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

 描述（由申请方提供）：致死性心律失常形式的心源性猝死是心力衰竭（HF）患者的主要死因。然而，尚不清楚HF重构的个体离子和结构变化如何促进单个肌细胞中的延迟后去极化（DAD），这可导致组织中的触发性心律失常。心律失常从根本上说是一种组织和器官水平的现象，需要多尺度的方法来充分理解亚细胞变化如何影响心脏的整体功能。钙（Ca）动力学的计算建模使我们深入了解肌浆网（SR）中的钙火花如何引起DAD，DAD可作为促炎触发因素。尽管有这些进展，目前的动作电位模型要么过于简单，要么计算密集，既纳入亚细胞重塑的影响，同时仍然准确地代表组织中的心律失常。我们的实验室已经开发了复杂的空间心肌细胞模型，结合亚细胞钙释放单元网络，可以模拟自发的钙火花和波，从而DAD。本研究的目的是使用亚细胞、细胞和组织尺度的模型确定DAD介导的HF触发性心律失常的潜在机制。具体目标1将重点关注亚细胞和细胞HF重塑如何促进DAD和触发单个肌细胞的活动。将以系统的方式模拟每个单独的HF重构变化，以分离对Ca火花同步化和DAD形成具有全局影响的关键机制。这不仅将提高我们对HF中DAD发生的理解，还将为DAD预防策略提供见解。具体目标2将侧重于阐明DAD介导的HF重塑组织中触发心律失常的机制。肌细胞和缝隙连接重塑可以产生DAD，DAD联合收割机形成致炎触发物和底物。将在电缆中模拟结合亚细胞和细胞重塑的偶联肌细胞，以确定HF重塑和电压-Ca反馈对组织中触发活动启动和传播的影响。这些拟议的研究不仅将导致更好地理解HF中的致瘤机制，而且还将为理解复杂生物系统所需的多尺度方法提供理想的培训。

 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.