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

基本信息

项目摘要

 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(由申请人提供):致命性心律失常形式的心源性猝死是心力衰竭(HF)患者死亡的主要原因。然而,目前尚不清楚心力衰竭重塑的个体离子和结构变化是如何促进的。单个肌细胞中的延迟后去极化(DAD)可导致组织中触发的心律失常。心律失常本质上是一种组织和器官水平的现象。一种多尺度的方法可以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) 中的钙火花如何产生 DAD。尽管取得了这些进展,但当前的动作电位模型要么太简单,要么计算量太大,无法既考虑亚细胞重塑的影响,又能够准确地表示组织中的心律失常。开发了包含亚细胞 Ca 释放单元网络的复杂空间肌细胞模型,该模型可以模拟自发的 Ca 火花和波,从而模拟 DAD。本研究的目标是使用亚细胞模型确定 DAD 介导的心力衰竭触发的潜在机制。具体目标 1 将重点关注亚细胞和细胞 HF 重塑如何促进 DAD 并触发单个肌细胞的活动,以系统的方式模拟每个单独的 HF 重塑变化。对 Ca 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 HF 中 DAD 发生的理解,而且还将提供对 DAD 预防策略的深入了解。具体目标 2 将重点阐明 DAD 介导的机制。心力衰竭重构组织中引发的心律失常和间隙连接重构可产生 DAD,它们结合形成心律失常触发因素和结合亚细胞和基质的耦合肌细胞。将在电缆中模拟细胞重塑,以确定心力衰竭重塑和电压钙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提高对心力衰竭致心律失常机制的理解,而且还将提供理想的结果。了解复杂生物系统所需的多尺度方法的培训。

项目成果

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Michael Bon-Hao Liu其他文献

Michael Bon-Hao Liu的其他文献

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{{ truncateString('Michael Bon-Hao Liu', 18)}}的其他基金

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:
    9122993
  • 财政年份:
    2016
  • 资助金额:
    $ 4.32万
  • 项目类别:

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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
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    9122993
  • 财政年份:
    2016
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    $ 4.32万
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