Myocarditis is an under recognized disease due to the variable nature of its presentation, different mechanisms and phases of myocardial damage and the difficulty in accurate diagnosis. As a consequence the evidence base for treatment is scant.
Virtually any infective, autoimmune, drug or toxin has been implicated in the pathogenesis of myocarditis. Common viral causes and their mechanism of action are detailed in Table 1. In brief myocyte damage may be caused directly (cardiotropic and vasculotropic viruses) or indirectly (lymphotropic viruses) by infiltration of the heart. Some viruses do not infect cardiac cells but cause cardiac injury by triggering a cytokine storm or invoking an adverse cellular response. Recently Parvovirus B19, HHV6 and Coxackie B (especially in young children) are the commonest viruses.
Mechanisms of Myocardial Damage
The initial damage caused by viruses may be direct effect on the myocyte or endothelium. Following infection the virus may be cleared, persist leading to chronic or recurrent myocarditis or lie dormant without causing disease. However much of myocardial inflammation is driven by the immune response to the initial insult (Figure 1). Immune cells are first recruited to the myocardium during the early acute phase of infection with the innate system triggered first with neutrophils, natural killer (NK) cells, and macrophages followed later by cells of the adaptive system including T & B cells. In most patients this leads to resolution of myocarditis and clinical recovery but in some, the immune reaction is excessive or persistent, mediated by pro-inflammatory cytokines, compounding the initial damage and leading to myocardial fibrosis and end stage cardiac failure indistinguishable from idiopathic DCM.
Figure 1. Martens & Accornero. Viruses in the Heart: Direct and Indirect Routes to Myocarditis and Heart Failure. Viruses 2021;13:1924
Myocarditis presents as several distinct clinical profiles. Typically, acute myocarditis presents with a poorly functioning ventricle with or without dilation, recent heart failure symptoms, and viral infectious symptoms in the preceding weeks. Fulminant myocarditis presents as cardiogenic shock; tachyarrhythmias are common, and inotropic or mechanical circulatory support (MCS) may be needed. Chronic persistent myocarditis occurs in the setting of cardiac symptoms such as chest pain, often with preserved systolic function, and histologist evidence of persistent myocardial inflammation.
Unfortunately the clinical presentation is not specific for myocarditis, neither are the echocardiogram, ECG and biomarkers features. A diagnostic algorithm is preented in Figure 2. Cardiac MRI has emerged as the imaging modality of choice, however there are many circumstances when it is not possible - mechanical support in progress, unstable patient etc. Biopsy has been the "gold standard" and the Dallas Criteria are still used, however the clinical situation may be too unstable to be a safe procedure and sampling errors are an issue - especially as cMRI suggests the greatest inflammation is the LV free wall, an inaccessible location for biopsy.
Both cMRI and immunohistochemical pathology do however provide the best means of identifying the viral insult, the phase of myocarditis and directing management.
Figure 2. Adapted from Diagnosis and Management of Myocarditis in Children. Yuk Law et al. Circulation. 2021;144:e123–e135. Figure 3.
The initial management of heart failure is no different than that of any other etiology. Supportive therapy, often including mechanical circulatory support and arrhythmia treatment may be needed, especially in fulminant myocarditis. Specific treatment can be directed against the specific viruses (if known) and the adverse effects of inflammation with immunosuppression (Table 1 and Figure 3). Conclusive data for specific treatments in children are not available. In adults targeting virus in their replicating (not latent) state appears to be of benefit by increasing the likelihood of their elimination and this corresponds to a clinical improvement. Immunosuppression has also been shown to improve the outcome in giant cell myocarditis.
Figure 3. Adapted from Myocarditis and inflammatory cardiomyopathy: current evidence and future directions. Nature Reviews Cardiology 2021;18:169. Figure 7
Specific antiviral therapy, when the features of myocarditis and replicating virus is present in the biopsy should be given. However standard qPCR for the viral genome may be positive, even of the virus is latent and, so when available, further testing for replication should be carried out utilizing technology e.g. RNAscope® able to detect single molecules necessary for viral replication. Table 1 outlines the specific antiviral treatments including Interferon dose and increasingly specific treatments are available for SARS-CoV-2. Consideration should also be given to removal of cytokines and other pro-inflammatory molecules with immunoadsorption. The anti-viral actions of interferon include direct killing, activation of antigen presenting dendritic cells, clonal expansion of virus-specific T cells and antibody producing B cells. IVIG has several anti-viral actions including preventing cell penetration, and activating the innate immune system cells and the complement pathways and is known to have significant activities against CMV, VZV, HSV, EBV, Parvovirus B19.
Immunosuppression is indicated in giant cell myocarditis, myocarditis in the absence of replicating virus and eosinophilic myocarditis*. Protocols are similar to those for cardiac transplantation - intravenous anti-thymocyte globulin and methylprednisolone, tacrolimus and mycophenolate mofetil. Anti-infective prophylaxis should be given as per the transplant protocol.
* Eosinophils are also implicated in parasite-mediated, drug- induced or hypersensitivity myocarditis
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Last Updated: April 2023