific CD4 T-cells if DCs are activated through toll-likereceptors and CD40 costimulation.79,80 In such a model, suppressionof activated autoreactive Th17-cells by IFN-g-producing monocyteslimits cardiac inflammation and prevents further tissue injury.81

Select knowledge gaps and opportunities in the pathogenesis ofmyocarditis† The heterogeneity of clinical presentations and incomplete

understanding of human immunopathology are obstacles tocurrent investigation.

† The major long-term consequence of myocarditis is chronicdilated cardiomyopathy, but the pathways that lead to myo-cardial fibrosis are poorly understood.

† Investigation of the pathways that lead to fibrosis and DCMafter viral injury requires bidirectional collaboration betweeninvestigators with small animal models that recapitulate latecardiac fibrosis and clinicians who take a multi-centre,programmatic approach to patient care.

† The genetic factors contributing to human myocarditis arepoorly understood. Advances in the genetics of myocarditiswill require multi-centre, pathogen-specific registries withlinked biobanks, core facilities with next generation wholegenome sequencing and candidate driven transcriptomic andmetabolomic studies.

Diagnosis and prognosisThe clinical presentation of acute myocarditis ranges broadly fromsubclinical disease to fulminant heart failure, and chest pain, palpi-tations, and syncope are not uncommon. Young children oftenhave a more fulminant presentation than adults.82 Men with pre-sumed viral myocarditis may have more severe damage thanwomen.83 A viral prodrome including fever and respiratory or gas-trointestinal symptoms frequently precedes the onset of myocar-ditis.84 Chest pain in acute myocarditis may resemble angina withischaemic electrocardiographic changes or be more typical forpericarditis, when both the epicardium and adjacent pericardiumare inflamed. In a representative sample of the adult patientsscreened in the European Study of the Epidemiology and Treat-ment of inflammatory Heart Disease, 72% had dyspnoea, 32%had chest pain, and 18% had arrhythmias.85

The sensitivity of cardiac biomarkers of myocardial injury variesdepending on the time from symptom onset to testing and thecut-off values used. For example, in acute paediatric myocarditis,the sensitivity of specificity of Troponin T (TnT) were 75 and75% when the cut-off was set at 0.026 ng/mL and 63 and 89%with a cut-off value of 0.071 ng/mL.86 Elevations of Troponin I(TnI) in patients with myocarditis were significantly correlatedwith ≤1-month duration of heart failure symptoms.87 Troponin Ior TnT are more commonly elevated than creatinine kinase MBin both adults and children with acute myocarditis.87–89 Non-specific serum makers of inflammation, including erythrocytesedimentation rate, C-reactive protein, and leucocyte count maybe elevated.

The most common electrocardiogram (ECG) findings arenon-specific T-wave changes.90 Occasionally, the ECG changesmay mimic acute myocardial infarction or pericarditis with STsegment elevation, ST segment depression, PR segmentdepression, and pathological Q-waves.91,92 Tachyarrhythmias are

Figure 3 Adapted from Kodama M. et al. Animal Models of Autoimmune Myocarditis, in Cooper, LT, ed, Myocarditis from Bench to Bedside.Humana Press, Towtowa, NJ 2003.


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often non-sustained and rarely cause haemodynamic compromisein adult viral myocarditis. The prognostic significance and optimalmanagement of non-sustained ventricular tachycardia in thesetting of acute myocarditis are not known. However, Q-wavesand a widened QRS complex, including left bundle branch block,are associated with higher rates of death or cardiactransplantation.90,93 –95

Echocardiography is useful to exclude other causes of heartfailure and identify ventricular thrombi. There are no specific echo-cardiographic features of myocarditis.96,97 Indeed, segmental orglobal wall motion abnormalities can mimic myocardial infarction.98

Patients with fulminant myocarditis tend to present with morenormal cardiac chamber dimensions and thickened walls, com-pared with patients with less acute myocarditis who have greaterleft ventricular dilation and normal wall thickness.99 Right ventricu-lar dysfunction is an uncommon but important predictor of deathor cardiac transplantation.100 Newer imaging techniques includingstrain echocardiography may have better specificity and specificityfor myocarditis.

