Mechanisms of Long Duration Fibrillation, Defibrillation and Refibrillation

描述(申请人提供)：许多心脏骤停(SCA)是由室颤(VF)引起的，这种室颤在除颤尝试之前已经存在了几分钟(长时间VF，LDVF)。然而，大多数对室颤基本机制的研究都是在室颤的前几十秒(短持续时间室颤，SDVF)进行的。但是，LDVF和SDVF不同。大多数除颤机制的研究都是研究SDVF后的电击，而不是LDVF。除颤后的自发复颤在LDVF后是常见的，随着复颤发作次数的增加，存活率逐渐降低。因此，一个至关重要的目标是开发治疗LDVF的改进疗法，包括更好的除颤技术和预防复颤的方法。在上一次授予期间，我们对浦肯野纤维中的焦点活动在LDVF维持、LDVF除颤和LDVF除颤后自发复颤机制中的重要性有了许多新的发现。这项应用的目标是(1)验证这些新发现并调查导致这些新发现的机制，以及(2)了解这些基本机制是如何在急性缺血(SCA的一个重要原因)的情况下改变的，并期望这些知识将导致SCA改进治疗的合理、定向的发展。下面列出的3个具体目标将使用室壁内和心内膜电记录、光学记录和微电极记录来实现。拟议的研究的一个好处是，三个特定的目标都将在相同的实验中实现。具体目的1.探讨LDVF维持的机制。我们将检验这样的假设：(1)浦肯野纤维的局部激活和(2)心内膜下母旋翼是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由于EADS、DADS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脑室区域，因为那里的解剖结构。具体目的2.探讨LDVF术后除颤失败的机制。我们将检验这一假设，即失败的电击后最早的休克后激活发生在浦肯野纤维中。如果是这样，我们将进行研究，以帮助区分是否由于EADS、DADS或异常自律性而发生病灶。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。我们将验证这一假设，即LDVF后的复颤和HF的除颤是由浦肯野纤维中的局灶性激活引起的。如果是这样，我们将进行研究，以帮助区分是否由于EADS、DADS或异常自律性而发生病灶。)对于所有这三个目标，我们将确定这些机制是如何在急性区域性缺血中改变的。) 公共卫生相关性：由室颤(VF)引起的心脏骤停是冠心病患者的一个重要问题。试图开发更好的治疗方法来提高心脏骤停复苏治疗的所有阶段的存活率，最好的方法是首先了解室颤的启动、室颤的维持、除颤失败和自发性房颤的基本机制。由于每年有100多万美国人患有冠心病，而心脏骤停是这些患者死亡的主要原因，我们认为，我们的研究拨款申请具有非常重要的意义，其目的是获得这一基本信息。)

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.)