A Toolbox of Potential Immune-Related Therapies for Inflammatory Cardiomyopathy

Abstract

Myocarditis is a multifactorial disorder, characterized by an inflammatory reaction in the myocardium, predominantly triggered by infectious agents, but also by antigen mimicry or autoimmunity in susceptible individuals. Unless spontaneously resolved, a chronic inflammatory course concludes with cardiac muscle dysfunction portrayed by ventricular dilatation, clinically termed inflammatory cardiomyopathy (Infl-CM). Treatment strategies aim to resolve chronic inflammation and preserve cardiac function. Beside standard heart failure treatments, which only play a supportive role in this condition, systemic immunosuppressants are used to diminish inflammatory cell function at the cost of noxious side effects. To date, the treatment protocols are expert-based without large clinical evidence. This review describes concept and contemporary strategies to alleviate myocardial inflammation and sheds light on potential inflammatory targets in an evidence-based order.

Keywords: Immunomodulation; Immunosuppression; Inflammatory cardiomyopathy.

Fig. 1

Empirical immunosuppression treatment options for endomyocardial biopsy-proven microbial-negative myocardial inflammation, based on reported clinical evidence and expert-opinions. Red gradient indicates higher risk of immunosuppression-associated side effects and poorer clinical experience. Different immunosuppressive combinations are clinically relevant in cases of drug-specific contraindications and/or severe side effects. AZP, azathioprine; MTX, methotrexate; RTX, rituximab; MMF, mycophenolate mofetil. *AZP is not recommended in cases with chronic liver disease. **Single-center experience, used in patients developing nephrotoxicity in response to CsA. ***Used in cases with EMB-proven persistent CD20+ B lymphocyte infiltrates

Fig. 2

Strategies for antagonizing NLRP3 pathway myocarditis-related key inflammatory components. (1) Upon binding of the S100A8/S1009 heterodimer to the Toll-like receptor 4 (TLR 4) or receptor for advanced glycation end product (RAGE) on an innate immune cell, reactive oxygen species (ROS) are generated in the cytosol, which leads to the activation and translocation of the nuclear factor kappa B (NF-κB) to the nucleus. Alternatively, viral single-stranded RNA, as by coxsackievirus B3 (CVB3), can activate the intracellular receptor nucleotide-binding oligomerization domain-containing protein 2 (NOD-2), which also activates NF-κB. The latter acts as transcription factor that stimulates the mRNA expression of the nucleotide the oligomerization domain-containing, leucine-rich repeat-containing, and pyrin domain-containing protein (NLRP3) inflammasome and of pro-IL-1ß. (2) Upon activation by K+ efflux, ATP, ROS, and other damage-associated molecular patterns, NLRP3 polymerizes with the adaptor protein ASC and caspase 1. Subsequently, caspase 1 cleaves pro-IL-1ß to its active form: IL-1ß. (3) The active cytokine IL-1ß is secreted to the extracellular space, where it binds to its receptor and induces autocrine and paracrine signaling on other immune cells. Q-compounds block step (1) upstream; colchicine blocks step (2); canakinumab and anakinra block step (3) via different mechanisms