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Management of Myocarditis-Related Cardiomyopathy in Adults

Originally publishedhttps://doi.org/10.1161/CIRCRESAHA.118.313578Circulation Research. 2019;124:1568–1583

    Abstract

    Myocarditis is generally a mild and self-limited consequence of systemic infection of cardiotropic viruses. However, patients can develop a temporary or permanent impairment of cardiac function including acute cardiomyopathy with hemodynamic compromise or severe arrhythmias. In this setting, specific causes of inflammation are associated with variable risks of death and transplantation. Recent translational studies suggest that treatments tailored to specific causes of myocarditis may impact clinical outcomes when added to guideline-directed medical care. This review summarizes recent advances in translational research that influence the utility of endomyocardial biopsy for the management of inflammatory cardiomyopathies. Emerging therapies for myocarditis based on these mechanistic hypotheses are entering clinical trials and may add to the benefits of established heart failure treatment.

    Myocarditis is defined as any heightened humoral or cellular immune response in the heart and accordingly manifests with diverse histological findings and clinical presentations, ranging from chest pain or mild dyspnea to acute cardiogenic shock. Up to 20% of myocarditis patients may subsequently develop a chronic inflammatory dilated cardiomyopathy (DCMi).1–3 Although myocarditis can result from a vast number of viruses, bacteria, protozoa, or fungi,4 the most frequently identified trigger is a narrow spectrum of viruses.2,5 Beyond infections, myocarditis can be caused by a direct toxic or immune-mediated reaction to drugs, including immune checkpoint inhibitors,6,7 and by systemic autoimmune disorders such as sarcoidosis or systemic lupus erythematosus.

    Most patients diagnosed with acute myocarditis recover without clinically relevant residual damage.1,8 For example, a recent multicenter registry of 684 patients with uncomplicated acute myocarditis documented overall benign short- and long-term outcomes.3 However, the clinical features of acute myocarditis can rapidly change in the first days of the illness, and as such, patients with a new diagnosis of suspected myocarditis and elevated troponin levels or ECG changes should be hospitalized for monitoring, based on expert opinion.2 In this window, some patients will manifest signs of heart failure, early cardiogenic shock, or unstable heart rhythm. Data from clinical registries linked with biobanks and limited clinical trials suggest that in acute cardiomyopathy, histological and molecular patterns obtained by endomyocardial biopsy (EMB) may inform prognosis and possibly alter outcome with disease- or pathogen-specific management.9 Based on case series of initially undiagnosed cardiomyopathy, several specific disorders may be identified on EMB and treatment based on this information may impact outcome (Table 1).10 For example, in a single-center registry of 210 EMB-proven myocarditis patients (enrolled at Charité Hospital, Berlin, Germany from 2015 to 2018) subjects with myocarditis were followed for 2 years with standard heart failure medication. The ejection fraction (EF) was found to be normal in approximately half of the patients (26% of the cases recovered and in 27%, the EF was initially not affected and stayed stable), whereas in half of the patients, the EF did not recover to normal (Figure 1).

    Table 1. Specific Forms of Myocarditis Identified via Endomyocardial Biopsy Diagnosis

    Myocarditis Forms
    Adenoviral myocarditis
    Enteroviral myocarditis
    Human herpesvirus 6 myocarditis
    Hypersensitivity myocarditis
    Checkpoint inhibitor-related myocarditis
    Eosinophilic cell myocarditis
    Giant cell myocarditis
    Idiopathic granulomatous myocarditis (cardiac sarcoidosis)
    Figure 1.

    Figure 1. Spontaneous course of ejection fraction after standard heart failure medication in endomyocardial biopsy-proven myocarditis patients. Pie chart illustrates observations of our single-center registry (enrolled at Charité, Department of Cardiology, Berlin, Germany, from 2015 to 2018) illustrating the course of myocarditis in a 2-y follow-up. From 210 patients who had biopsy-proven myocarditis, and came to our hospital with ECG changes, elevated troponin levels and impaired ejection fraction (EF), we found that in 47% the cases, EF did not recover to normal (gray and yellow) after 2-y standard heart failure therapy. In 53% of the cases, EF was found to be normal: EF recovered in 26% of the cases (orange) after 2 y. In 27%, EF was initially not affected and stayed stable.

    The remainder of this article will outline currently recommended and emerging cause-specific treatment strategies for patients with acute myocarditis. Data from trials and registries of chronic myocarditis (DCMi >3 months) are cited when relevant to acute management (Figure 2), recognizing that there is no distinct clinical or pathological boundary between acute and chronic myocarditis.

    Figure 2.

    Figure 2. Proposed treatment options in complicated myocarditis according to endomyocardial biopsy results and clinical settings. Scheme represents treatment options for complicated myocarditis depending on endomyocardial biopsy results and clinical presentation, following expert-based recommendations and consensus,2,11–16 which still need to be proven in large randomized clinical trials. Parvovirus B19+ (B19V) active: signs of active/acute B19V systemic infection; B19V DNA persistence: no signs of systemic B19V infection; low cardiac copy numbers (B19V DNA <500 genomic equivalents/µg).17 + indicates positive; −, negative; ciHHV-6, chromosomally integrated human herpesvirus type 6; DCM, dilated cardiomyopathy; DCMi, inflammatory dilated cardiomyopathy; HF, heart failure; LV, left ventricle; MC, myocarditis; and PROPELLA, prolonged LV Impella.

