Abstract
Arrhythmogenic cardiomyopathy (ACM) is a genetic-based cardiac disease accompanied by severe ventricular arrhythmias and a progressive substitution of the myocardium with fibrofatty tissue. ACM is often associated with sudden cardiac death. Due to the reduced penetrance and variable expressivity, the presence of a genetic defect is not conclusive, thus complicating the diagnosis of ACM. Moreover, no conventional therapies exist for fibrofatty substitution. Over the past years human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) and primary cardiac stromal cells (CStCs) have demonstrated to be suitable in vitro tools to model ACM pathophysiology. In fact, studies on ACM biospecimens showed dysregulated metabolic and redox status when compared to healthy control (CTR) subjects. However, despite these efforts there is still a substantial lack of information on the possible metabolic and redox alterations that contribute to the unfavorable phenotype of ACM cells. Hence, the aim of the present study was to perform a comprehensive mitochondrial and metabolic analysis of ACM cells. Metabolomic profiling was performed with ACM and CTR plasma using the Biocrates AbsoluteIDQ® p180 assay and in ACM- and CTR-derived cells, using an untargeted approach. Mitochondrial fitness analyses included ultrastructure, membrane potential, network connection, respiratory capacity, ROS production and cellular redox system. Our overall results provide evidence for metabolic and mitochondrial changes as co-factors in ACM progression.
Funding Sources: This research was funded by the Joint Project Südtirol- FWF (grant number 23623; Italy-Austria) and the Department of Innovation, Research and University of the Autonomous Province of Bolzano-South Tyrol (Italy).