Mechanisms of Long Duration Fibrillation, Defibrillation and Refibrillation

描述（由申请人提供）：虽然许多心脏骤停（SCA）是由除颤前持续数分钟的心室颤动（VF）（长时间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（短时间VF [SDVF]）的第一分钟进行的。LDVF与SDVF明显不同，体外除颤与内除颤的冲击电位梯度分布也明显不同。除颤后自发性再颤在低密度房颤后很常见，但在重度房颤后不常见。本提案的目标是利用狗的电测绘来获得关于LDVF机制的基本信息，以及它们与SDVF、LDVF的除颤和LDVF后的自发再颤的区别，希望这些知识将有助于改进SCA的治疗。具体的目标都将在同一个实验中实现。具体目标探讨LDVF维持的机制，并与SDVF维持的机制进行比较。有待检验的假设包括：(1)LDVF由浦肯野纤维产生的波前维持，而非SDVF； (2) LDVF是存在动作电位持续时间恢复的I型VF，而不是传导速度恢复重要的II型VF； (3) VF期间工作心肌的传导阻滞是由前进波前的难耐性、低兴奋能力、坏死区域或异质Connexin 43表达引起的。具体目标2。探讨LDVF后除颤失败的机制。将检验以下假设：LDVF后的除颤与SDVF后的除颤不同：(1)除颤需要更高的最小冲击电位梯度，(2)心肌对冲击的破坏性影响更敏感，或(3)冲击成功阻止了LDVF，但VF很快复发。在工作心肌中记录激活之前，浦肯野活化发生在休克后暂停期间，这一假设将得到验证。具体目标3。探讨低密度房颤除颤后约1分钟自发性再颤发生的机制。将检验以下假设：再颤产生于(1)病灶，(2)再入，(3)浦肯野纤维，(4)乳头肌插入，(5)LDVF期间缺血引起的坏死区域，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.