    Diagnostic Strategies for Suspected Myocarditis Presenting as Acute or Chronic Heart Failure

    Troponin and echocardiography should be performed in acute cardiomyopathy due to suspected myocarditis (class of recommendation 1, level of evidence C).2,11 Although cardiac magnetic resonance imaging (cMRI) using parametric native myocardial mapping techniques has an area under the curve of ≈90% for the diagnosis of acute inflammation,18 the utility of cMRI in hemodynamically unstable patients is often limited by fast or irregular heart rates and mechanical ventilation (Table 2).18 In patients with myocarditis presenting as acute heart failure with shock, or high-grade heart block or symptomatic ventricular tachycardia, an EMB-guided approach is recommended (American Heart Association and European Society of Cardiology [ESC] class of recommendation 1, level of evidence B). In this clinical scenario, the use of EMB may provide pathway-specific information to inform the likelihood of recovery or transplantation and offering intervention strategies.2,12,20,21 In clinically stable patients with suspected acute myocarditis, the prognosis is usually good, and cMRI may be helpful to confirm the diagnosis and modify risk of subsequent arrhythmias or cardiovascular death based on the presence or absence of delayed gadolinium enhancement. cMRI is most accurate to diagnose acute myocarditis in subjects with <2 to 3 weeks of symptoms, because scar and inflammation appear similar at later stages on tissue characterization sequences.18,22–24 Furthermore, cMRI is useful for risk stratification according to, for example, the scar pattern.24 However, if recovery does not occur over time, or the onset of the disease is longer than 3 months ago, the diagnostic accuracy of cMRI is low.18,22,23 This accounts for patients with heart failure of >3-month duration associated with a dilated left ventricle (LV), who do not profit from classical heart failure medication (Table 2; class of recommendation IIaC).2,20,21,25 In this clinical scenario, an EMB-based diagnostic approach, enabling identification of inflammation, relevant as treatment target26–29 and for refining prognosis,30 can close this gap.

    Table 2. When to Perform Magnetic Resonance Imaging or Endomyocardial Biopsy? When Alone and When Together? (Following Consensus of the Authors, Which Is in Agreement With Other Experts in the Field)12,18,19

    cMRIEMB
    Shock(−)++
    AMC without complications+
    AMC with unstable arrhythmia(−)+
    DCMi (>3 mo)+*++
    Assess response to therapy+(+)

    AMC indicates acute myocarditis; cMRI, cardiac magnetic resonance imaging; DCMi, inflammatory cardiomyopathy; and EMB, endomyocardial biopsy.

    *A negative result does not exclude ongoing low-gradient inflammation.

    †Therapy selection/decision.

    ‡Therapy failure/nonresponder.

    Role of EMB in the Selection of Specific Treatment Options in Myocarditis

    The role of EMB to guide management has not been evaluated in large clinical trials. Nonetheless, professional societies including the American Heart Association and ESC2,21 have endorsed consensus-based recommendations2,11,25 for EMB use and analyses. The ESC position paper recommends characterization of the inflammatory responses, and evaluation of cardiac viral persistence, for the selection of treatment regimes. Emerging therapies for myocarditis based on these mechanistic hypotheses are entering clinical trials. Though, consistent evidence from robust randomized clinical trials supporting cause-based therapies are still lacking. As long as robust randomized clinical trials are absent, the available data advocate an EMB-based approach, at least for selected clinical scenarios in centers with expertise. The following sections will provide a current summary of ongoing and proposed clinical trials that use these tools for pathway and pathogen-specific treatments.

    Immunohistochemistry and viral genome analysis may define immune cells and specific pathogens. These new tools are supplanting the Dallas criteria, which suffered from high sampling error rate >25%,31,32 interreader variability in interpretation and of prognostic value.31,32 One exception is giant cell myocarditis (GCM), a rare, rapidly progressive form of myocarditis33 characterized by diffuse inflammatory infiltration of the myocardium with lymphocytes and multinucleated giant cells in the absence of granulomas,1 for which routine hematoxylin and eosin stain has an 80% sensitivity due to the diffuse endocardial pattern of inflammation.34 Immunohistochemistry using a panel of monoclonal and polyclonal antibodies (including anti-CD3, anti-CD68, and antihuman leukocyte antigen-DR) is recommended to characterize the inflammatory infiltrate.35 Case series suggest that quantification of the immunohistological pattern and cell subtypes, determination and quantification of the virus type and copy number, respectively, and gene expression analysis impact prognosis.29,36 For example, in a series of 181 patients, positive immunohistology for immune cells (CD3 and CD68) and expression of human leukocyte antigen-DR-α molecules, but not the Dallas criteria alone predicted rate of death or transplant.30

    Since cardiac inflammation is often patchy, at least 6 samples are necessary to reduce the EMB sampling error.31 The false-negative rate can be further reduced with the use of cMRI,37 electroanatomic mapping,38–41 or 18F-fluorodeoxyglucose positron emission tomography42 guidance to identify regions of inflammation in selected cases. Correlative studies with cMRI and EMB have demonstrated that immunohistochemistry compliments the diagnostic value of cMRI.18,43

    The safety of EMB has improved in the past 20 years with the use of smaller, flexible bioptomes.44 The complication rate of EMB in specialized centers44 is lower than that of coronary angiography (<0.05%).45 Widespread use of EMB is limited because immunohistology and molecular analysis require specialized expertise and equipment that is currently limited to a few specialized centers. Enthusiasm for an EMB-guided management strategy has also been limited because clinical trials to validate EMB-guided treatment strategies based on EMB results have had small sample sizes.27,46,47

