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（埃兹）和延迟（DAD）的离子和细胞机制，更好地理解心律失常导致心脏性猝死的机制。埃兹通常归因于在复极储备降低的情况下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电流门控）。DAD归因于自发SR Ca以Ca波的形式释放，刺激Ca敏感性内向电流，如Na-Ca交换。最近，我们已经提出了一种机制（混沌同步）的证据，埃兹同时创建触发器和增强组织基质的脆弱性，以促进致命的心律失常。一个类似的理论还不存在，但正在开发中，为DAD。这个项目的目标是：i）探索埃兹的细胞基础，使运动中的混沌同步过程; ii）测试理论预测的转子是否由L型Ca电流介导（与心脏组织的双兴奋性相关）可作为尖端扭转型室性心动过速的机制在心脏组织中通过实验检测到; 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和埃兹; iii）探索EAD和DAD之间的相互作用，EAD和DAD一起产生触发物并通过增加诱发VF的组织电分散来修改底物。为了实现这些目标，我们将联合收割机膜片钳（包括动态膜片钳技术）和荧光染料在细胞水平的研究与光学映射在组织水平的研究。进一步了解后去极化导致致命性心律失常的细胞机制对于开发新的治疗方法至关重要。 公共卫生相关性：这项拟议中的研究将研究室性心律失常导致的心脏性猝死的机制，每年有30多万美国公民过早死亡。我们的目标是利用这些信息来开发新的疗法，以预防这种致命的心脏病表现。

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.