Fibrillation and Defibrillation

描述（由申请人提供）：本基金申请的目的是通过了解室颤（VF）和电除颤的发病机制，在机制层面上开发一种合理的方法来治疗心脏性猝死。我们已经证明，动态因素，如电恢复和兴奋性，有助于启动和维持在VF的波。这些动力因素的改变导致兔心室室颤的两种类型。1型室颤与陡峭的动作电位时程（APD）恢复、正常的兴奋性和多个小波有关。2型VF与平坦APD恢复、降低的兴奋性和时空周期性相关。我们还开发了方法，同时地图膜电位（Vm）和细胞内钙（Cai）在正常和患病兔心室。初步结果表明，蔡循环是一个关键因素，控制多个方面的动态波稳定性。此外，我们还发现Cai循环在电除颤机制中也可能发挥作用。由于电击是唯一有效的治疗VF，我们建议进行进一步调查的重要性，蔡循环的机制，心室除颤。我们将使用正常家兔和缺血性心肌病和起搏诱导心肌病的家兔模型来进行这些研究。同时Vm和Cai标测和单细胞跨膜电位记录将用于确定Cai循环、后去极化和除颤电击后触发活动之间的关系。具体目标1将检验Cai循环在1型VF的电击后重新启动中很重要的假设。具体目标2将检验Cai循环在2型VF电击后再启动中很重要的假设。具体目标3将检验Cai循环在确定脆弱性上限方面很重要的假设。我们期望这些研究将提高对心室除颤机制的理解，并导致更好地管理有心脏性猝死风险的患者。

DESCRIPTION (provided by applicant): The objective of this grant application is to develop a rational approach to therapy of sudden cardiac death through understanding of the pathogenesis of ventricular fibrillation (VF) and electrical defibrillation at the mechanistic level. We have demonstrated that dynamic factors, such as electrical restitution and excitability, contribute to initiation and maintenance of wavebreak during VF. Alteration of these dynamic factors results in two types of VF in rabbit ventricles. The type 1 VF is associated with steep action potential duration (APD) restitution, normal excitability and multiple wavelets. Type 2 VF is associated with flat APD restitution, reduced excitability and spatiotemporal periodicity. We also developed methods to simultaneous map membrane potential (Vm) and intracellular calcium (Cai) in normal and diseased rabbit ventricles. Preliminary results suggest that Cai cycling is a critical factor that controls multiple aspects of dynamic wave stability. Furthermore, we found that Cai cycling might also play a role in the mechanisms of electrical defibrillation. Because electrical shock is the only effective therapy for VF, we propose to perform further investigations on the importance of Cai cycling in the mechanisms of ventricular defibrillation. We will use normal rabbits and rabbit models of ischemic cardiomyopathy and pacing-induced cardiomyopathy to pursue these studies. Simultaneous Vm and Cai mapping and single cell transmembrane potential recordings will be used to determine the relationship between Cai cycling, afterdepolarizations and triggered activity after defibrillation shocks. The Specific Aim 1 will test the hypothesis that Cai cycling is important in the post-shock re-initiation of Type 1 VF. The Specific Aim 2 will test the hypothesis that Cai cycling is important in the post-shock reinitiation of Type 2 VF. The Specific Aim 3 will test the hypothesis that Cai cycling is important in determining the upper limit of vulnerability. We expect that these studies will improve the understanding of the mechanisms of ventricular defibrillation and lead to better management of patients at risk of sudden cardiac death.