Afterdepolarizations and Cardiac Arrhythmias

后除极和心律失常

• 批准号: 7943845
• 负责人: James N Weiss
• 金额: $ 40.69万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943845
• 关键词: Action Potentials; Address; Affect; Arrhythmia; Behavior; Cardiac; Cells; Computer Simulation; Coupling; Event; Feedback; Fibroblasts; Fire - disasters; Fluorescent Dyes; Gap Junctions; Generations; Goals; Heart; Heart Diseases; Image; Individual; Life; Maintenance; Maps; Mediating; Microelectrodes; Microscopic; Modeling; Motion; Muscle Cells; Nature; Neonatal; Optics; Oryctolagus cuniculus; Patch-Clamp Techniques; Physiologic pulse; Process; Property; Public Health; Rattus; Research; Research Project Grants; Research Proposals; Role; Sarcoplasmic Reticulum; Shapes; Techniques; Testing; Time; Tissues; Torsades de Pointes; Ventricular; Ventricular Arrhythmia; Ventricular Fibrillation; Ventricular Premature Complexes; Ventricular Tachycardia; base; improved; indium arsenide; monolayer; novel; patch clamp; prevent; public health relevance; sudden cardiac death; theories; virtual; voltage

DESCRIPTION (provided by applicant): The overall objective of this research project is to achieve a better understanding of the mechanisms of arrhythmias causing sudden cardiac death by tackling the ionic and cellular mechanisms of early (EADs) and delayed (DADs) after depolarizations. EADs are classically attributed to reactivation of the L-type Ca current or to spontaneous sarcoplasmic reticulum (SR) Ca release (i.e. SR Ca release not directly gated by the L-type Ca current) in the setting of reduced repolarization reserve. DADs are attributed to spontaneous SR Ca release in the form of Ca waves stimulating Ca-sensitive inward currents such as Na-Ca exchange. Recently, we have presented evidence for a mechanism (chaos synchronization) by which EADs simultaneously create triggers and enhance tissue substrate vulnerability to promote lethal arrhythmias. A comparable theory does not yet exist, but is being developed, for DADs. The goals of this project are: i) to explore the cellular basis of EADs that set the process of chaos synchronization in motion; ii) to test whether theoretically-predicted rotors mediated by the L-type Ca current (related to the biexcitability of cardiac tissue) can be detected experimentally in cardiac tissue as a mechanism of Torsades de pointes; iii) to explore the cellular basis of DADs, specifically how the microscopic behavior of Ca release units in the sub cellular Ca cycling network integrates to generate Ca alternans, Ca waves, DADs and EADs at the whole cell level; iii) to explore the interactions between EADs and DADs that together generate triggers and modify substrate by increasing tissue electrical dispersion predisposing to VF. To accomplish these goals, we will combine patch clamp (including a dynamic patch clamp technique) and fluorescent dye studies at the cellular level with optical mapping studies at the tissue level. Improved understanding of the cellular mechanisms of after depolarizations which cause lethal arrhythmias is essential for developing novel therapy. PUBLIC HEALTH RELEVANCE: The proposed research will study the mechanisms of sudden cardiac death due to ventricular arrhythmias, which prematurely takes the lives of more than 300,000 U.S. citizens each year. The goal is to use this information to develop novel therapies to prevent this deadly manifestation of heart disease.

描述（由申请人提供）：该研究项目的总体目标是通过解决去极化后早期（EAD）和延迟（DAD）的离子和细胞机制，更好地理解心律失常导致心源性猝死的机制。 EAD 通常归因于复极储备减少的情况下 L 型 Ca 电流的重新激活或自发肌浆网 (SR) Ca 释放（即 SR Ca 释放不是由 L 型 Ca 电流直接门控）。 DAD 归因于自发的 SR Ca 以 Ca 波的形式释放，刺激 Ca 敏感的内向电流，例如 Na-Ca 交换。最近，我们提出了一种机制（混沌同步）的证据，通过该机制，EAD 同时创建触发器并增强组织基质的脆弱性，从而促进致命性心律失常。针对 DAD 的类似理论尚不存在，但正在开发中。该项目的目标是： i) 探索 EAD 的细胞基础，其启动混沌同步过程； ii) 测试理论上预测的由 L 型 Ca 电流（与心脏组织的双兴奋性相关）介导的转子是否可以在心脏组织中通过实验检测到，作为尖端扭转型室速的机制； iii) 探索 DAD 的细胞基础，特别是亚细胞 Ca 循环网络中 Ca 释放单元的微观行为如何整合以在全细胞水平产生 Ca 交替、Ca 波、DAD 和 EAD； iii) 探索 EAD 和 DAD 之间的相互作用，它们共同产生触发器并通过增加易诱发室颤的组织电分散来改变基质。为了实现这些目标，我们将细胞水平的膜片钳（包括动态膜片钳技术）和荧光染料研究与组织水平的光学图谱研究结合起来。更好地了解导致致命性心律失常的后去极化的细胞机制对于开发新疗法至关重要。 公共健康相关性：拟议的研究将研究室性心律失常导致的心源性猝死的机制，室性心律失常每年夺走超过 300,000 名美国公民的生命。我们的目标是利用这些信息来开发新的疗法来预防心脏病的这种致命表现。