Mechanisms of Long Duration Fibrillation, Defibrillation and Refibrillation

描述（由申请人提供）：许多心脏骤停（sca）是由心室颤动（VF）引起的，在尝试除颤之前已经存在了几分钟（长时间VF， LDVF）。然而，大多数关于VF基本机制的研究都是在VF的前几十秒进行的（短时间VF， SDVF）。然而，LDVF和SDVF不同。大多数关于除颤机制的研究都是针对SDVF后的电击，而不是LDVF后的电击。LDVF患者除颤后自发性再颤很常见，随着再颤发作次数的增加，生存率逐渐降低。因此，一个至关重要的目标是发展改进的治疗LDVF的方法，包括更好的除颤技术和预防再颤的方法。在上一个资助期间，我们发现了浦肯野纤维在LDVF维持、LDVF除颤和LDVF除颤后自发性再颤机制中的重要性。本应用程序的目标是(1)验证这些新发现并研究导致它们的机制，(2)了解急性缺血如何改变这些基本机制，急性缺血是SCA的一个重要原因，期望这些知识将导致合理的、有针对性的改进SCA治疗的发展。下面列出的3个具体目标将通过心内膜和心内膜电记录、光学记录和微电极记录来完成。所提出的研究的一个优点是，这三个具体的目标都将在同一实验中完成。具体目标探讨LDVF维持的机制。我们将验证以下假设：(1)浦肯野纤维的局灶性激活和(2)心内膜下母转子是LDVF维持的主要机制。如果假设1是正确的，我们将进行研究，以帮助区分焦点是由EADs、DADs还是异常自动性引起的。如果假设2成立，我们将根据解剖结构确定转子是否位于特定的心室区域。具体目标2。探讨LDVF后除颤失败的机制。我们将检验这一假设，即在失败的冲击后最早的冲击后激活是在浦肯野纤维中局部出现的。如果是这样，我们将进行研究，以帮助区分焦点是由EADs、DADs还是异常自动性引起的。具体目标3。探讨低密度房颤除颤后1分钟自发性再颤发生的机制。我们将检验LDVF后的再颤和HF的除颤是由浦肯野纤维引起的局灶性激活引起的假设。如果是这样，我们将进行研究，以帮助区分焦点是由EADs、DADs还是异常自动性引起的。)对于这三个目标，我们将确定这些机制如何被急性局部缺血改变。)

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. ) PUBLIC HEALTH RELEVANCE: Sudden cardiac arrest caused by ventricular fibrillation (VF) is an important problem in patients with coronary heart disease. The attempt to develop better therapies to improve survival from sudden cardiac arrest at all stages of its resuscitative treatment can best be performed by first understanding the basic mechanisms of VF initiation, the maintenance of VF, defibrillation failure, and spontaneous refibrillation. Because coronary heart disease affects more than a million Americans a year and sudden cardiac arrest is a leading cause of death in these patients, we believe our research grant application, the goal of which is to obtain this basic information, is highly significant.)