Triggered arrhythmias induced by heart failure remodeling: A multi-scale computational approach

心力衰竭重塑诱发的心律失常：一种多尺度计算方法

• 批准号: 9767259
• 负责人: Michael Bon-Hao Liu
• 金额: $ 4.32万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767259
• 关键词: ATP phosphohydrolase; Action Potentials; Acute myocardial infarction; Affect; Arrhythmia; Ca(2+)-Transporting ATPase; Calcium; Calcium Oscillations; Cardiac; Cardiovascular system; Cause of Death; Cell model; Cells; Chronic; Clinical; Clinical Research; Complex; Computer Simulation; Coupled; Coupling; Disease; Down-Regulation; Electrophysiology (science); Endoplasmic Reticulum; Exhibits; Failure; Feedback; Future; Gap Junctions; Goals; Heart Rate; Heart failure; Impairment; In Vitro; Individual; Influentials; Ion Channel; L-Type Calcium Channels; Laboratories; Lead; Mechanics; Mediating; Modeling; Muscle Cells; Organ; Oryctolagus cuniculus; Patients; Play; Prevention strategy; Property; Pump; Relaxation; Research; Risk; Role; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Structure; Subcellular structure; Syndrome; Testing; Tissue Model; Tissues; Training; Tubular formation; Up-Regulation; Ventricular; clinically relevant; complex biological systems; experimental study; heart cell; heart function; heart rhythm; improved; indium arsenide; insight; mortality; public health relevance; simulation; sudden cardiac death; tool; voltage

 DESCRIPTION (provided by applicant): Sudden cardiac death in the form of lethal arrhythmias is a major cause of death in patients in heart failure (HF). However, it is still not wll understood how the individual ionic and structural changes of HF remodeling promote delayed after-depolarizations (DADs) in single myocytes which can lead to triggered arrhythmias in tissue. Arrhythmias are fundamentally a tissue and organ level phenomenon which necessitates a multi-scale approach to fully understand how subcellular changes can affect the heart's function as a whole. Computational modeling of calcium (Ca) dynamics has given us insight into how calcium sparks in the sarcoplasmic reticulum (SR) can give rise to DADs that can act as arrhythmogenic triggers. Despite these advances, current action potential models have either been too simple or too computationally intensive to both incorporate the effects of subcellular remodeling while still accurately representing arrhythmias in tissue. Our lab has developed complex spatial myocyte models incorporating the subcellular Ca release unit network that can simulate spontaneous Ca sparks and waves and thus DADs. The goal of this study is to determine the underlying mechanisms of DAD-mediated triggered arrhythmias in HF using models at the subcellular, cellular, and tissue scales. Specific Aim 1 will focus on how subcellular and cellular HF remodeling promotes DADs and triggered activity in single myocytes. Each individual HF remodeling change will be simulated in a systematic manner to isolate the key mechanisms that are globally influential for Ca spark synchronization and DAD formation. This will not only improve our understanding of DAD-genesis in HF, but also provide insight into DAD prevention strategies. Specific Aim 2 will focus on elucidating the mechanisms of DAD-mediated triggered arrhythmias in the remodeled tissue of HF. Myocyte and gap junctional remodeling can generate DADs that combine to form both arrhythmogenic triggers and substrates. Coupled myocytes incorporating the subcellular and cellular remodeling will be simulated in a cable to identify the effects of HF remodeling and voltage-Ca feedback on triggered activity initiation and propagation in tissue. These proposed studies will not only lead to improved understanding of arrhythmogenic mechanisms in HF, but also would provide ideal training in the multi-scale approaches required to understand complex biological systems.

 描述（由适用提供）：以致命性心律不齐形式突然心脏死亡是心力衰竭患者（HF）的主要死亡原因。但是，仍然不知道HF重塑的单个离子和结构变化如何促进单个肌细胞中的延迟降低后极化（DAD），从而导致组织中的心律不齐。心律不齐是从根本上是组织和器官水平的现象，它需要采用多尺度方法来充分了解亚细胞变化如何影响心脏的整体功能。钙（CA）动力学的计算模型使我们深入了解了肌浆网中钙火花（SR）如何产生可以充当心律失常触发器的DAD。尽管有这些进展，但当前的动作潜在模型在计算上太简单或太密集了，以至于既结合了亚细胞重塑的效果，又可以准确地代表组织中心律不齐的效果。我们的实验室开发了复杂的空间心肌模型，这些模型结合了细胞释放单元网络，该模型可以模拟赞助CA火花和波浪，从而模拟了爸爸。这项研究的目的是使用亚细胞，细胞和组织尺度上的模型来确定HF中DAD介导的心律不齐的基础机制。特定的目标1将集中于亚细胞和细胞HF重塑如何促进爸爸并触发单个肌细胞的活性。每个单独的HF重塑变化将以系统的方式进行模拟，以隔离全球影响CA Spark同步和DAD形成的关键机制。这不仅将提高我们对HF中父亲生成的理解，还可以洞悉爸爸预防策略。具体目标2将集中于阐明HF重塑组织中DAD介导的触发心律不齐的机制。心肌细胞和间隙连接重塑可以产生与心律失常触发器和底物形成共同的父亲。偶联的心肌细胞增加了亚细胞和细胞重塑，将在电缆中模拟，以识别HF重塑和电压-CA反馈对触发活性启动和组织中传播的影响。这些提出的研究不仅会提高人们对HF心律失常机制的了解，而且还将在了解复杂的生物系统所需的多规模方法中提供理想的训练。