Cardiovascular magnetic resonance (CMR) in suspected myo-carditis can localize and quantitate tissue injury, includingoedema, hyperaemia, and fibrosis.101 In a recent series of 82patients with myocarditis all of whom had biopsy-proven disease,CMR alone made the correct diagnosis in 80% (66 out of 82)cases.102 However, both T2- and T1-weighted imaging areneeded to achieve optimal sensitivity and specificity, and in con-trast to older reports, CMR abnormalities do not correlateclosely with endomyocardial biopsy (EMB) evidence of myocar-ditis.39 When two or more of the three ‘Lake Louise’ criteria arepositive, myocardial inflammation can be predicted with a diagnos-tic accuracy of 78%; if only delayed, post-gadolinium enhancementimaging is performed, the diagnostic accuracy drops to 68%.101

Prospective clinical studies of the prognostic value of CMR areneeded to identify whether tissue characterization adds to themanagement or outcome of patients with myocarditis.

Confirmation of myocarditis still requires histological or immu-nohistological evidence of inflammation in heart tissue. Endomyo-cardial biopsy can be performed with a very low majorcomplication rate when performed by highly experienced oper-ators.103 In experienced hands, left ventricular biopsy is as safeas right ventricular biopsy.39 An AHA/ACCF/ESC joint scientificstatement recommended that EMB should be performed (Class Iindication) in patients with heart failure and (i) a normal sizedor dilated left ventricle, ,2 weeks of symptoms, and haemo-dynamic compromise and also in (ii) patents with a dilated ventri-cle, 2 weeks to 3 months of symptoms, new ventriculararrhythmias or Mobitz type II second degree or third degreeheart block, or who fail to respond to usual care within 1–2weeks.104 More recently, EMB-based criteria (inflammationpresent by immunohistology and viral genomes absent by poly-merase chain reaction) have been used to define a cohort ofpatients with chronic DCM who respond to immunosuppres-sion.105 In clinical practice, EMB should be used in those scenariosin which the incremental prognostic and therapeutic informationgained from biopsy outweighs the risk and cost. This will vary bymedical centre, depending on availability of necessary facilitiesand expertise.

Select knowledge gaps and opportunities in the diagnosis and prog-nosis of myocarditis† The incidence and prevalence of myocarditis are unknown.

There is an immediate need for inexpensive, sensitive, andspecific diagnostic tests that can be used in population-basedstudies in regions without access to advanced imaging orcardiac catheterization laboratories.

† Gender issues: the protective effect of estrogens and the roleof viral myocarditis in peripartum cardiomyopathy areincompletely understood.

† Paediatric cases: the optimal strategy for diagnosingmyocarditis in children is controversial and based largelyon expert opinion.

† Molecular inflammatory markers in peripheral blood com-bined with newer echocardiographic and CMR imaging tech-niques and EMB may lead to more accurate diagnosis andaetiology-specific treatments.

TreatmentCardiomyocytes can be destroyed by direct virus damage, the anti-viral immune response, or a truly autoimmune injury. Since adultcardiomyocytes rarely regenerate, recovery of myocardial functiondepends on the residual myocardial tissue. The treatment responseof acute and chronic myocarditis therefore depends on the specificcauses of the disease, severity of irreversible tissue alterations atthe onset of treatment and consequently on the potential of themyocardium to compensate for such processes. If the pre-treatment damage is severe, aetiology-specific treatment optionsat best can halt rapid progression of the disease but will notachieve significant improvement in ventricular function.

Treatment for heart failureThe mainstay of treatment for myocarditis presenting as dilated cardi-omyopathy is an optimal heart failure medical regimen. If the left ven-tricular ejection fraction (LVEF) is ,40%, we recommend that anangiotensin-converting enzyme-inhibitor/angiotensin receptorblocker and/or a b-adrenergic blocking agent be used according tothe current AHA/ACCF and ESC guidelines for the management ofheart failure.106–108 Supporting this strategy are experimentalstudies that show captopril and candesartan improve myocarditis inmurine myocarditis models.109,110 Non-steroidal anti-inflammatoryagents such as indomethacin should be considered for patients witha myopericarditis-like syndrome of chest pain and normal or near-normal ventricular function because they can worsen cardiomyopathyin experimental models.111 In addition to guideline-based medicalmanagement, we recommend that patients with acute myocarditisrefrain from competitive athletics for a period of months after theacute infection or until ventricular recovery has been documentedby non-invasive imaging.

