Multi-scale Modeling of Calcium Mediated Triggered Activity in the Heart

描述（由申请人提供）：仅在美国，心律失常每年就导致超过30万人死亡。尽管几十年来进行了广泛的研究，但这些心律失常的潜在机制尚未完全了解。一个共同的机制，被认为是各种心律失常的基础，是在心脏的异位局灶兴奋的存在。这些异位病灶破坏了正常的窦性心律，并可产生触发性兴奋，从而导致心脏再入和/或波分形。值得注意的是，我们还不清楚是什么决定了这些焦点激发的时间、位置和形态。许多实验研究表明，在单细胞水平上，异常钙循环在这些局灶兴奋的形成中起着至关重要的作用。这些研究得到了基于基因的研究的证实，表明在易发生异位活动和纤颤的心脏中发现了钙循环蛋白的特定突变。然而，在组织和整个心脏水平上连接亚细胞Ca和局灶兴奋的详细机制尚不清楚。在这个项目中，我们建议开发一个多尺度计算框架，可以用来描述钙介导的异位灶的性质。我们的目的是探索异常钙循环如何在亚细胞水平上累积超过数千个细胞，形成组织中的异位灶。我们的计算机模型将通过弥合离子通道、细胞电生理和组织尺度电活动之间的差距，揭示潜在的机制。

DESCRIPTION (provided by applicant): Cardiac arrhythmias are responsible for more than 300,000 deaths per year in the US alone. Despite extensive research over many decades the underlying mechanisms for these arrhythmias are not completely understood. A common mechanism, believed to underlie a wide variety of arrhythmias, is the presence of ectopic focal excitations in the heart. These ectopic foci disrupt the normal sinus rhythm, and can produce triggered excitations which can lead to reentry and/or wave fractionation in the heart. Remarkably, it is not understood what determines the timing, location, and morphology of these focal excitations. Many experimental studies have shown that abnormal calcium cycling, at the single cell level, plays an essential role in the formation of these focal excitations. These studies are corroborated by gene based studies showing that specific mutations of Ca cycling proteins are found in hearts prone to ectopic activity and fibrillation. However, the detailed mechanisms linking subcellular Ca and focal excitations at the tissue and whole heart level is not known. In this project we propose to develop a multi-scale computational framework that can be used to describe the properties of Ca mediated ectopic foci. Our aim is to explore how abnormal Ca cycling at the subcellular level can summate over thousands of cells to form ectopic foci in tissue. Our computer models will shed light on the underlying mechanisms by bridging the gap between ion channels, cell electrophysiology, and tissue scale electrical activity. PUBLIC HEALTH RELEVANCE: In this project we apply multi-scale mathematical modeling to understand the underlying mechanisms for ectopic focal excitations in the heart. Insight into these mechanisms will help cardiac researchers develop gene based, or pharmacological treatments, of a wide variety of cardiac arrhythmias.