The Role of the Immune System in Pathobiology and Therapy of Myocarditis: A Review

Abstract

The role of the immune system in myocarditis onset and progression involves a range of complex cellular and molecular pathways. Both innate and adaptive immunity contribute to myocarditis pathogenesis, regardless of its infectious or non-infectious nature and across different histological and clinical subtypes. The heterogeneity of myocarditis etiologies and molecular effectors is one of the determinants of its clinical variability, manifesting as a spectrum of disease phenotype and progression. This spectrum ranges from a fulminant presentation with spontaneous recovery to a slowly progressing, refractory heart failure with ventricular dysfunction, to arrhythmic storm and sudden cardiac death. In this review, we first examine the updated definition and classification of myocarditis at clinical, biomolecular and histopathological levels. We then discuss recent insights on the role of specific immune cell populations in myocarditis pathogenesis, with particular emphasis on established or potential therapeutic applications. Besides the well-known immunosuppressive agents, whose efficacy has been already demonstrated in human clinical trials, we discuss the immunomodulatory effects of other drugs commonly used in clinical practice for myocarditis management. The immunological complexity of myocarditis, while presenting a challenge to simplistic understanding, also represents an opportunity for the development of different therapeutic approaches with promising results.

Keywords: autoimmune disease; drug repurposing; immune system; immunosuppressive therapy; myocarditis; systemic immune-mediated disease.

Figure 1

Diagnostic criteria for clinically suspected myocarditis, modified from Caforio et al. [1]. Myocarditis is a highly heterogeneous disease; these criteria were defined in 2013 by the European Society of Cardiology (ESC) Working Group on Myocardial and Pericardial Diseases with the purpose of facilitating clinicians in recognizing myocarditis and addressing selected patients to second- or third-level examinations and possible etiological treatment. ^a Clinically suspected myocarditis is diagnosed if ≥1 clinical presentation (upper panel) and ≥1 diagnostic criteria (lower panel) from different categories are present; if no symptoms are reported, ≥2 diagnostic criteria (lower panel) should be met. Legend: CMR: cardiac magnetic resonance; ECG: electrocardiogram; LGE: late gadolinium enhancement; LV: left ventricle; RV: right ventricle; TnI: troponin I; TnT: troponin T.

Figure 2

A schematic résumé of possible myocarditis etiologies; adapted from Brociek et al. [15] and from Tschöpe et al. [16]. The list is not exhaustive. ^a Viral presence in the myocardium is to be assessed through viral Polymerase Chain Reaction (PCR). Legend: CAR: coxsackievirus and adenovirus receptor; CMV: cytomegalovirus; EBV: Epstein–Barr virus; HCV: hepatitis C virus; HHV-6: human herpesvirus 6; HIV: human immunodeficiency virus; ICI: immune checkpoint inhibitors.

Figure 3

Immunomodulatory effects of repurposed drugs in myocarditis. The figure shows the main pathogenetic mechanisms in myocarditis that are targeted not only by classical immunosuppressive agents, but also by other drugs with a different primary mechanism of action. (PPAR = Peroxisome Proliferator Activated Receptor; SGLT-2 = Sodium/Glucose Cotransporter 2; ARNI = Angiotensin receptor-neprilysin inhibitors; ACE = Angiotensin converting enzyme; AT1R = Angiotensin-II Receptor 1; DDP-4 = Dipeptidyl Peptidase 4; NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells; Th = T helper lymphocyte; M = macrophage; MHC-II = Major histocompatibility complex class II; APC = antigen presenting cell). Created with BioRender.com.