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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：心力衰竭 (HF) 是发病和死亡的主要原因，对全球因心律失常导致的猝死造成重大影响。超过 50% 的心力衰竭患者死亡是由心力衰竭引起的；然而，人们对心力衰竭引起的分子重塑与猝死风险增加之间的联系仍知之甚少，这导致预防心律失常死亡的药物治疗无效，且心律失常风险的治疗方法不充分。拟议研究的总体目标是探索一套新的机制，通过这些机制，从亚细胞微区到整个心脏的心力衰竭重塑会导致致命风险增加。具体来说，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塑和肾上腺素神经支配的异质性以及疾病诱导的重塑而局部放大。在心室结构中产生 i) 心律失常触发因素和 ii) 它们的该项目提出了一种研究人类心力衰竭心律失常发生的综合实验/计算方法，将为了解亚细胞区室的破坏如何影响 L 型 Ca 通道功能提供新的见解。 HF 细胞。该数据将用作综合人类 HF 肌细胞模型的输入，经过验证后，将在器官水平 HF 模型中实施，从而提供信息。器官级模型将在移植的 HF 人类心脏的实验中收集，模型组件将与 HF 人类心脏几何/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的机制。 1)“热点”，从中发出触发活动，以及 2) 心率接近静息时的致心律失常底物，导致触发活动退化为室颤关于致心律失常底物和的模拟结果。这些心率下的室颤可能性将在心力衰竭患者的临床研究中得到验证。完成此处提出的研究将有助于更好地了解导致人类心力衰竭和猝死的机制。心力衰竭对其受害者和医疗保健系统的影响 1) 通过建议有针对性的有效的新分子疗法，2) 通过提出新的和改进的方法对心力衰竭患者进行心律失常风险分层。