Inflammation in the Pathogenesis of Arrhythmogenic Cardiomyopathy: Secondary Event or Active Driver?

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a rare inherited cardiac disease characterized by arrhythmia and progressive fibro-fatty replacement of the myocardium, which leads to heart failure and sudden cardiac death. Inflammation contributes to disease progression, and it is characterized by inflammatory cell infiltrates in the damaged myocardium and inflammatory mediators in the blood of ACM patients. However, the molecular basis of inflammatory process in ACM remains under investigated and it is unclear whether inflammation is a primary event leading to arrhythmia and myocardial damage or it is a secondary response triggered by cardiomyocyte death. Here, we provide an overview of the proposed players and triggers involved in inflammation in ACM, focusing on those studied using in vivo and in vitro models. Deepening current knowledge of inflammation-related mechanisms in ACM could help identifying novel therapeutic perspectives, such as anti-inflammatory therapy.

Myocarditis-like Episodes in Patients with Arrhythmogenic Cardiomyopathy: A Systematic Review on the So-Called Hot-Phase of the Disease

“…While in the last few years the possible role of inflammation in ACM onset and progression led to a significant number of publications, few detailed clinical studies on a large cohort of patients with “hot-phases” can be found [ 23 , 24 , 25 , 26 ]. We were able to select only 9 studies describing cohorts of patients affected with ACM who showed myocarditis-like episodes [ 5 , 8 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

“…Several studies suggested that inflammation, either reactive to internal influences or triggered by exogenous factors, has a role in the pathogenesis of ACM. In addition, most of the evidence on the role of inflammation and autoimmunity in this disease derives from studies on desmosomal forms of disease, while non-desmosomal, as well gene-elusive forms, require further studies to assess the role of inflammation and of possible modifier factors [ 23 , 24 , 25 , 26 , 33 ]. Studies on murine models supported the evidence that ACM inflammation can precede the onset of overt histological and electrical abnormalities [ 34 ].…”

“…However, the mechanistic link between cell death and inflammation remains to be fully explained [ 35 ]. Cardiomyocyte death could be a primary event due to genetically determined desmosomal disruption, enhanced by a secondary immune reaction, leading to amplified cell death [ 23 , 24 , 25 , 26 ]. In addition, circulating anti-DSG2 autoantibodies, anti-heart autoantibodies (AHAs) and anti-intercalated disk autoantibodies (AIDAs) were identified in patients with ACM, suggesting that autoimmune response against intercalated disk components and myosin could play a role in the pathogenesis of the disease [ 36 , 37 ].…”

Arrhythmogenic Cardiomyopathy: Exercise Pitfalls, Role of Connexin-43, and Moving beyond Antiarrhythmics

“…Cardiomyocyte loss is a fundamental pathological mechanism for triggering the infiltration of immune cells and innate inflammation of the myocardial tissue, itself. The considerably damaged myocardium follows an abnormal fibrofatty deposition, acting as a flawed reparative response [ 123 ].…”

Defective Desmosomal Adhesion Causes Arrhythmogenic Cardiomyopathy by Involving an Integrin-αVβ6/TGF-β Signaling Cascade

“…These data fuel the hypothesis that disruption and rearrangement of the ICD in response to impaired adhesion between cardiomyocytes is a crucial initial step, at least in case of mutations in desmosomal molecules. Other mechanisms described in patients or translational models, such as aberrant WNT or Hippo/YAP signaling, or immune cell infiltrations, 2 , 28 may be secondary responses and in part even represent adaptive attempts to rescue the functional consequences of such severe structural aberrations.…”