    Current and Emerging Treatments for Acute Myocarditis

    All patients with acute myocarditis should receive guideline-directed medical treatment for heart failure and arrhythmias, if applicable.48–50 In addition, 3 to 6 months’ abstinence from competitive sports after myocarditis diagnosis is recommended by expert consensus to decrease risk of remodeling and sudden death.51 Nonstandard and cause-specific treatment of myocarditis depends on the clinical presentation, histology and at times, on molecular diagnosis. In a recent series of 187 adult patients with acute myocarditis, the majority (132) presented with >1 month of symptoms, and only 55 of 187 (29%) required inotropes or mechanical circulatory support (MCS).52 This series and others identified the need for inotropic or MCS as the clinical phenotype that defines patients at highest risk of adverse outcomes. Similarly, patients with acute cardiomyopathy complicated by hemodynamically unstable arrhythmias should be considered for EMB early to identify specific and treatable causes of heart failure.36,53 Specific forms of acute myocarditis, including GCM and eosinophilic myocarditis, may only be diagnosed by EMB. Based on histology, GCM can be distinguished from cardiac sarcoidosis and eosinophilic heart disease.53 Since the first report of the Multicenter Giant Cell Myocarditis Study Group, treatment of GCM includes immunosuppressive treatment with cyclosporine and prednisone, sometimes combined with azathioprine.33 Abrupt cessation of immunosuppressive therapy within the first 2 years after diagnosis has been associated with fatal disease recurrence.54 Eosinophilic heart disease is often clinically fulminant and characterized by the overproduction of cytotoxic eosinophils, which infiltrate and damage the myocardium in the acute phase, followed sometimes by valve involvement and apical obliteration that evolves into endomyocardial fibrosis.55 The rate of death, heart transplantation, and MCS are up to 46% in eosinophilic myocarditis due to hypersensitivity reaction.56 The most common treatment regime for eosinophilic heart disease includes corticosteroids sometimes combined with azathioprine, pegylated IFN (interferon)-α-2a, or mepolizumab, depending on cause.57

    In contrast to the anecdotal benefits of immunosuppressive therapy for these uncommon disorders, the use of immunosuppression or intravenous immunoglobulin for acute nonviral lymphocytic myocarditis is not recommended.58,59 Negative clinical trials, performed in the 1980s and 1990s, relied on standard histological or Dallas criteria to define inflammation without assessment of viral infection. These limitations led to criticism of the methodology and a search for better definitions of myocarditis and attempts to define clinically meaningful viral infection. A diagnosis of lymphocytic myocarditis in patients requiring MCS increases the likelihood of bridge to recovery.60

    In cardiogenic shock due to acute myocarditis, inotropes such as milrinone levosimendane, or dobutamine, or MCS,61 including venoarterial extracorporeal life support may provide bridge to durable MCS, transplant or recovery.62–66 Extracorporeal life support increases afterload on the LV, which, in the absence of additional LV venting, can cause LV dilation and pulmonary edema.67 Elevated LV afterload activates cardiac mechanotransduction pathways,68 integrins and integrin-related proteins68 and (Figure 3),69 myocardial inflammation. The combination of increased load and inflammation promotes unfavorable cardiac remodeling. These observations have led to the hypothesis that an MCS strategy that decreases afterload may increase the likelihood of ventricular recovery or remission (Figure 3).67,70 Intra-aortic balloon pumps or axial flow pumps like the Impella systems (2.5, CP, 5.0) can support peripheral circulation to varying degrees and have been used as a bridge to recovery.71–73 Impella-based strategies may be used in isolation or in combination with extracorporeal life support (ECMO plus Impella: ECMELLA),74–77 in combination with right ventricular Impella RP (BI-PELLA),78 or as prolonged use of the LV Impella (PROPELLA).67 Anecdotal case reports suggest that PROPELLA can both decrease inflammation and afterload to promote myocardial recovery/remission in patients with chronic fulminant myocarditis.67,79 Clinical trials, preferably with EMB analysis, are required to validate the PROPELLA concept.

    Figure 3.

    Figure 3. Hypothetical schematic presentation illustrating how mechanical unloading could abrogate pathogenic (inflammatory) processes in myocarditis. Hypothetical scheme illustrates how myocarditis via activation of the innate and adaptive immune system induces cardiac dysfunction (negative inotropy, microvascular-induced ischemia, and fibrosis), which leads to mechanical stress in terms of wall stress, shear stress, and volume load. Mechanical stress, in turn, induces mechanotransduction pathways involving integrins and integrin-related proteins, which stimulate chemokine production and activate immune cells, further boosting the inflammatory process. Therefore, mechanical unloading could be a novel treatment strategy for myocarditis.

    Insights From Management Trials in Chronic Inflammatory Cardiomyopathy

    EMB-based therapy has been proposed to vary by viral genome presence, virus type, and virus load. EMB-defined myocarditis cohorts studied in registries and proposed trials include: virus-negative/autoimmune, entero- and adenovirus-, human herpesvirus type 6-, and parvovirus B19 (B19V)-positive patients, in approximate order of their clinical use/acceptance.

    Virus-Negative/Autoimmune Inflammatory Cardiomyopathy

    Steroid-Based Treatment Regimes

    In contrast to earlier studies of acute cardiomyopathy in which viral pathogens were not assessed, recent studies in EMB virus-negative patients with chronic DCMi suggest that the use of immunosuppressive therapy with prednisone and azathioprine can improve cardiac function (Table 3).27–29,47 A recent registry using the ESC immunohistochemical criteria for DCMi,2 suggested beneficial effects of immunosuppressive therapy with prednisone and azathioprine in DCMi patients.28 However, short duration of follow-up of <1 year has limited the impact and applicability of these data in clinical practice. Another limitation of this registry is the lack of a control group. A larger retrospective case series from the Innsbruck and Maastricht Cardiomyopathy Registry also demonstrated an association between immunosuppressive therapy results and heart transplantation-free survival as compared with standard heart failure therapy alone.29 This study included the largest-to-date patient population (including a control group) with DCMi and provides the first long-term outcome (100 months). Current American Heart Association and ESC position statements differ on the strength of recommendation about the use of immunosuppressive therapy in this clinical scenario. Alternative regimes include steroid-based regimes combined with cyclosporine or mycophenolat-mofetil or immunoadsorption with IgG substitution.80–82 The cause of treatment failure in the setting of immunosuppression-treated DCMi is an area of active investigation that includes studies of viral reactivation, and alternative inflammatory pathways not targeted by the first-line therapies.

