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

 描述(申请人提供)：致命性心律失常形式的心脏性猝死是心力衰竭(HF)患者的主要死亡原因。然而，目前尚不清楚HF重构的个体离子和结构变化如何促进单个心肌细胞的延迟后除极(DADS)，从而导致组织中触发的心律失常。心律失常基本上是一种组织和器官水平的现象，需要多尺度的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肌浆网(SR)中的钙火花如何引起DAD，从而作为心律失常的触发因素。尽管有这些进展，但目前的动作电位模型要么过于简单，要么计算过于密集，无法既包含亚细胞重塑的影响，又能准确地表示组织中的心律失常。我们的实验室开发了复杂的空间心肌细胞模型，结合了亚细胞钙释放单位网络，可以模拟自发的钙火花和波，从而模拟DADS。这项研究的目的是利用亚细胞、细胞和组织尺度的模型来确定DAD介导的心衰触发心律失常的潜在机制。具体目标1将集中在亚细胞和细胞内HF重塑如何促进DADS和单个心肌细胞的触发活动。将以系统的方式模拟每个单独的HF重塑变化，以分离对钙火花同步和DAD形成具有全球影响的关键机制。这不仅将提高我们对DAD在心力衰竭发病机制中的认识，也为DAD的预防策略提供了新的思路。具体目标2将集中于阐明DAD介导的心力衰竭重塑组织中触发心律失常的机制。心肌细胞和缝隙连接重塑可以产生DAD，它们结合在一起形成致心律失常的触发物和底物。结合亚细胞和细胞重塑的偶联心肌细胞将在电缆中模拟，以确定HF重塑和电压-钙反馈对触发的组织中活动的启动和传播的影响。这些拟议的研究不仅将有助于更好地理解心力衰竭的心律失常发生机制，而且还将提供理解复杂生物系统所需的多尺度方法的理想培训。

 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.