Antiviral treatmentTreatment of early diseaseElimination of viral translation, transcription, and proliferation withthe use of antiviral medications that target viral attachment tohost-cell receptors, virus entry, or virus uncoating, e.g. Pleconaril,


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WIN 54954, or soluble CAR-Fc, would be effective in the earlystages, but, unfortunately, most adult patients present in thechronic phases of disease (Figure 1).112 These agents, therefore,are of limited use in virus-associated heart disease. The currentchallenge of antiviral therapy in patients with chronic cardiac viralinfections therefore is the timing of treatment that prevents pro-gressive myocardial injury by viral clearance before chronicallyinfected heart tissue has irreversible damage.

Treatment of chronic viral heart diseaseInterferon-betaInterferons serve as a natural defense against many viral infections.Their innate production is associated with clinical recovery fromviral infection and subsequent sequelae, while exogenous adminis-tration is protective. Type I interferons therefore constitute apromising choice for treatment of chronic viral cardiomyopathy.Currently, there is no approved treatment for chronic viral heartdisease, but data from uncontrolled open labelled phase IIstudies have demonstrated that subgroups of patients, who hadnot improved upon regular heart failure medication, may get sig-nificant benefit even years after onset of chronic disease.

In a first study, patients with persistent enterovirus and adenovirusinfections of the myocardium responded well to a 6-monthsinterferon-beta (IFN-b1a) course.113 Complete elimination ofenteroviral and adenoviral genome was proved by follow-up biopsiestaken 3 month after termination of the antiviral therapy. Virus clear-ance was paralleled by an improvement of mean left ventricular func-tion, a decrease in ventricular size, an amelioration of heart failuresymptoms, and a decrease of infiltrating inflammatory cells. Ofnote, no patient deteriorated and patients with severely affectedLV-dysfunction gained most benefit.113

The drug is usually administered subcutaneously every other dayin addition to constant heart failure medication for a 6–months’period. In order to limit IFN-specific side effects, the patientshould enter a run-in period to improve tolerance following astepped regimen, during which the patient receives 2 × 106 IUIFN-b per application every other day for 1 week. Within the fol-lowing 2 weeks, the study medication can be elevated to 4 × 106

and 6 × 106 IU IFN-b, respectively, and continued for the follow-ing 21 weeks. The IFN-b1a medication was well tolerated with nounexpected non-cardiologic or cardiologic side effects. Frequentlyreported IFN-associated side effects were fatigue, influenza-likesymptoms, and injection site erythema but symptoms vanished reg-ularly during the first 4 weeks of treatment. No major clinicalevents occurred during the treatment phase or follow-up.

If patients with a severely depressed cardiac contractility (LVEF,25%) are treated with an immunmodulatory drug such as IFN-b,LV function should be close-mesh monitored by echocardiography.Between Week 4 and 12, patients complain for a mild aggravation ofheart failure symptoms which is often associated with a walloedema, a slight increase of LV-dimensions and a minor deteriorationof LVEF. Complains regularly disappear within 1 or 2 weeks followedby an direct and continuous improvement of heart failure in �40% ofpatients. Improvement may start with a delay of for 2–4 months in25–30% of patients. This outlined course, which is probably causedby an IFN-induced cellular immune response, preferentially concernsviruses that infect cardiomyocytes (e.g. enteroviruses). It is

uncommonly observed in infections such as parvovirus B19 orhuman herpesvirus 6 which according to a distinct pathophysiologydo not directly affect contractile cells of the myocardium.

Parvovirus B19 and human herpes virus 6 respond less well uponIFN-b treatment with respect to virus clearance and haemodynamicchanges, although affected patients too improve clinically despiteincomplete virus clearance following reduction of virus load and/orimprovement of endothelial dysfunction.114,115 Complete clearanceof those viruses may need longer treatment intervals, higher doses,or even a complete change of the antiviral treatment regimens. Cur-rently, effective treatment conditions for viruses other than entero-virus and adenovirus have not yet been tested consequently.

