Pathophysiological Regulation of Atrial Alternans and Atrial Fibrillation

心房交替和心房颤动的病理生理调节

基本信息

批准号：
9907864
负责人：
LOTHAR A BLATTER
金额：
$ 38.75万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9907864
关键词：
3-Dimensional Action Potentials Arrhythmia Atrial Fibrillation Calcium Cardiac Cell Communication Cell model Cells Chlorides Complex Computer Models Computer Simulation Coupling Disease Ectopic beats Electrophysiology (science)Etiology Event Feedback Frequencies Generations Goals Heart Heart Atrium Heart Diseases Heart failure Heterogeneity Ice Image Inositol Intracellular Signaling Proteins Left Link Mediating Membrane Mitochondria Modeling Muscle Cells Organ Oryctolagus cuniculus Pharmacology Play Predisposition Probability Property Proteins Refractory Regulation Risk Risk Factors Role Sarcoplasmic Reticulum Severities Signal Pathway Signal Transduction Source Surface System Testing Therapeutic Therapeutic Intervention Time Tissues Tubular formation Up-Regulation Validation Ventricular design intercellular communication novel pressure receptor spatiotemporal sudden cardiac death targeted treatment theories therapy design uptake voltage

项目摘要

PROJECT SUMMARY/ABSTRACT Atrial fibrillation (AF), the most common form of cardiac arrhythmia, is preceded by episodes of alternans in the atrium. These beat-to-beat alternations in action potential (AP) duration, contraction strength and Ca transient (CaT) amplitude form a dynamic AF substrate by creating temporal and spatial heterogeneity of electrical tissue properties and Ca signaling. Heart failure (HF) induced atrial remodeling changes the expression and regulation of key Ca handling proteins thereby promoting profound changes of excitation-contraction coupling (ECC) that further increase susceptibility to atrial arrhythmogenic Ca release and alternans. Due to the lack or paucity of a transverse tubular system atrial ECC reveals unique features that are strikingly different from ventricular myocytes and make atrial cells especially prone to develop alternans. The bidirectional coupling of membrane voltage (Vm) and [Ca]i regulation (Vm↔[Ca]i coupling) creates complex feedback mechanisms that play a pivotal role for the generation of alternans. Therefore, the overall goal of this proposal is to establish an experimentally tested mechanistic model of atrial alternans and to establish a mechanistic link between atrial alternans, atrial remodeling in HF and AF at the cellular, multicellular and whole heart level. Specific aim 1. Identify the cellular mechanisms of electrical (AP duration, APD) and CaT alternans in atrial myocytes. We will test the hypothesis that disturbances of atrial Ca signaling during ECC (sarcoplasmic reticulum (SR) Ca load hypothesis vs. refractoriness hypothesis) are the primary cause of alternans and through the regulation of Ca-dependent membrane conductances (voltage-gated L-type Ca, Na/Ca exchange, Ca-dependent chloride and small conductance Ca-activated K currents) Ca alternans determines electrical APD alternans and increase the propensity of proarrhythmic Ca release events. Specific aim 2. Identify the HF remodeling attributes that enhance atrial alternans propensity. We will test the hypothesis that atrial Ca signaling proteins and pathways as well as the ECC mechanism undergo profound remodeling in HF that result in a higher propensity of atrial alternans. In a rabbit left-ventricular HF model we will further test how enhanced IP3 receptor-mediated Ca release, increased SR Ca leak and remodeled mitochondrial Cauptake facilitates the probability of atrial alternans. Specific aim 3. Establish a mechanistic causation linking atrial alternans and AF. Tissue arrhythmia (AF) requires cell-to-cell communication, an arrhythmogenic focus (ectopic activity) and transient or permanent tissue inhomogeneity (conduction heterogeneity). In Langendorff perfused hearts (normal and HF) the spatio- temporal properties of tissue-wide APD and CaT alternans and the relationship to AF inducibility will be investigated by atrial bipolar electrograms, multielectrode surface mapping and Ca imaging. In cell pairs cell-to- cell communication mechanism underlying alternans will be investigated. Therapeutic strategies will be developed to curtail the increased risk of alternans and AF in HF.

项目概要/摘要心房颤动 (AF) 是最常见的心律失常形式，其发生之前会出现交替性心律失常发作。心房的动作电位 (AP) 持续时间、收缩强度和 Ca 瞬时变化。 (CaT) 振幅通过创建电的时间和空间异质性来形成动态 AF 基质组织特性和 Ca 信号传导。心力衰竭（HF）诱导的心房重塑改变了表达和。调节关键的 Ca 处理蛋白，从而促进兴奋-收缩耦合的深刻变化 (ECC) 进一步增加了由于缺乏或导致房性心律失常的 Ca 释放和奥特那的易感性。横向管状系统心房 ECC 的缺乏揭示了与心室肌细胞并使心房细胞特别容易产生交替。膜电压 (Vm) 和 [Ca]i 调节（Vm↔[Ca]i 耦合）创建了复杂的反馈机制，因此，该提案的总体目标是建立一个替代方案。经过实验测试的心房交替机制模型，并建立心房交替之间的机制联系 alternans，HF 和 AF 中细胞、多细胞和整个心脏水平的心房重塑。具体目标 1. 确定电（AP 持续时间，APD）和 CaT 交替的细胞机制我们将检验 ECC（肌浆细胞）期间心房 Ca 信号传导紊乱的假设。网状（SR）钙负荷假说与不应性假说）是交替的主要原因通过调节 Ca 依赖性膜电导（电压门控 L 型 Ca、Na/Ca 交换、 Ca 依赖的氯化物和小电导 Ca 激活的 K 电流）Ca 交替决定电 APD 交替并增加促心律失常 Ca 释放事件的倾向。具体目标 2. 确定增强心房交替倾向的心力衰竭重塑属性。检验心房 Ca 信号蛋白和通路以及 ECC 机制经历的假设心力衰竭的巨大重塑导致兔子左心室心力衰竭的心房交替倾向更高。我们将进一步测试如何增强 IP3 受体介导的 Ca 释放、增加 SR Ca 渗漏和重塑的线粒体 Cauptake 促进心房交替的可能性。具体目标 3. 建立心房交替和 AF 之间的机制因果关系。需要细胞间通讯、致心律失常病灶（异位活动）以及短暂或永久在 Langendorff 灌注心脏（正常和心力衰竭）中，组织不均匀性（传导异质性）。组织范围 APD 和 CatT 交替的时间特性以及与 AF 诱导性的关系将是通过心房双极电图、多电极表面测绘和细胞对细胞间 Ca 成像进行研究。将研究替代疗法背后的细胞通讯机制。开发用于减少心力衰竭中奥特那和房颤风险增加。