Exploration of Arrhythmogenic Triggers and Substrates in Heart Failure

心力衰竭致心律失常触发因素和基质的探索

• 批准号: 9198047
• 负责人: IGOR R EFIMOV
• 金额: $ 69.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198047
• 关键词: Adrenergic Agents; Affect; Arrhythmia; Behavior; Cardiac Myocytes; Caveolae; Cell physiology; Cells; Cessation of life; Chemosensitization; Clinical Research; Complex; Coupling; Data; Development; Disease; Electrophysiology (science); Fiber; Fibrosis; Generations; Genes; Geometry; Health Expenditures; Healthcare Systems; Heart; Heart Rate; Heart failure; Heterogeneity; Hospitalization; Hot Spot; Human; Incidence; Ion Channel; Link; Location; MRI Scans; Membrane; Modeling; Molecular; Morbidity - disease rate; Muscle Cells; Organ; Pathologic; Patients; Pharmacology; Phosphorylation; Proteins; Research; Resolution; Rest; Risk; Risk stratification; Scanning; Signal Transduction; Source; Structure; Sudden Death; Thinness; Tubular formation; Validation; Ventricular; Ventricular Fibrillation; aging population; end of life; experimental study; global health; improved; insight; mortality; nerve supply; non-Native; novel; patch clamp; prevent; public health relevance; simulation; spatiotemporal; statistics; sudden cardiac death; voltage

 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.

 描述（由适用提供）：心力衰竭（HF）是发病率和死亡率的主要原因，对全球健康支出显着贡献。由于心律不齐引起的猝死 在HF患者中造成50％以上的死亡；但是，将HF诱导的分子重塑与猝死风险增加的机制尚不清楚。这导致了无效的药理疗法，以防止心律不齐的死亡以及HF患者心律不齐的风险分层的方法不足。拟议的研究的总体目标是探索一组新型的机制，通过这些机制，HF重塑，从细胞亚微区域到整个心脏，导致人类HF中致命性心律失常的风险增加。我们建议，我们建议调查肌细胞微域降解对L型Ca通道和细胞功能的降解的影响如何通过电生理重新构造和疾病诱导的II阵列的反思结构中的电位生理重塑和肾上腺素结构的异质性在区域扩增。 变性为心室效果（VF）。该项目提出了人类HF中心律失常的综合实验/计算方法。超分辨率扫描斑块夹将提供新的见解，以了解亚细胞隔室的破坏如何影响HF细胞中L型Ca通道的功能。该数据将用作对综合人HF肌细胞模型的输入，该模型将在验证后将在器官级HF模型中实现。蛋白质和微观结构分布数据，告知器官级模型的蛋白质和微观结构分布数据将在具有外植的HF人类心脏的实验中收集。 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.在HF患者的临床研究中，将验证有关心律失常和VF可能性的模拟结果。此处提出的研究的完成将导致对导致人体HF心律不齐和猝死的机制有更多的了解。预计这种机械理解将减少HF对受害者的影响和对医疗保健系统的影响1）提出靶向且有效的新分子疗法，以及2）通过导致HF患者的心律不齐风险地层的新方法和改进的方法。