Afterdepolarizations and Cardiac Arrhythmias

描述（由申请人提供）：本研究项目的总体目标是通过解决去极化后早期（EADs）和延迟（DADs）的离子和细胞机制，更好地了解心律失常引起心源性猝死的机制。在复极化储备减少的情况下，EADs通常归因于l型Ca电流的再激活或自发肌浆网（SR） Ca释放（即SR Ca释放不直接由l型Ca电流控制）。DADs归因于自发的SR Ca释放，以Ca波的形式刺激钙敏感的内向电流，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，EADs同时创建触发器并增强组织底物脆弱性，从而促进致命性心律失常。一个类似的理论目前还不存在，但正在开发中。该项目的目标是：i)探索在运动中设置混沌同步过程的EADs的细胞基础；ii)测试理论预测的由l型Ca电流介导的转子（与心脏组织的双兴奋性有关）能否作为点扭转的机制在心脏组织中被实验检测到；iii)探索DADs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在整个细胞水平上集成以产生Ca交替、Ca波、DADs和ead；iii)探索EADs和DADs之间的相互作用，它们共同产生触发器，并通过增加易发生VF的组织电色散来修饰基底。为了实现这些目标，我们将结合膜片钳（包括动态膜片钳技术）和细胞水平的荧光染料研究与组织水平的光学作图研究。进一步了解导致致死性心律失常的去极化后的细胞机制对开发新的治疗方法至关重要。

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.