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)的最初几分钟后驱动快速激动率。本申请建议测量浦肯野系统在维持长持续期室颤(LDVF)中的作用，并确定浦肯野系统的中断是否会终止或显著改变LDVF的激活模式。具体目的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性，以确定在全脑缺血和LDVF快速激活率期间，这两种组织类型之间是否存在显著变化。我将测试一种假设，即工作心肌中膜电位的上升将浦肯野系统的静息电位提高到阈值以上，从而导致浦肯野系统内的快速激活。具体目标2是直接测绘和测量LDVF期间浦肯野系统的活动。我们将验证这样的假设，即激活出现在浦肯野系统中靠近浦肯野-心肌连接处的部位。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。具体目的4是确定是否有针对浦肯野系统的起搏或药物干预，可以终止室颤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心脏激活映射技术，提高我的演示和写作技能，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从事心律失常研究的领先研究机构的终身教职。在独立阶段，我将继续研究LDVF中的浦肯野系统，并建立一个由外部资助的研究实验室，以研究心律失常的启动和持续，并开发干预措施，以提高潜在致命心律失常患者的存活率。相关性(参见说明)：美国成年人每年大约发生450,000例心脏性猝死(SCD)。室性心动过速通常是室颤发作的结果，它会在几分钟内导致心输出量的急剧下降和对重要器官的不可逆转的损害。浦肯野系统可能在维持前2分钟的室颤中起重要作用，针对浦肯野系统的治疗可能会提高这些患者的存活率。

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.