    Table 3. Use of Immunosuppressive Therapy in Virus-Negative Patients With Chronic Idiopathic Inflammatory Cardiomyopathy

    RCT / RegistryNo. of PatientsPatient CollectiveTreatmentEnd Points
    Wojnicz et al4784DCM patients with increased HLA expressionImmunosuppression for 3 moPrimary end point: no significant differences in the primary end point (a composite of death, heart transplantation, and hospital readmission)
    Secondary end point: LV-EF increased significantly in the immunosuppression group compared with the placebo group after 3 mo of follow-up
    At the end of the follow-up period, 71.4% patients from the immunosuppression group vs 30.8% patients from the placebo group were improved (P=0.001)
    Frustaci et al (TIMIC study)2785Myocarditis and chronic (>6 mo) heart failure patients, unresponsive to conventional therapy, with no evidence of myocardial viral genomesGroup 1 (43 patients) prednisone 1 mg/kg per day for 4 wk followed by 0.33 mg/kg per day for 5 mo and azathioprine 2 mg/kg per day for 6 mo in addition to conventional heart failure therapyImprovement of LV-EF and decrease in LV dimensions and volumes compared with baseline
    No major adverse reactions
    Group 2 (42 patients): placebo in addition to conventional heart failure therapyNo improvement of LV-EF that significantly worsened compared with baseline
    Escher et al26114Chronic myocarditis or inflammatory cardiomyopathy following Caforio et al2 (≥14 infiltrating inflammatory cells/mm2)Prednisone and azathioprine for 6 moImprovement of LV-EF compared to baseline after 6-mo period (LV-EF rising from 44.6±17.3% to 51.8±15.5%; P=0.006)
    Merken et al29209Inflammatory cardiomyopathy following Caforio et al2 (≥14 infiltrating inflammatory cells/mm2)After 1:1 propensity score matchingImproved long-term outcome (eg, heart transplantation-free survival) as compared with standard heart failure therapy alone
    90: immunosuppressive therapy
    90: placeboA significant larger increase of LV-EF after a mean of 12-mo follow-up, as compared with patients receiving standard heart failure treatment only

    DCM indicates dilated cardiomyopathy; EF, ejection fraction; HLA, human leukocyte antigen; LV, left ventricular; RCT, randomized clinical trial; and TIMIC, Tailored Immunosuppression in Inflammatory Cardiomyopathy.

    Rituximab

    CD20 B lymphocytes are known to contribute to the pathogenesis of myocardial damage by direct toxicity, augmentation of T-cell effector mechanisms, and increased monocyte activation.83–87 Corticosteroids do not effectively block CD20 B lymphocytes.88–91 The relevance of CD20 B lymphocytes in cardiac impairment has often been described in rheumatology diseases, like rheumatoid arthritis, or myositis, and further follows from the cardiac improvement after treatment with rituximab, a chimeric monoclonal antibody against the pan B-cell surface molecule CD20, in Lupus-myocarditis patients92 and patients with cardiac graft rejections after heart transplantation93,94 seen in single-center studies. Based on own single-center observations of CD20 B lymphocytes presence in EMB of DCMi patients, which illustrate that 63% of steroid nonresponders are CD20 B lymphocyte positive, we hypothesize that CD20 B lymphocytes-driven DCMi is a subclass of DCMi and that treatment of this subclass of patients, in the absence of cardiotropic viral persistence, with rituximab, might significantly improve cardiac function and alleviate signs and symptoms of heart failure. A first observational study in patients is in progress.

    Virus-Positive Inflammatory Cardiomyopathy

    Enterovirus and Adenovirus
    Interferon-β

    A host of experimental and clinical data supports the role of enteroviruses, such as Coxsackie B virus, as causal agents in acute human myocarditis. However, randomized clinical trials of antiviral therapy have not yet established viruses as therapeutic targets in acute myocarditis. Some insight may be gained from the BICC (betaferon in chronic viral cardiomyopathy) phase-2 trial, which randomized patients with DCMi to placebo or 2 doses of IFN-β. Subjects had to have a positive EMB diagnosis for enterovirus, adenovirus, or B19V. Fifteen of the subjects in the trial had entero- and adenovirus-positive EMB and experienced viral clearance after IFN-β.95,96 However, IFN-β was not associated with B19V DNA clearance.95,97 These data suggest that in some patients with enterovirus or adenovirus genomes on EMB, IFN-β may play a role in accelerating viral clearance. The impact on clinical end points such as death or heart transplantation remains uncertain.

    Human Herpesvirus Type 6-Positive Patients
    Ganciclovir/Acyclovir/Valacyclovir

    Human herpesvirus 6 (HHV-6) A and B are lymphotropic viruses with lifelong persistence, primarily associated with noncardiac disease. Genomes have been detected in patients with myocarditis, suggesting possible causality for myocarditis and DCMi. Compared to B19V infections, latent HHV-6 infections are less frequently associated with an inflammatory process of the myocardium,98 but HHV-6 persistence can have an impact on cardiac dysfunction.98 Antiviral agents targeting HHV-6 as well as INF-β do not clear HHV-6 genomes from the myocardium. Nonetheless, some experienced centers advocate the use of immunosuppressive drugs in combination with antiviral medications such as ganciclovir, acyclovir, or valacyclovir in fulminant myocarditis associated with HHV-6 and severe cardiac inflammation, in part because HHV-6–associated inflammation is a poor prognostic marker.30 At this time, additional clinical trials are needed to determine whether HHV-6 is a useful therapeutic target in acute myocarditis.

