Fibrillation and Defibrillation

描述（由申请人提供）：本资助申请的目的是通过了解心室颤动（VF）的发病机制和电除颤的机制水平，开发一种合理的治疗心源性猝死的方法。我们已经证明了动态因素，如电恢复和兴奋性，有助于在VF过程中产生和维持波破。这些动力因素的改变导致了兔心室两种类型的室颤。1型VF与动作电位持续时间（APD）恢复较陡、兴奋性正常和多小波相关。2型VF与APD平坦恢复、兴奋性降低和时空周期性相关。我们还建立了同时绘制正常和患病兔心室膜电位（Vm）和细胞内钙（Cai）的方法。初步结果表明，Cai循环是控制动波稳定性多个方面的关键因素。此外，我们发现Cai循环也可能在电除颤机制中发挥作用。由于电击是唯一有效的治疗室性颤动的方法，我们建议进一步研究Cai循环在心室除颤机制中的重要性。我们将使用正常兔和兔缺血性心肌病和起搏性心肌病模型来进行这些研究。同时Vm和Cai映射和单细胞跨膜电位记录将用于确定除颤后Cai循环、后去极化和触发活动之间的关系。具体目标1将检验Cai循环在1型VF休克后再启动中重要的假设。特异性目的2将检验Cai循环在2型VF休克后再启动中重要的假设。具体目标3将检验Cai循环在确定脆弱性上限方面的重要假设。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.