Information taken from uncontrolled cohorts of treated virus-positive patients may be, however, of limited value for generaltreatment recommendations for a number of reasons. Accordingto animal and cell culture studies, different viruses and even differ-ent virus subtypes may respond in distinct and unpredictable waysto immunomodulatory treatment. Furthermore, virus load and thetype of the infected cell, both of which influence course of thedisease and drug response, have to be taken into consideration.Despite such comprehensible reservations, a recent randomized,placebo controlled phase II trial (BICC-Study) has confirmed thateven patients with a long history who had not responded to con-ventional heart failure treatment can get clinical and haemo-dynamic benefit from an IFN therapy.115

Response to the IFN-b1a therapy may be influenced by thevirus-associated local inflammation and the extent of the myocardialinjury at the time when the specific therapy is started. The lack ofhaemodynamic improvement in some of the patients is not unex-pected, if the long history and the above-mentioned pathogenetic sug-gestions are taken into consideration. In view of the informationderived from other virus infections of the heart, one can expect thatthe chronic enteroviral and adenoviral infections or thevirus-associated inflammatory process may already have caused con-siderable myocardial damage and consequently, ventricular dysfunc-tion may be unable to recover completely in those patients who didnot improve despite virus clearance. Nevertheless, the completeclearance of both viruses after treatment suggests that early biopsy-based diagnosis and timely treatment may prevent disease progressionand thereby improve the outcome of chronic viral cardiomyopathy.

Select knowledge gaps and opportunities in the treatment ofmyocarditis† Studies have not been done to determine when and how to

discontinue standard heart failure therapy in patients whorecovery LV function.

† More work is needed to identify patient cohorts who willbenefit from tailored antiviral or immunosuppressivetherapy.

† The optimal time frame to initiate immunosuppressive treat-ment improves cardiac function and health without impair-ment of a healing immune processes is unknown.

† With respect to our limited knowledge of involved patho-logical processes and optimal treatment conditions, preven-tion of disease progression rather than curative treatmentmay turn out to be the most realistic short-term goal.


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ImmunosuppressionMyocardial inflammatory processes due to pathogenic autoimmu-nity may survive myocardial virus elimination and warrant immuno-suppressive treatment in order to prevent later immune-mediatedmyocardial injury.116 –118 Immunosuppression demands biopsy-based exclusion of virus from treated patients since virus-positivepatients do not improve upon anti-inflammatory treatment, whilevirus-negative patients with post-infectious or auto-immune inflam-matory processes respond well in early clinical trials.105,117,119,120

Frequently administered anti-inflammatory drugs are immuno-globulins, corticosteroids, azathioprine, and cyclosporine, whichare administered on top of regular heart failure medication.a-Methylprednisolone is generally given at Charite Hospital, at adose of 1 mg/kg body weight, initially for 4 weeks. Depending onthe body weight, azathioprine is administered at a dose of 100–150 mg daily in addition to the corticosteroid. The steroiddosage is titrated down every 2 weeks in increments of 10 mguntil a maintenance dose of 10 mg is reached. The treatment dur-ation should last for 3 to 6 months. Actual data of first randomizedtrials confirm efficacy of those treatment regimens in carefullyselected patients.105,118

Sustained beneficial effects of immunosuppression on heartfailure symptoms, left ventricular dimensions, and LVEF in immuno-histologically biopsy-proven inflammatory cardiomyopathy havebeen confirmed in a randomized trial with 41 patients at 2 yearsfollow-up after ≥3 months of treatment with corticosteroidsand azathioprine.118 This trial ultimately validates the diagnosticsensitivity and accuracy of cell adhesion molecule (CAM) abun-dance for indlammatory cardiomyopathy (DCMi) even in theabsence of lymphocytic infiltration, possibly due to the close func-tional association between CAM induction and immunocompetentinfiltration and cytokine induction,121 and thus constitutes animportant criterion for selecting those patients who will likelybenefit from immunosuppression. Furthermore, this studyshowed that a 3-month regimen may equally be effective as pre-vious trials that used 6 months of immunosuppression, and thatbeneficial effects last for an extended period of time (2 years). Inanother recently published randomized trial (TIMIC study), theauthors confirmed a positive treatment response in patients withchronic active myocarditis.105 Thirty-eight out of 43 patients onimmunosuppressive therapy (88%) showed a improvement ofcardiac function and dimensions, defined as an increase of .10percentage points in the absolute EF and a reduction of LV end-diastolic volume (EDV) or LV end-diastolic diameter (EDD) 10%(i.e. LVEF from 26.4+ 6.9 to 48.0+7.3%, LVEDV from 258.0+52.5 to 125.9+ 29.6, and LVEDD from 68.6+7.4 to 52.8+6.3 mm). None of the untreated patients show at 6 monthimprovement of LVEF, that significantly worsened compared withbaseline. In particular, 35 out of 42 patients (83%) showedfurther impairment of cardiac function (LVEF from 27.6+6.6 to19.5+4.8, LVEDV from 244.7+48.0 to 287.3+48.0, andLVEDD from 69.2+ 7.9 to 75.3+ 7.4), while the remaining 7patients remained stationary. Finally, LVEF declined to baseline(27.2+ 5.6%) or lower (19.7+4.4%) values.

