The Landscape of Cell Death Processes with Associated Immunogenic and Fibrogenic Effects in Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a heritable myocardial disease characterized by life-threatening ventricular arrhythmias and sudden cardiac death. Cardiomyocyte death is an essential pathogenic mechanism in ACM, but the cell death landscape has never been elucidated. Our study aimed to address this problem based on RNA-sequencing (RNA-seq) data. Myocardial RNA-seq data from arrhythmogenic right ventricular cardiomyopathy (ARVC) patients and normal controls were obtained from the Gene Expression Omnibus database (GSE107475, GSE107311, GSE107156, GSE107125). Signature gene sets of cell death processes, immune cells, and pathways were collected. Single-sample gene-set enrichment analysis calculated the enrichment scores for these signature gene sets. The RNA-seq data of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) derived from an ACM patient were used for validation (GSE115621). Weighted gene coexpression network analysis (WGCNA) was applied to identify coexpression modules. Immunogenic cell death, apoptosis, necroptosis, and pyroptosis were significantly up-regulated in ARVC. Positive correlations of these four up-regulated cell death processes with immune cells and pathways were found within the ARVC myocardium. In the ARVC sample cluster with higher cell death levels, central memory CD4 T cell, memory B cell, type 1 T helper cell, mast cell, natural killer T cell, and plasmacytoid dendritic cell were more substantially infiltrated. Similarly, immune pathways were more up-regulated in this cluster. Positive linear correlations were found between cell death, immune responses, and myocardial fibrosis within the ARVC samples. Eventually, WGCNA identified a shared coexpression module related to these mechanisms. This study first demonstrated the landscape of cell death processes in the ACM (ARVC) myocardium and their positive correlations with immune responses and myocardial fibrosis. These mechanisms have potential interactions and jointly contribute to the pathogenesis of ACM.