Exploration of Arrhythmogenic Triggers and Substrates in Heart Failure

 描述（由申请人提供）：心力衰竭（HF）是发病率和死亡率的主要原因，对全球卫生支出有重大贡献。心律失常导致猝死 导致超过50%的HF患者死亡;然而，HF诱导的分子重塑与猝死风险增加之间的联系机制仍知之甚少。这导致预防猝死的药物治疗无效，以及HF患者心律失常风险分层方法不足。拟议研究的总体目标是探索一套新的机制，通过该机制，从亚细胞微域到整个心脏，HF重构导致人类HF致死性心律失常风险增加。具体而言，我们建议研究肌细胞微区降解对L型Ca通道和细胞功能的影响如何通过电生理重构和肾上腺素能神经支配的异质性以及疾病诱导的心室结构重构产生i）心律失常触发因素和ii）它们的局部放大艾德。 心室纤颤（VF）。该项目提出了一个综合的实验/计算方法，在人类HF的hemogenesis。超分辨率扫描膜片钳技术将为研究亚细胞区室的破坏如何影响HF细胞中L型钙通道的功能提供新的视角。该数据将用作整合人HF肌细胞模型的输入，该模型在验证后将在器官水平HF模型中实施。将在使用心脏衰竭的人心脏的实验中收集通知器官水平模型的蛋白质和微结构分布数据。模型组件将与HF人类心脏几何形状/结构的MRI扫描相结合，以开发多尺度HF心室模型，然后将其用于确定负责形成1）“热点”（触发活动源自该热点）和2）心率接近静息时的致心律失常基质（导致触发活动退化为VF）的机制。将在HF患者的临床研究中验证在这些心率下关于致炎底物和VF可能性的模拟结果。完成这里提出的研究将导致对人类HF中导致心律失常和猝死的机制的更深入的理解。这种机制的理解预计将减少HF对其受害者和医疗保健系统的影响，1）通过提出有针对性的和有效的新分子疗法，2）通过导致新的和改进的方法来对HF患者的心律失常风险分层。

 DESCRIPTION (provided by applicant): Heart failure (HF) is a major cause of morbidity and mortality, contributing significantly to global health expenditure. Sudden death due to arrhythmia is responsible for over 50% of deaths among HF patients; however, the mechanisms linking HF-induced molecular remodeling to increased sudden death risk remain poorly understood. This has resulted in ineffective pharmacologic therapy for preventing sudden arrhythmic death and in inadequate approaches to arrhythmia risk stratification of HF patients. The overall objective of the proposed research is to explore a novel set of mechanisms by which HF remodeling, from the sub-cellular microdomain to the whole heart, leads to increased risk of lethal arrhythmias in human HF. Specifically, we propose to investigate how the impact of the degradation of myocyte microdomains on L-type Ca channel and cellular function is amplified regionally by the heterogeneities in electrophysiological remodeling and adrenergic innervation as well as by the disease-induced remodeling in ventricular structure to produce i) arrhythmia triggers and ii) their degeneration into ventricular fibrillation (VF). The project presents an integrated experimental/computational approach to arrhythmogenesis in human HF. Super-resolution scanning patch clamp will provide novel insight into how disruption of sub-cellular compartments affects L-type Ca channel functioning in the HF cell. This data will be used as input into an integrative human HF myocyte model, which following validation, will be implemented in organ-level HF models. Protein and microstructure distribution data informing the organ-level models will be gathered in experiments with explanted HF human hearts. Model components will be combined with MRI scans of HF human heart geometry/structure to develop multiscale HF ventricular models which will then be used to determine the mechanisms responsible for the formation of 1) "hot spots", from which triggered activity emanates, and 2) arrthythmogenic substrates at heart rates near rest, causing the degradation of triggered activity into VF. Simulation results regarding the arrhythmogenic substrate and VF likelihood at these heart rates will be validated in a clinical study of HF patients. Completion of the studies proposed here will result in a greater understanding of the mechanisms leading to arrhythmias and sudden death in human HF. Such mechanistic understanding is expected to reduce the impact of HF on its victims and on the health-care system 1) by suggesting targeted and effective new molecular therapies, and 2) by leading to new and improved approaches to arrhythmia risk stratification of HF patients.