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

Figures

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  Figure 1. Effect of inflammation on ACM heart. The progressive myocyte death (apoptosis and/or necrosis) and myocardial degeneration due to desmosomal defects leads to the accumulation of inflammatory cell infiltrates, that ultimately results in tissue remodeling by abnormal fibro-adipose deposition as a reparative response to replace loss of cardiomyocytes. It remains to be clarified whether the inflammatory process is the first event that determines the death of cardiomyocytes and the consequent repair process or rather is a reactive phenomenon.

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  Figure 2. Players involved in the inflammatory theory of ACM pathogenesis, ultimately leading to fibro-fatty replacement. Defects in the desmosomes caused by pathogenic mutations (A) trigger signaling cascades leading to the dysregulation of the Wnt pathway (inhibition) and the Hippo, GSK3β, NFκB, and TGF-β1/p38 MAPK pathways (activation) (B). Abnormalities in these signaling pathways lead to the activation of inflammatory, apoptotic, and fibrotic/adipogenic genes, thus resulting in the secretion of inflammatory cytokines (i.e., TNF-α, IL-1, IL-6, IL-8, IL-17) and the infiltration of inflammatory cells (i.e., T-lymphocytes, neutrophils, macrophages, mast cells) (C) and cellular damage associated with cardiac cell death (D) and fibro-fatty replacement (E). During tissue injury and myocardial degeneration, damaged mitochondria release danger-associated molecular patterns (DAMPs, as reactive oxygen species (ROS) and mitochondrial (mt)DNA fragments), thus further precipitating the immune responses and perpetuating inflammation, apoptosis and fibro-adipogenesis (F). Physical stress due to strenuous exercise not only causes mechanical injury and cell death in the presence of damaged desmosomes,…