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室颤（VF）（长持续时间VF [LDVF]）引起的，但大多数VF和除颤研究都是在VF（短持续时间VF [SDVF]）的第一分钟内使用内部除颤电极进行的。LDVF明显不同于SDVF，体外除颤的冲击电位梯度分布明显不同于体内除颤。除颤后的自发性再纤颤在LDVF后很常见，但在SDVF后不常见。本提案的目标是使用犬的电标测来获得有关LDVF机制的基本信息，以及它们与SDVF、LDVF除颤和LDVF后自发性再纤颤的区别，希望这些知识将导致SCA治疗的改进。具体目标都将在相同的实验中实现。具体目标1。探讨LDVF的维持机制，并与SDVF的维持机制进行比较。待检验的假设包括（1）由浦肯野纤维产生的波前维持LDVF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很重要的II型VF，以及（3）VF期间工作心肌中的传导阻滞是由不应性、前进波前的低兴奋能力、坏死区域或异质性连接蛋白43表达。具体目标2。研究LDVF后除颤失败的机制。将测试LDVF后除颤与SDVF后除颤的不同之处在于（1）除颤需要更高的最小电击电位梯度，（2）心肌对电击的损伤效应更敏感，或（3）电击成功停止LDVF但VF迅速复发。将检验浦肯野激活发生在工作心肌中记录激活之前的休克后暂停期间的假设。具体目标3。探讨LDVF除颤后约1分钟发生自发性再纤颤的机制。将检验以下假设：（1）病灶、（2）折返、（3）浦肯野纤维、（4）乳头肌附着、（5）LDVF期间缺血引起的坏死区域或（6）心肺复苏期间胸外按压引起的再灌注。

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.