Currently available data show that immunosuppressive therapyin patients with biopsy-proven, virus-negative inflammatory

cardiomyopathy is an effective and safe option in addition to sup-portive treatment for recovery of cardiac failure. However, largerstudies powered to detect a difference in clinical endpoints such asheart failure hospitalization, transplantation, and death are stillneeded.

Intravenous immunoglobulinand immunoadsorptionThe first data of acute myocarditis treated with intravenous immu-noglobulin (IVIG) suggested that use of high-dose IVIG for treat-ment of acute myocarditis is associated with improved recoveryof left ventricular function and with a tendency to better survivalduring the first year after presentation.122 Later investigationsand randomized studies which compared IVIG and cortisone treat-ment revealed that the treatment with intravenous immune globu-lin in children was not effective.123 Freedom from death ortransplantation was 81% at 1 year, and 74% at 5 years, with nodifference between the modes of treatments. The median timeto recovery of function was also comparable between thegroups. Thus, treatment with intravenous immune globulinappear to confer no advantage to steroid therapy alone.124

The rationale for immunoadsorption is to lower cardiotoxicantibodies in the patient’s plasma, and with serial treatmentsover 5 or more days, extract antibodies and immune complexesfrom the heart as well. The plasma is separated from cellular com-ponents by a centrifuge or column and passed through an immu-noadsorbtion column. IgG and to a lesser degree IgA and IgMare non-specifically adsorbed during repetitive sessions. PlasmaIgG levels are partially restored by infusion of 0.5 g/kg polyclonalIgG .18 h after the last apheresis treatment. The favourablehaemodynamic results of immunoadsorption in patients withDCMi may be related to removal of functionally active cardiacautoantibodies or other immunologically active compounds, sinceimmunoadsorption leads to biopsy-proven decrease in lymphocy-tic infiltration and CAM expression.

Summary and perspectivesCurrent pharmacological heart failure therapy ofmyocarditis-associated cardiomyopathy mainly focuses on decreas-ing the activity of the neuroendocrine system but does not directlyinfluence virus-induced inflammatory cardiomyopathy.Interferon-b suppresses erythrovirus replication while at thesame time it improves replication and viability of human ECs.46

Accumulating experimental and clinical data indicate that cellulartransplantation may improve myocardial function.26,125,126

Mesenchymal stem cells (MSCs) have anti-apoptotic, anti-fibroticproperties, are non-immunogenic, and possess immunomodulatoryproperties.127 –129 They suppress T-cell responses, induce apopto-sis of activated T cells and increase T regulatory cells.130 –132

Interferon-g primes MSC-mediated immunoregulatory effectsand induces nitric oxide (NO) production in MSCs the latter ofwhich exerts anti-apoptotic effects on cardiomyocytes and hasantiviral properties in a NO-dependent manner.129,133 – 135 Thesedifferent strategies including pharmacological and gene therapeutic


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approaches directed at blocking viral replication or stimulating theantiviral-directed immune response, are under investigation inexperimental and clinical studies.70,114,136,137 Because of the lowrate of diagnosis, multi-centre collaborations with standardizedevaluations and treatment protocols, mechanistically orientedregistries, and core molecular diagnostic facilities will be needed.

FundingBasic experimental diagnostic and clinical works have been supportedby a grant from the German Research Foundation (DFG), Transregio-nal Collaborative Research Centre ‘Inflammatory Cardiomyopathy–Molecular Pathogenesis and Therapy’ (SFB TR 19 04) (HPS, UK,Charite Berlin).

Conflict of interest: none declared.

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The management of myocarditis - European Heart Journal

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