Project Summary Cardiovascular disease is the leading cause of death in the United States and accounts for 1 in every 5 deaths. Sudden cardiac death is responsible for nearly half of all heart disease related mortality and is often attributed to the occurrence of lethal ventricular arrhythmias. Ventricular arrhythmias also are a major source of morbidity and mortality in patients with structural heart disease. Antiarrhythmic drug therapy provides only limited efficacy in preventing ventricular arrhythmias and while implantable cardioverter defibrillators provide life-saving therapy to terminate the arrhythmia once it has occurred, they do not prevent them from occurring. For these reasons, catheter ablation of ventricular arrhythmias has emerged as an additional therapy for many patients with refractory ventricular tachycardia (VT). However, VT ablation procedures are complex and multiple procedures are often required to achieve modest long-term success. Therefore, there is a critical need for additional VT therapies. Cardiac stereotactic body radiation therapy (cSBRT) has emerged as an adjunctive noninvasive approach that can be utilized to treat patients with VT that is refractory to standard antiarrhythmic drug therapy and catheter ablation with clinical efficacy observed in some very complex patients. However, the clinical response following cSBRT has been highly variable and the electrophysiologic mechanism is unclear. We believe that better understanding the mechanisms of cSBRT will help refine and guide clinical cSBRT paradigms, optimize patient selection, and better define the appropriate role this therapy should have in clinical practice. We propose a series of experiments to investigate the association between cSBRT dose and structural and electrophysiologic changes using longitudinal cardiac magnetic resonance (CMR) imaging and high-resolution electroanatomic mapping in a large animal model of chronic myocardial infarction and reentrant VT. In Aim 1, we will investigate the impact of cSBRT dose (15Gy, 25Gy, and 35Gy) at short and intermediate follow-up timepoints. We will also investigate the long-term impact of cSBRT delivered at the dose currently used clinically (25Gy) out to 1 year. In Aim 2, we will similarly investigate structural and electrophysiologic changes that occur in patients undergoing clinically indicated cSBRT compared to catheter ablation. This study will give a new understanding of the dose and time relationship of cSBRT on the heart that will be essential in moving this field forward.