Atrial arrhythmias and Ca2+ waves in HF: simulation and experimental studies

描述（由申请人提供）：心力衰竭（HF）和心房颤动（AF）在美国影响超过500万患者，并导致大量发病率和死亡率。越来越多的证据表明，心衰和房颤之间存在密切关系，一些研究表明，很大一部分心衰患者会发展为房颤。然而，尽管多年的努力，心衰和房颤之间的联系机制仍未得到很好的理解。HF的一个众所周知的特征是亚细胞结构的重塑，它破坏了心脏细胞中离子通道之间精细调谐的钙信号。此外，这种破坏促进了亚细胞Ca波的形成，这被认为是导致心脏心律失常的诱因。本研究的目的是通过在亚细胞、全细胞和组织尺度上建立Ca的多尺度计算模型，探索亚细胞重塑与心律失常之间的精确联系。该模型将直接基于最先进的激光扫描共聚焦成像完整的狗心房实验诱发HF。我们解决这个问题的方法是首先建立亚细胞Ca信号的详细模型，这将揭示结构重排如何破坏l型Ca通道（LCC）和RyR通道之间的耦合保真度。通过分析心房细胞中数千个信号单位的种群动态，我们将确定波形成的机制，以及它们如何在整个细胞水平上破坏钙循环。这些计算研究将直接基于我们在完整心房的单个细胞和细胞群中的亚细胞Ca的成像数据。我们的目标是拟合详细的波特性，如成核位点的数量和波的传播速度，并记录由于亚细胞Ca波引起的Ca失调的性质。最后，基于我们的研究结果，我们将继续开发HF细胞电压和Ca的现象学模型，该模型可用于模拟二维和三维心脏组织。然后，我们将探讨HF中的Ca失调如何通过形成异位灶兴奋和能够诱导和维持再入的异质电生理底物来促进房颤的形成。我们的实验和模拟相结合的方法将为HF和AF之间的机制关系提供重要的新见解。

DESCRIPTION (provided by applicant): Heart failure (HF) and atrial fibrillation (AF) affect more than 5 million patients in the US and cause substantial morbidity and mortality. There is increasing evidence of a close relationship between HF and AF, and several studies have shown that a large fraction of patients with HF go on to develop AF. However, despite years of effort, the mechanism linking HF and AF is not well understood. A well- established feature of HF is the remodeling of subcellular structures which disrupts the finely tuned Ca signaling between ion channels in the cardiac cell. Furthermore, this disruption promotes the formation of subcellular Ca waves which are believed to drive triggered arrhythmias in the heart. The goal of this study is to explore the precise link between subcellular remodeling and arrhythmias using a multi-scale computational model of Ca at the subcellular, whole cell, and tissue scale. This model will be based directly on state-of-the-art laser scanning confocal imaging of the intact dog atrium in experimentally- induced HF. Our approach to this problem is to first develop a detailed model of subcellular Ca signaling, which will shed light on how structural rearrangement disrupts the coupling fidelity between L-type Ca channels (LCC) and RyR channels. By analyzing the population dynamics of thousands of signaling units in an atrial cell we will determine the mechanisms for wave formation, and how they disrupt Ca cycling at the whole cell level. These computational studies will be directly based on our imaging data of subcellular Ca within single cells and groups of cells in the intact atrium. Our aim is to fit detailed wave properties such as the number of nucleation sites and wave propagation velocity, and also to record the nature of Ca dysregulation due to subcellular Ca waves. Finally, based on our findings, we will proceed to develop a phenomenological model of voltage and Ca of HF cells, which can be used to simulate two and three dimensional cardiac tissue. We will then explore how Ca dysregulation in HF can contribute to the formation of AF through formation of both ectopic focal excitations and a heterogeneous electrophysiological substrate capable of inducing and maintaining reentry. Our combined experimental and simulation approach will provide critical new insights into the mechanistic relationship between HF and AF.