    The HHV-6 genome is also able to integrate into telomeres of human chromosomes, which allows germline transmission of HHV-6. Chromosomally integrated HHV-6 affects any nucleated cell and can be detected in about 1% of patients with HHV-6 infection. Chromosomally integrated HHV-6 can reactivate from its integrated state and is associated with an increased risk of myocarditis. Anecdotally HHV-6 patients with cardiac symptoms and reactivated chromosomally integrated viruses may benefit from antiviral treatment with, for example, ganciclovir.99 However, viral clearance from the myocardium is uncommon.100,101

    Parvovirus B19

    In contrast to enteroviruses, which infect cardiac myocytes, B19V can infect cardiac endothelial cells,17,102 and can probably cause microangiopathy, endothelial,97 and diastolic dysfunction.103 A pathogenic role of B19V is supported by elevated circulating endothelial microparticles,104 capsid protein VP-1 (viral protein-1) damage to circulating angiogenic cells and cell culture experiments demonstrating that B19V modulates inflammatory signaling and apoptosis in endothelial cells.105,106 Other data support molecular mimicry between B19V and cardiac antigens.107 However, a substantial majority of normal hearts have B19V genomes, bringing a causal role for B19V in myocarditis into question.108–110 A variety of methods have been proposed to distinguish pathogenic from incidental infection, including viral load,17,111,112 the presence of other cardiotropic viruses,111 and active replicating B19V viral RNA.17,113,114 At present, additional studies are needed to establish a causal role for B19V in acute myocarditis and validate anti-B19V therapeutic strategies. However, for patients who still had cardiac symptoms, 3 different unapproved treatment approaches are actually discussed or under investigation.

    Immunoglobulins

    Intravenous immunoglobulin (IgG, IgA, and IgM [IgGAM]) have both anti-inflammatory and antiviral effects. Intravenous immunoglobulin may replace antibodies, enhance viral clearance, neutralize pathogens, and enhance clearance of inflammatory cytokines that contribute to myocyte destruction.115 In DCM patients, without evaluation of cardiac viral persistence, a randomized placebo-controlled trial of intravenous immunoglobulin was shown to be ineffective (IMAC Trial [Intervention in Myocarditis and Acute Cardiomyopathy]).46 However, small trials and nonrandomized registries in patients with chronic cardiomyopathy including EMB-proven B19V,116 B19V and adenovirus13 and cytomegalovirus, suggest a niche for their therapeutic potential.13 In B19V-associated DCMi patients, registry data indicate that clinical improvement can be noted, but only inflammation is successfully eliminated, whereas B19V eradication is limited.13 The efficacy of intravenous IgG to reduce B19V viral load in chronic B19V-positive cardiomyopathy patients with a B19V viral load above 200 copies/µg DNA has recently been completed (URL: http://www.clinicaltrials.gov. Unique identifier: NCT00892112).

    Telbivudine

    Telbivudine is an antiviral synthetic nucleoside analog that inhibits both DNA and RNA-dependent DNA polymerases, which is especially effective for retroviral and para-retroviral (hepatitis B viruses) infections.117 In addition, telbivudine exhibits pleiotropic immunomodulatory/anti-inflammatory, endothelial-protective, antiapoptotic, and antioxidative properties.118–122 The DNA genome of the single-stranded B19V, which has often been linked to the pathogenesis of myocarditis and its progression, DCM,123 replicates through a specific rolling-hairpin mechanism to generate a double-stranded DNA molecule, mimicking the second strand DNA synthesis during hepatitis B viruses replication.124 Therefore, telbivudine, which preferentially inhibits the DNA-dependent single-stranded DNA synthesis, may interfere with the unique replication mode of B19V. Telbivudine was evaluated in a small single-patient use study to treat B19V mRNA-positive patients, the PreTopic Study (EudraCT-Number: 2016-004825-17).9 In this initial clinical experience, telbivudine was associated with improvement of clinical symptoms, clearance of mRNA levels, and reduction in CD3 infiltrates.122 Since more data are not available, the use of telbivudine cannot be recommended from studies or registries.

    Prednisone and Azathioprine

    According to the hypothesis, that the finding of cardiac B19V copy number might not represent an active viral infection and virus induced-inflammation, an immunosuppressive therapy could still be reasonable. Recent preliminary findings from the CAPACITY (Cortisone in Parvovirus Inflammatory Cardiomyopathy)-observational trial demonstrated that immunosuppressive treatment with prednisone and azathioprine in addition to standard heart failure medication in B19V DNA-positive patients was associated with resolved inflammation and improved LV-EF in B19V DNA-positive patients in the absence of B19V replication.125 The significance of these findings needs to be confirmed in a larger trial. At this time, an immunosuppressive therapy strategy for chronic DCMi B19V-positive patients remains uncertain and cannot be generally recommended.

    Emerging Immunomodulatory Therapeutic Strategies

    A number of anti-inflammatory treatments that are pathway-specific, in contrast to the agents used in older trials, are entering early phase clinical evaluation (Table 4). These agents primarily modulate effector arms of the innate and adaptive immunity.

