Project Summary Nodal dysfunction in patients often requires the implantation of a pacemaker to maintain physiologically normal heart rates. Historically, a pacemaker in the right ventricular apex has delivered pacing pulses to the ventricles. In some patients, chronic pacing in the right ventricle may lead to ventricular dyssynchrony, pacing induced cardiomyopathy, and increased congestive heart failure incidence. Biventricular pacing has been shown to lead to improved performance compared to right ventricular pacing, but up to 1/3 of patients are non-responders to biventricular pacing. Permanent His bundle and left bundle branch (LBB) pacing has recently been shown to lead to less heart failure and improved synchronicity, with a trend towards a mortality benefit as compared to the standard right ventricular or biventricular lead placement. Limitations that have slowed the adoption of His bundle pacing include 1) higher pacing thresholds as compared to other lead configurations, which may reduce battery life in implanted devices for patients with high pacing demand, and 2) a lack of selectivity in sensing and pacing the His bundle and adjacent ventricular myocardium. Therapies such as antitachycardia pacing (ATP) that utilize sensing may be less effective if the His activation and the local myocardial activations lead to inappropriate calculation of the ventricular tachycardia (VT) cycle length. ATP is an effective technique to terminate ventricular tachycardias without delivering high-energy, painful shocks. However, efficacy of ATP techniques with a His bundle or LBB lead has not been demonstrated. Using a canine model of ischemia-reperfusion induced VT, the hypothesis will be tested that ATP will utilize the His-Purkinje network to terminate VT with greater efficacy than standard right ventricular lead ATP therapy. A novel, transvenous, multielectrode pacing lead is proposed that will allow for low threshold, selective sensing and pacing of the His bundle and the adjacent ventricular myocardium. Refinement of the lead configuration will be performed in ex vivo canine hearts, and validation of the new lead will be demonstrated in an in vivo, chronic dog model. The lead configuration will be deployable with currently available tools and techniques and will allow the physician to optimize the pacing therapy based on the response of individual patients. Completion of this project will lead to a substantially improved lead system for His bundle pacing and LBB applications and demonstrate the effectiveness of ATP therapy with His bundle and LBB leads. This translational project may have an immediate impact on pacemaker implantation for many of the one million patients worldwide that are implanted with pacemakers each year.