Mechanisms of Long Duration Fibrillation, Defibrillation and Refibrillation

描述(申请人提供)：虽然许多心脏骤停(SCA)是由除颤前持续几分钟的室颤(长持续VF[LDVF])引起的，但大多数关于VF和除颤的研究都是在使用内部除颤电极的VF(短持续VF[SDVF])的第一分钟进行的。LDVF与SDVF有明显不同，体外除颤的激波电位梯度分布明显不同于内除颤。除颤后的自发性房颤在LDVF后常见，但在SDVF后不常见。这项建议的目的是利用狗的电地形图来获得关于LDVF的机制以及它们与SDVF、LDVF的除颤和LDVF后的自发复颤有何不同的基本信息，希望这些知识将有助于改进SCA的治疗。具体的目标都将在相同的实验中实现。具体目的1.探讨LDVF的维持机制，并与SDVF的维持机制进行比较。有待检验的假说包括(1)LDVF而不是SDVF由浦肯野纤维产生的波前维持，(2)LDVF是动作电位时程恢复的I型VF，而不是传导速度恢复重要的II型VF，以及(3)VF期间工作心肌的传导阻滞是由于前进的波前、坏死区或连接蛋白43表达不应性、低兴奋能力引起的。具体目的2.探讨LDVF术后除颤失败的机制。假设LDVF后的除颤不同于随后的SDVF，因为(1)除颤需要更高的最小电击电位梯度，(2)心肌对电击的损害更敏感，或(3)电击成功地阻止了LDVF，但VF迅速复发。这一假设将得到验证，即浦肯野激活发生在工作心肌记录到激活之前的休克后停顿期间。具体目的3.探讨LDVF除颤后约1分钟发生自发性复颤的机制。假说将被检验为：(1)病灶，(2)折返，(3)浦肯野纤维，(4)乳头肌插入，(5)LDVF期间缺血引起的坏死区，或(6)心肺复苏期间胸部按压引起的再灌注。

DESCRIPTION (provided by applicant): While many sudden cardiac arrests (SCA), are caused by ventricular fibrillation (VF) lasting several mins (long duration VF [LDVF]) before defibrillation, most studies of VF and defibrillation have been performed during the first min of VF (short duration VF [SDVF]) with internal defibrillation electrodes. LDVF differs markedly from SDVF and the distribution of the shock potential gradient for external defibrillation differs markedly from internal defibrillation. Spontaneous refibrillation following defibrillation is common after LDVF but not SDVF. The goal of this proposal is to use electrical mapping in dogs to obtain basic information about the mechanisms of LDVF and how they differ from SDVF, defibrillation of LDVF, and spontaneous refibrillation following LDVF, with the hope that this knowledge will lead to improved therapy for SCA. The specific aims will all be accomplished in the same experiments. Specific Aim 1. Investigate the mechanisms of maintenance of LDVF and compare them to those of SDVF maintenance. Hypotheses to be tested include (1) LDVF but not SDVF is maintained by wavefronts arising from Purkinje fibers, (2) LDVF is type I VF in which action potential duration restitution is present rather than type II VF in which conduction velocity restitution is important, and (3) conduction block in the working myocardium during VF is caused by refractoriness, low excitatory capability of the advancing wavefronts, regions of necrosis, or heterogeneous Connexin 43 expression. Specific Aim 2. Investigate the mechanisms of failed defibrillation following LDVF. Hypotheses will be tested that defibrillation following LDVF differs from that following SDVF in that (1) a higher minimum shock potential gradient is needed to defibrillate, (2) the myocardium is more sensitive to the damaging effects of shocks, or (3) the shock successfully halts LDVF but VF quickly recurs. The hypothesis will be tested that Purkinje activation occurs during the postshock pause before activation is recorded in working myocardium. Specific Aim 3. Investigate the mechanisms of spontaneous refibrillation occurring about 1 min following defibrillation for LDVF. Hypotheses will be tested that refibrillation arises from (1) a focus, (2) reentry, (3) Purkinje fibers, (4) papillary muscle insertions, (5) necrotic regions caused by ischemia during LDVF or (6) reperfusion caused by chest compressions during cardiopulmonary resuscitation.