    Table 4. Novel Promising Strategies for the Treatment of Myocarditis

    Strategy(Pre)clinical EvidenceEvidence of TargetEvidence of Therapy
    IL-1β inhibitors
     Anakinraacute MI,126 acute decompensated heart failure,127 HFpEF,128 and idiopathic recurrent pericarditis
    fulminant myocarditis129,130
    +++++
     Canakinumabpatients with previous MI and hs-CRP levels ≥2 mg/L (CANTOS)131+++++
     Colchicinepericarditis with pericardial effluent,132–135 stable coronary artery disease,136 and postpericardiotomy syndrome137,138+++++
    HMGB1 inhibitorspatients suffering from acute myocarditis and troponin I–induced experimental autoimmune myocarditis139++++
    S100A9 inhibitors
     Q-compoundsautoimmune disease and cancer140,141
    CVB3 myocarditis and DCM142,143
    ++
    Modulation of T cells
     Treg cells transferexperimental model of CVB3-induced myocarditis: prophylactic144,145 and therapeutic146 use++++
     IL-2 agonistsexperimental evidence in rodent MI model147++
    Global immunomodulation
     MSC (autologous, allogeneic, PLX)experimental models of CVB3-induced myocarditis,148–152 chronic Chagas cardiomyopathy,153 and autoimmune-induced DCMi154+++++
    trial in nonischemic DCM patients155
     CardAPsexperimental model of CVB3-induced myocarditis156++
    Nanocarriersexperimental autoimmune myocarditis157++

    Grade of evidence: +, weak; ++, moderate; +++, strong. CANTOS indicates Canakinumab Anti-inflammatory Thrombosis Outcome Study; CardAPs, cardiac-derived adherent proliferating cells; CVB3, coxsackievirus B3; DCM, dilated cardiomyopathy; DCMi, inflammatory dilated cardiomyopathy; HFpEF, heart failure with preserved ejection fraction; HMGB1, high-mobility group box-1; hs-CRP, high-sensitivity C-reactive protein; IL, interleukin; MI, myocardial infarction; MSC, mesenchymal stromal cells; PLX, placental-derived and expanded mesenchymal stromal cells; and Treg, T regulatory.

    IL-1β Inhibitors

    IL (interleukin)-1 is a pivotal proinflammatory cytokine amplifying the innate immune response. Upstream of IL-1 is the inflammasome, a cytosolic molecular structure composed of an adaptor protein, procaspase-1, and a sensor molecule. The best-characterized inflammasome has a sensor molecule called NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing-3).158 NLRP3 can be activated by infectious triggers known as pathogen-associated molecular patterns, including coxsackievirus B3 (CVB3) RNA,159 and by endogenous stimuli known as damage-associated molecular patterns such as heat shock proteins, breakdown products of the extracellular matrix, oxidized lipoproteins, ATP, cholesterol crystals, and S100 proteins.158 On activation of the NLRP3 inflammasome, procaspase-1 is converted to active caspase-1, which then cleaves the pro–IL-1 into mature IL-1β.160 Experimental data suggest that the NLRP3 inflammasome plays a central role in myocarditis.158,159,161–163 Therefore, biological treatments that block the IL-1 pathway,164 including the IL-Ra (IL-1 receptor antagonist) anakinra, the fully human IgG1 anti–IL-1β monoclonal antibody, canakinumab, and colchicine are potential candidates to treat myocarditis. Observational data demonstrated a decrease in EMB NLRP3 mRNA expression in CVB3-positive patients, who eliminated CVB3 and improved cardiac function over time.159 An inverse correlation between IL-1β and the antiviral IFN-β158 further supports that acute CVB3 myocarditis subjects would be a reasonable cohort in whom to study these compounds in phase 1 clinical trials.

    Anakinra

    Early studies by Ikonomidis et al165 of patients with rheumatoid arthritis without heart failure, indirectly suggested a beneficial effect of IL-1 blockade therapy on cardiac function. Anakinra has been evaluated in clinical trials in patients with more common cardiovascular disorders, including acute myocardial infarction (VCU-ART [Virginia Commonwealth University-Anakinra Remodeling Trial]-1 and VCU-ART-2 pilot studies),126,166 acute decompensated heart failure,127,167 heart failure with preserved EF,128,168 and idiopathic recurrent pericarditis.169 In brief, anakinra blunted the acute inflammatory response associated with ST-segment elevation acute myocardial infarction. Although it failed to show a statistically significant effect on LV-EF in the examined cohort of clinically stable patients with near-normal LV dimensions and function, it led to a numerically lower incidence of heart failure.126 The safety and efficacy of anakinra during the acute phase of ST-segment elevation myocardial infarction will be further explored in a randomized placebo-controlled double-blinded multicenter study with a follow-up of 12 months.170 In recently decompensated systolic heart failure, anakinra treatment for 12 weeks, but not for 2 weeks, improved peak Vo2, suggesting a benefit for prolonged anakinra treatment.167 In heart failure with preserved ejection fraction, IL-1 blockade with anakinra for 14 days significantly reduced the systemic inflammatory response and improved the aerobic exercise capacity of patients with heart failure with preserved ejection fraction and elevated plasma CRP (C-reactive protein) levels,128 whereas treatment with anakinra for 12 weeks failed to improve peak Vo2 in a group of obese heart failure with preserved ejection fraction patients.168 In patients with colchicine resistance and corticosteroid-dependent recurrent pericarditis, anakinra reduced the risk of recurrence over a median of 14 months.169 Individual patients with fulminant myocarditis have recovered after anakinra was added to standard therapy.129,130 A double-blind, randomized clinical trial phase IIb evaluating ARAMIS (anakinra versus placebo for the treatment of acute myocarditis) is currently ongoing.171

    Canakinumab

    The anti–IL-1β monoclonal antibody, canakinumab, has been shown to safely reduce high-sensitivity CRP, IL-1β, and IL-6 levels in patients with stable coronary artery disease (CANTOS [Canakinumab Anti-inflammatory Thrombosis Outcome Study] trial131). Its potential still needs to be proven in myocarditis scenarios.

