Determinants of Arrhythmogenic Risk In Arrhythmogenic Cardiomyopathies and Mitral Valve Prolapse

摘要 心律失常性心肌病是心脏的遗传性或获得性异常，其提供基质和 引发和维持室性心律失常的触发器。室性心律失常包括罕见的过早 心室收缩（PVC）更多地涉及PVC的负担，然后可以触发持续的 室性心动过速，即使自行终止，也是未来非终止性VT的预兆， 血流动力学不稳定且如果不通过除颤终止则致命。不同的细胞，分子， 环境病因学已被认为可以解释心肌病的发病机制 包括纤维化和瘢痕、心肌细胞的病理性兴奋性，甚至是来自于骨骼或骨骼的影响， 骨髓来源的髓样细胞。我们假设，虽然心肌病有不同的 它们具有共同的细胞、分子和微环境特征， 包含可被靶向以获得治疗益处的定型的致肿瘤小生境。这一行政 资助的R 01 HL 162369的补充，标题为“发现致心律失常的分子靶点 心肌病治疗学”的重点是研究单细胞空间的致瘤性心肌病， 分辨率这一补充的目标是应用这些方法来剖析细胞和分子 在以纤维化为基质的模型中致炎性心肌病微环境 并与电触发器合谋，首先在一个致心肌病小鼠模型中， R 01，然后与来自人致心律失常性二尖瓣脱垂（MVP）的心脏组织进行比较，其中 二尖瓣装置的纤维化作为基质。我们的目标是定义：（1）细胞亚群，分子 途径，和潜在的细胞通讯途径激活的机械诱导的促凋亡 使用单细胞/细胞核RNA-Seq的基质和（2）机械- 通过结合结构组织学分析和空间转录组学以及单个 细胞分辨率smFISH。所提出的补充产生的结果将有利于原来的促癌 心肌病为重点的R 01通过确定治疗靶点的致瘤性心肌病以及 CAROL法案的目标是建立动态风险评估技术和揭示机制， 致瘤MVP。

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.