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

心力衰竭中的房性心律失常和 Ca2 波：模拟和实验研究

• 批准号: 8733271
• 负责人: Yohannes Shiferaw
• 金额: $ 62.71万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8733271
• 关键词: Action Potentials; Address; Affect; Architecture; Arrhythmia; Atrial Fibrillation; Behavior; Calcium; Calcium Oscillations; Calcium Signaling; Canis familiaris; Cardiac; Cardiac Myocytes; Cell Count; Cell model; Cell physiology; Cells; Characteristics; Clinical; Clinical Research; Complex; Computer Simulation; Confocal Microscopy; Coupling; DNA Sequence Rearrangement; Data; Electrophysiology (science); Frequencies; Goals; Heart; Heart Atrium; Heart failure; Image; Incidence; Individual; Ion Channel; L-Type Calcium Channels; Laser Scanning Confocal Microscopy; Lasers; Lead; Left; Left atrial structure; Light; Link; Measurement; Measures; Mediating; Modeling; Morbidity - disease rate; Muscle Cells; Nature; Pathology; Patients; Photons; Population; Population Dynamics; Property; Ryanodine Receptor Calcium Release Channel; Scanning; Signal Transduction; Signaling Protein; Simulate; Site; Subcellular structure; Testing; Time; Tissues; Variant; base; computer framework; computer studies; improved; insight; model development; mortality; novel; public health relevance; research study; simulation; spatial relationship; three-dimensional modeling; voltage

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.

描述（由申请人提供）：心力衰竭 (HF) 和心房颤动 (AF) 影响着美国超过 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力衰竭和房颤之间存在密切关系，多项研究表明，很大一部分心力衰竭患者会继续发展为房颤。然而，尽管经过多年的努力，连接 HF 和 AF 的机制仍不清楚。心力衰竭的一个公认特征是亚细胞结构的重塑，这会破坏心脏细胞离子通道之间精细调节的 Ca 信号传导。此外，这种破坏促进了亚细胞 Ca 波的形成，据信这会引发心脏中的心律失常。本研究的目的是利用亚细胞、全细胞和组织尺度的 Ca 多尺度计算模型来探索亚细胞重塑和心律失常之间的精确联系。该模型将直接基于实验诱发的心力衰竭中完整狗心房的最先进的激光扫描共焦成像。我们解决这个问题的方法是首先开发一个详细的亚细胞 Ca 信号传导模型，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元的群体动态，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 Ca 循环。这些计算研究将直接基于我们完整心房中单细胞和细胞群内亚细胞 Ca 的成像数据。我们的目标是拟合详细的波特性，例如成核位点的数量和波传播速度，并记录亚细胞 Ca 波引起的 Ca 失调的性质。最后，根据我们的发现，我们将继续开发 HF 细胞电压和 Ca 的现象学模型，可用于模拟二维和三维心脏组织。然后，我们将探讨心力衰竭中的 Ca2+ 失调如何通过异位局灶性兴奋和能够诱导和维持折返的异质电生理基质的形成，从而促进房颤的形成。我们的实验和模拟相结合的方法将为 HF 和 AF 之间的机械关系提供重要的新见解。