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.