Cardiomyocyte - non myocyte interplay as a novel platform for mechanistic insights and therapeutic approaches in ACM heart failure – ACM-HF

Arrhythmogenic Cardiomyopathy (ACM) is a genetic disease, mainly affecting young people and athletes, characterized by progressive cardiomyocyte (CM) loss, fibro-adipose replacement and inflammation leading to right/biventricular heart failure (HF) and malignant arrhythmias. We recently demonstrated that human cardiac mesenchymal stromal cells (C-MSCs) are crucial contributors to ACM pathogenesis and are thus potential treatment targets. It has been recognized that CM-non myocytes interplay underlies ACM-HF. To mimic this axis, study the cellular interplay and develop a platform to test potential therapeutics, we will exploit an innovative patient-derived model combining CMs from induced pluripotent stem cells, Stromal cells and Inflammatory mediators (CSI model). Thus, the aims are: 1) determine the relative contribution of each cell type to ACM pathogenesis and underpinning mechanisms; 2) screen the ability of FDA-approved epigenetic drugs and a library of secreted factors to revert the ACM phenotype in human C-MSCs; 3) validate the capability of selected molecules to treat ACM degeneration in the CSI model. Gender and genetic background are considered in sourcing cells. With this project we expect to elucidate mechanisms underlying ACM pathogenesis and to identify new disease targets and potential therapeutics. Clinical partners ensure adequate patient recruitment. Engagement activities towards patient associations and advocacy groups will provide the pertinent evidence gaps, and explain why the project questions and outcomes are relevant to patients and caregivers.