Role of the Purkinje System in Long Duration Ventricular Fibrillation

描述（由申请人提供）：间接证据表明，浦肯野系统可能在室颤（VF）最初几分钟后驱动快速激动率。本申请提出测量浦肯野系统在维持长持续时间VF（LDVF）中的作用，并确定浦肯野系统的破坏是否可能终止或显著改变LDVF激活模式。具体目标1是测量浦肯野系统和工作心肌的跨膜电压和动作电位特征，以确定在全脑缺血和LDVF快速激活速率期间这两种组织类型之间是否存在显著变化。我将检验这样一个假设，即工作心肌的膜电位升高使浦肯野系统的静息电位升高到阈值以上，从而导致浦肯野系统内的快速激活。具体目标2是直接映射和测量LDVF期间浦肯野系统的活动。我们将检验这一假设，即激活出现局灶性在浦肯野系统的网站接近浦肯野-心肌交界处。具体目标3是化学消融浦肯野系统，以确定浦肯野系统对LDVF激活率和模式的影响。具体目标4是确定是否存在针对浦肯野系统的起搏或药物干预，这些干预可能终止VF或显著降低除颤阈值。在拟议工作的指导阶段，我将学习有价值的新的心脏激活映射技术，提高我的演讲和写作技巧，并通过课程学习细胞生理学。在指导阶段结束时，我将准备好并有资格接受一家领先的研究机构进行心律失常研究的终身职位。在独立阶段，我将继续研究LDVF的浦肯野系统，并建立一个由壁外资助的研究实验室，研究心律失常的发生和持续，并制定干预措施，以提高潜在致命性心律失常患者的生存率。相关性（见说明）：美国成年人每年约有45万例心脏性猝死（SCD）。SCO通常由VF发作引起，VF在几分钟内导致心输出量急剧减少和对重要器官的不可逆损伤。浦肯野系统可能在最初2分钟后的VF维持中起重要作用，靶向浦肯野系统的治疗可能会改善这些患者的生存率。

DESCRIPTION (provided by applicant): Indirect evidence has indicated that the Purkinje system may be driving the rapid activation rate after the first few minutes of ventricular fibrillation (VF). This application proposes to measure the role of the Purkinje system in the maintenance of long duration VF (LDVF) and to determine if disruption of the Purkinje system may terminate or significantly alter LDVF activation patterns. Specific Aim 1 is to measure transmembrane voltage and action potential characteristics of the Purkinje system and working myocardium to determine if there are significant changes between these two tissue types during the global ischemia and rapid activation rate of LDVF. I will test the hypothesis that the rising membrane potential in the working myocardium raises the resting potential in the Purkinje system above threshold, which causes rapid activation within the Purkinje system. Specific Aim 2 is to directly map and measure the activity of the Purkinje system during LDVF. We will test the hypothesis that activation appears focally in the Purkinje system at sites close to Purkinje- myocardial junctions. Specific Aim 3 is to chemically ablate the Purkinje system to determine the influence of the Purkinje system on LDVF activation rates and patterns. Specific Aim 4 is to determine if there are pacing or pharmacological interventions which target the Purkinje system that may terminate VF or significantly lower the defibrillation threshold. During the mentored phase of the proposed work, I will learn valuable new cardiac activation mapping techniques, improve my presentation and writing skills, and learn cellular physiology through coursework. By the end of the mentored phase, I will be prepared and qualified to accept a tenure-track position at a leading research institution conducting cardiac arrhythmia research. During the independent phase, I will continue to investigate the Purkinje system in LDVF and establish an extramurally funded research laboratory to study the initiation and perpetuation of cardiac arrhythmias and to develop interventions to improve survival rates of patients with potentially lethal cardiac arrhythmias. RELEVANCE (See instructions): Approximately 450,000 sudden cardiac deaths (SCD) occur each year among U.S. adults. SCO often results from the onset of VF, which causes a dramatic decrease in cardiac output and irreversible damage to vital organs within a few minutes. The Purkinje system may play an important role in the maintenance of VF after the first 2 minutes and therapy targeting the Purkinje system may improve survival of these patients.