    Colchicine

    Colchicine is a plant alkaloid that has been used for centuries to treat gout.172 Pharmacologically, it interacts with the cytoskeleton protein tubulin, disrupting the cytoskeleton-dependent cellular processes including motility, mitosis, chemotaxis, and adhesion, primarily of neutrophils. NLRP3 inflammasome assembly, and subsequent IL-1β production are also profoundly inhibited by colchicine.136,172,173 Additionally, colchicine has antifibrotic and endothelial-protective features.173 Colchicine has been shown to improve cardiac outcomes in inflammatory cardiac disorders,136 including pericarditis,132–135 coronary artery disease,136 and postpericardiotomy syndrome.137,138

    The 2015 ESC guideline on the management of pericarditis recommends colchicine as first-line treatment for different forms of pericarditis.174 However, clinical trials in pericarditis, specifically associated with troponin elevation have not been performed.132,134,135 The overlap of inflammatory mechanisms between myocarditis and pericarditis nonetheless suggests that colchicine may benefit myocarditis, at least in some immunologic milieu.133 For example, in a C57BL/6J murine model of CVB3-induced myocarditis, colchicine improved myocarditis through reduction of NLRP3 activity.175 Gultekin et al176 also reported a small case series with improvement of EF in 5 myocarditis patients following low-dose colchicine in addition to conventional heart failure therapy. Negative results of colchicine in experimental CVB3-induced C3H mice177 suggest that colchicine may be most relevant in a subset of human disease with specific immunophenotypes.

    HMGB1 Inhibitors

    HMGB1 (high-mobility group box-1), an ubiquitous nuclear protein involved in transcription regulation, DNA replication and repair, and nucleosome assembly, is passively released by necrotic tissues or actively secreted by stressed cells.178 Levels of this damage-associated molecular pattern are elevated in EMB and plasma of patients with acute myocarditis. In troponin I-immunized mice, HMGB1 expression is increased in myocardium and serum. Inhibition of HMGB1 in this model decreased tissue damage.139 Additional studies are necessary to further define the mechanisms underlying these observations. Nonetheless, HMGB1 may be a therapeutic target in acute autoimmune myocarditis.179

    S100A9 Inhibitors

    The damage-associated molecular patterns, also called alarmins, S100A8 and S100A9 (alternatively known as MRP8 [myeloid-related protein] and MRP14, respectively) are Ca2+-binding proteins belonging to the S100 family. They predominantly form the heterodimer S100A8/S100A9,180 which has physiological and proinflammatory functions under various conditions,181 whereas S100A8 and S100A9 homodimers are proinflammatory per se.182 These alarmins are abundantly expressed in neutrophils and monocytes and are released during inflammatory responses.181 Accumulating evidence demonstrates an involvement of S100A8 and S100A9 in cardiovascular disorders like coronary artery disease183 and viral infections.184 Related to myocarditis, CVB3-positive patients express more EMB S100A8 and S100A9 versus CVB3-negative patients. A decrease in myocardial expression of S100A8 and S100A9 is associated with an improved clinical outcome in CVB3-positive patients, who eliminated the CVB3 virus over time.142 Based on the relevance of S100A8 and S100A9 in CVB3 myocarditis185 and accumulating data on S100A8 and S100A9 activation of the NLRP3 inflammasome,186 S100A8/A9 seems an attractive therapeutic target for the treatment of acute CVB3 myocarditis. Quinoline-3-carboxamides (Q-compounds), including paquinimod,140 tasquinimod,141 and laquinimod that bind to S100A9, preventing S100A9 binding to Toll-like receptor-4 and the receptor for advanced glycated end products140 are currently in clinical development for both autoimmune disease and cancer. Their potential to treat myocarditis has not been evaluated to date.

    In a clinical study of nonviral, autoimmune myocarditis, S100A8 expression in the myocardial proteome predicted recovery from DCM after treatment with immunoadsorption. These data suggest that S100A8 in EMB or S100A8/S100A9 in serum may be useful to refine selection for immunotherapies in patients with myocardial inflammation.143 Data from translational clinical studies of other clinical settings suggest an association between high serum levels of S100A8/S100A9 and risk for future myocardial infarction and cardiovascular death in healthy individuals.183 Existing biomarkers including troponin, natriuretic peptides, and copeptin midregional proadrenomedullin do not provide a high degree of diagnostic or prognostic accuracy in acute myocarditis.14 The potential value of S100A8/S100A9 as a biomarker for myocarditis is currently under investigation.187

    Modulation of T Cells

    Regulatory T Cells Transfer and IL-2 Agonists

    CD4+CD25+FoxP3+ regulatory T (Treg) cells, a subset of CD4+ cells, constituting 5% to 10% of the peripheral T cells, are increasingly being recognized as crucial for the resolution or progression of myocarditis.188 Studies in myocarditis144 and DCM189 have shown that Treg cells are quantitatively and qualitatively impaired under these conditions and consequently ineffective to balance the immune system. Particularly in autoimmune myocarditis, a lower proportion of Treg cells has been shown to be associated with a greater Th17 response and more severe autoimmune myocarditis,190 whereas patients with idiopathic DCM have a reduced ratio of Treg/Th17 cells in the blood.191 Th17 cells and associated cytokines appear as major drivers mainly in chronic myocarditis. This follows from findings where depletion of IL-17, or of signal transducer and activator of transcription 3, both critical for Th17 differentiation, results in decreased severity of autoimmune myocarditis in mice.192,193 Further evidence states that IL-17A stimulates cardiac fibroblasts to produce GM-CSF (granulocyte macrophage colony-stimulating factor) and CCL2 (C-C motif chemokine ligand 2; also known as monocyte chemoattractant protein-1), which is critical for the recruitment and differentiation of proinflammatory Ly6Chi monocytes/macrophages.194,195

    Restoration of the Treg/Th17 balance196 via direct Treg cell application might therefore be an attractive strategy to treat myocarditis. This hypothesis is corroborated by experimental studies showing that prophylactic144,145 and therapeutic146 adoptive transfer of Treg cells improves CVB3 myocarditis. Thanks to new technologies allowing Treg cell expansion,197 production of Treg cells for clinical application are possible. Alternatively, the use of IL-2 agonists,147 promoting Treg cell production and mature Treg cell survival and suppressor function,198 can be used. The therapeutic potential of Treg cells in DCMi patients still needs to be investigated.

