Determinants of Arrhythmogenic Risk In Arrhythmogenic Cardiomyopathies and Mitral Valve Prolapse

点击翻译按钮获取中文摘要

Abstract Arrhythmogenic cardiomyopathies are inherited or acquired abnormalities of the heart that provide substrate and triggers that initiate and sustain ventricular arrhythmias. Ventricular arrhythmias range from infrequent premature ventricular contractions (PVCs) to more concerning burdens of PVCs, which can then trigger sustained ventricular tachycardia, which even if self-terminating, are harbinger of future non-terminating VT, which can be hemodynamically unstable and fatal if not terminated by defibrillation. Diverse cellular, molecular, and environmental etiologies have been suggested to explain the pathogenesis of arrhythmogenic cardiomyopathies including fibrosis and scar, pathologic excitability of cardiomyocytes, and even influences from resident or bone marrow derived myeloid cells. We hypothesize that although arrhythmogenic cardiomyopathies have distinct origins and etiologies, they share a common set of cellular, molecular, and microenvironmental features comprising a stereotyped arrhythmogenic niche that can be targeted for therapeutic benefit. This administrative supplement to the funded R01 HL162369 entitled, “Uncovering Molecular Targets for Arrhythmogenic Cardiomyopathy Therapeutics” is focused on studying arrhythmogenic cardiomyopathy with single cell spatial resolution. The goal of this supplement is to apply these methods to dissect the cellular and molecular microenvironment of the arrhythmogenic cardiomyopathy niche in models where fibrosis serves as a substrate and conspires with electrical triggers, first in an arrhythmogenic cardiomyopathy mouse model from the funded R01 and then by comparison to heart tissue from human arrhythmogenic mitral valve prolapse (MVP), where fibrosis of the mitral valvular apparatus acts as a substrate. We aim to define: (1) the cell subsets, molecular pathways, and potential cellular communication pathways activated by mechanically-induced arrhythmogenic substrates using single cell/nuclei RNA-Seq and (2) the spatial location and organization of the mechanically- induced arrhythmogenic niche by combining structural histologic analysis with spatial transcriptomics and single cell resolution smFISH. Results generated by the proposed supplement will benefit the original arrhythmogenic cardiomyopathy-focused R01 by identifying therapeutic targets for arrhythmogenic cardiomyopathy as well as the CAROL Act goal of building dynamic risk assessment technologies and uncovering mechanisms underlying arrhythmogenic MVP.