Mechanisms of Long Duration Fibrillation, Defibrillation and Refibrillation

描述（由申请人提供）：许多心脏骤停（SCA）是由尝试除颤前几分钟存在的室颤（VF）引起的（长持续时间VF，LDVF）。然而，大多数对VF基本机制的研究都是在VF的前几十秒（短持续时间VF，SDVF）期间进行的。但是，LDVF和SDVF不同。大多数除颤机制的研究都研究了SDVF后的电击，而不是LDVF。除颤后的自发性再纤颤在LDVF后很常见，随着再纤颤发作次数的增加，生存率逐渐降低。因此，一个至关重要的目标是开发用于治疗LDVF的改进疗法，包括更好的除颤技术和预防再纤颤的方法。在上一个资助期间，我们取得了许多新的发现的重要性，在浦肯野纤维的机制，LDVF的维护，除颤LDVF，和自发性再纤颤除颤LDVF。本申请的目的是（1）验证这些新发现并研究导致这些发现的机制，以及（2）了解急性缺血（SCA的重要原因）如何改变这些基本机制，并期望这些知识将导致SCA治疗方法的合理、定向开发。将使用壁内和内膜电记录、光学记录和微电极记录来实现以下3个特定目标。拟议研究的一个优点是，这3个具体目标都将在相同的实验中完成。具体目标1。探讨LDVF维持机制。我们将检验以下假设：（1）浦肯野纤维中出现的局灶性激活和（2）内膜下母转子是LDVF维持的主要机制。如果假设1为真，我们将进行研究，以帮助区分病灶是否因埃兹、DAD或异常自律性而发生。如果假设2为真，我们将确定转子是否位于特定的心室区域，因为那里的解剖结构。具体目标2。研究LDVF后除颤失败的机制。我们将测试的假设，最早的休克后激活失败的休克后出现局灶性浦肯野纤维。如果是这样，我们将进行研究，以帮助区分病灶是由于埃兹、DAD还是异常自律性引起的。具体目标3。研究LDVF除颤后约1分钟发生自发性再纤颤的机制。我们将检验这一假设，即LDVF和HF除颤后的再纤颤是由浦肯野纤维的局灶性激活引起的。如果是这样，我们将进行研究，以帮助区分病灶是由于埃兹、DAD还是异常自律性引起的。对于这三个目标，我们将确定急性局部缺血如何改变这些机制。)

DESCRIPTION (provided by applicant): Many sudden cardiac arrests (SCAs) are caused by ventricular fibrillation (VF) that has been present for several minutes before defibrillation is attempted (long duration VF, LDVF). Yet, most studies of the basic mechanisms of VF have been performed during the first tens of seconds of VF (short duration VF, SDVF). However, LDVF and SDVF differ. Most studies of the mechanism of defibrillation have investigated shocks following SDVF, not LDVF. Spontaneous refibrillation after defibrillation is common following LDVF and survival progressively decreases as the number of refibrillation episodes increase. Therefore, a vitally important goal is the development of improved therapies for the treatment of LDVF, including better defibrillation techniques and ways to prevent refibrillation. During the last grant period, we made many new findings about the importance of focal activity arising in Purkinje fibers in the mechanisms of LDVF maintenance, defibrillation of LDVF, and spontaneous refibrillation following defibrillation of LDVF. The goals of this application are (1) to verify these new findings and investigate the mechanisms responsible for them, and (2) to obtain knowledge of how these basic mechanisms are altered by acute ischemia, an important cause of SCA, with the expectation that this knowledge will lead to the rational, directed development of improved therapy for SCA. The 3 specific aims listed below will be accomplished using intramural and endocardial electrical recordings, optical recordings, and microelectrode recordings. An advantage of the proposed studies is that the 3 specific aims will all be accomplished during the same experiments. Specific Aim 1. Investigate the mechanisms of LDVF maintenance. We will test the hypotheses that (1) focal activation arising in Purkinje fibers and (2) subendocardial mother rotors are the primary mechanism for LDVF maintenance. If hypothesis 1 is true, we will perform studies to help differentiate if the foci occur because of EADs, DADs, or abnormal automaticity. If hypothesis 2 is true, we will determine if the rotors are located in a particular ventricular region because of the anatomic structure there. Specific Aim 2. Investigate the mechanisms of failed defibrillation following LDVF. We will test the hypothesis that earliest post-shock activation following failed shocks arises focally in Purkinje fibers. If so, we will perform studies to help differentiate if the foci occur because of EADs, DADs, or abnormal automaticity. Specific Aim 3. Investigate the mechanisms of spontaneous refibrillation occurring ~1 min following defibrillation for LDVF. We will test the hypothesis that refibrillation following LDVF and defibrillation in HF is caused by focal activation arising in Purkinje fibers. If so, we will perform studies to help differentiate if the foci occur because of EADs, DADs, or abnormal automaticity. ) For all 3 aims, we will determine how these mechanisms are altered by acute regional ischemia. )