    Mesenchymal Stromal Cells

    Mesenchymal stromal cells are well known for their cardioprotective and particularly immunomodulatory properties and have consistently been shown to improve myocarditis in experimental models of CVB3-induced myocarditis,148–152 chronic Chagas cardiomyopathy,153 and autoimmune-induced DCMi.154 Given the relevance of the cardiosplenic axis, that is, the homing of immune cells from the spleen to the heart and their subsequent involvement in cardiac remodeling,199,200 in myocarditis,157 particularly the immunomodulatory properties of mesenchymal stromal cells may be a benefit in myocarditis. Similar to mesenchymal stromal cells, EMB-derived mesenchymal-like stromal cells (CardAP cells) have been shown to improve experimental myocarditis.156 Clinical-grade placenta-derived mesenchymal-like stromal cells, expanded in a 3-dimensional bioreactor system,201–203 have been shown to increase Treg cells and to induce cardioprotection in different experimental models of heart failure.204,205 Their low alloimmunogenicity allows their use as a human leukocyte antigen-unmatched off-the-shelf product.202 Transendocardial injection of autologous and allogeneic mesenchymal stromal cells in nonischemic DCM patients have been shown to be safe and clinical efficient in the randomized POSEIDON-DCM trial (Percutaneous Stem Cell Injection Delivery Effects On Neomyogenesis-DCM).155

    Nanocarriers

    Multiple strategies are under investigation to target cardiac tissue to increase efficacy and decrease toxicity of proposed pharmacological treatments. Nanocarriers are nanomaterials used to transport biological or pharmacological agents and are made of polymers, liposomes, carbon-based materials, or metals such as gold. They can be designed to decrease the degradation of the drug,206,207 to deliver a biological agent like siRNA157 or antagomIR,208 and to direct these molecules to a target organ like the heart.209–211 In the setting of myocarditis or DCMi, nanocarriers have been evaluated or will be of value (1) to reduce monocyte maturation in the bone marrow and trafficking to the heart157,212; (2) target fibroblasts to reduce the fibrosis following the inflammatory phase; and (3) target myocytes to reduce apoptosis.

    Future Directions for Management of Acute Myocarditis

    Since publication of the Myocarditis Treatment Trial59 nearly 25 years ago, substantial mechanistic insights have resulted in only a few definite clinical advances in acute myocarditis disease management. The diagnosis of myocarditis by EMB permits specific therapy for GCM, eosinophilic myocarditis, and meaningful refined prognosis for patients requiring MCS. The prognostic value of a viral genome amplified from heart tissue seems to vary with the virus. No antiviral therapy has been shown in a clinical trial (or adequately studied) to modify the risk of death or heart transplantation in acute myocarditis. The absence of a viral genome may select a cohort with chronic myocarditis that responds to azathioprine and prednisone, after maximal guideline-directed medical therapy has been implemented. There are many ongoing and planned interventional trials based on EMB findings that may expand the use of EMB in the near term. Until more definitive studies have been reported, individual patient decisions should be made with shared decision-making that includes the uncertainties in our present knowledge of myocarditis management strategies. These uncertainties also underlie the differing classes of recommendation between guidelines and position statements for EMB in acute myocarditis.

    Detailed EMB-based analysis from translational studies has led to the identification of novel diagnostic and prognostic markers that differentiate the mechanistically heterogeneous pool of patients with myocarditis in smaller cohorts who may benefit from individualized interventions.9,101,213,214 Though, the field is still in its infancy and data showing benefit of cause-based therapies are limited due to the lack of large, randomized clinical trials. The greatest obstacles to design adequately powered trials to achieve these clinical advances remain the rarity of acute severe myocarditis215 and the significant rate of improvement in patients with guideline-directed medical care. The insights gained from analysis of the tissue compartment remain invaluable for research and the advancement of knowledge, which is needed to impact clinical care. The call for cause-based large randomized clinical trials to evaluate target-specific therapies is open.

    Nonstandard Abbreviations and Acronyms

    ARAMIS

    Anakinra Versus Placebo for the Treatment of Acute Myocarditis

    B19V

    parvovirus B19

    BICC

    betaferon in chronic viral cardiomyopathy

    CANTOS

    Canakinumab Anti-Inflammatory Thrombosis Outcome Study

    CAPACITY

    Cortisone in Parvovirus Inflammatory Cardiomyopathy

    CCL2

    C-C motif chemokine ligand 2

    cMRI

    cardiac magnetic resonance imaging

    CRP

    C-reactive protein

    CVB3

    coxsackievirus B3

    DCMi

    inflammatory dilated cardiomyopathy

    EF

    ejection fraction

    EMB

    endomyocardial biopsy

    ESC

    European Society of Cardiology

    GCM

    giant cell myocarditis

    GM-CSF

    granulocyte macrophage colony-stimulating factor

    HHV-6

    human herpesvirus 6

    HMGB1

    high-mobility group box-1

    IFN

    interferon

    IL

    interleukin

    IL-Ra

    IL-1 receptor antagonist

    LV

    left ventricle

    MCS

    mechanical circulatory support

    NLRP3

    nucleotide-binding domain and leucine-rich repeat pyrin domain containing-3

    PROPELLA

    prolonged LV Impella

    Treg

    regulatory T cells

    VCU-ART

    Virginia Commonwealth University-Anakinra Remodeling Trial

    Footnotes

    Correspondence to Leslie T. Cooper, MD, Department of Cardiovascular Medicine, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224. Email

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