Ventricular tachycardia can be a life-threatening arrhythmia that requires effective and timely treatment. This treatment often takes the form of catheter based ablation; however, the success rates are modest. Moreover, the ablation procedure is invasive, done under general anesthesia, and can take many hours in patients who already have compromised cardiac function, putting them at risk for more complications. Recently, radiation therapy, like that used in oncology has been used to ablate cardiac arrhythmias. Initially performed in patients who had run out of other options, the success in a few patients has opened the possibility of wider use. However, despite this promising success, the biophysics of how radiation affects the cardiac tissue, the timeline of scar formation, the acute and more chronic effect on the electrical propagation and the dose response are all unknown. The time to response in radiation ablation in the reported studies is also highly variable, ranging from immediate to more than 6 weeks for any results. More importantly, although radiation ablation is non-invasive, it often requires an invasive electrophysiology study to identify the target site(s), an essential step that determines the success or failure of the procedure. We propose to address both these limitations by using our proven expertise in the fields of imaging, electrophysiology, computational modeling, and radiation oncology to advance the use of radiation as a noninvasive means of ablation with the following aims: (1) Determine the dose response and structural and functional effects of radiation on the cardiac tissue; (2) Create radiation targeting strategies using personalized computational models of ventricular arrhythmias in a pre-clinical VT model and patients; (3) Carry out non-invasive radiation ablation treatment in a pre-clinical infarct model with ventricular tachycardia. In aim 1 we will address the biophysics of ablation by performing electrophysiology studies at different time points after ablation with different doses to understand the effects of radiation on electrical propagation. We will be doing serial MRIs to create a dose response and to evaluate the heart for structural remodeling like edema, fibrosis, and scar. To provide a physiological basis for the effects, we will do histology, protein expression analysis and confocal microscopy. In aim 2 we will use MRI to assess patients with pre-existing ventricular scar and make personalized simulation models to determine the VT circuit and the critical part of the circuit to target with radiation. Our existing database of VT patients, with MR images and ECGs with VT and detailed map of the VT will provide the opportunity for validation of these models along with a pre-clinical VT model. Finally, in aim 3 we will treat suitable VT pre-clinical model with radiation instead of the traditional radiofrequency to further understand the mechanism underlying ablation with radiation. Improving our understan...