Abstract Radiofrequency (RF) ablation of ventricular tachycardia (VT) in ischemic cardiomyopathy is fraught with limitations due to suboptimal efficacy, risk of complications, and frequent need for repeat procedures. Ischemic VT arises as a result of reentrant circuits within or around the myocardial scar of an infarct. The co-localization of ventricular arteries, veins, and nerves, is an anatomical fact, determined by the embryology of coronary vessels. Just as myocardial infarctions have a “culprit” or “infarct-related artery”, there commonly exists an “infarct-related vein” or veins in VT substrate. Additionally, it is well known that autonomic innervation -in anatomical proximity to the veins- plays an important role in post-MI arrhythmogenesis. We have developed an approach to target ablation-refractory VTs via ethanol delivery in the coronary veins that provide venous return from arrhythmogenic sites (venous ethanol, VE). Beyond an initial set of case reports, we have validated the utility of VE in a large, multinational registry, in which we establish the safety and efficacy of VE in RF-refractory VT. Given the co-localization of epicardial arteries, veins and nerves, VE may be particularly suited to impact infarct innervation. Thus, a central goal of this proposal is to capitalize on the presence of coronary veins on the epicardial aspect of a myocardial scar as a therapeutic opportunity of unique mechanisms. We hypothesize that VE added to conventional catheter ablation improves the results of VT ablation. We propose a single-site, investigator-initiated clinical trial on VE. In Aim 1-R61 phase-, we propose to finalize the design of randomized clinical trial to assess the clinical efficacy, and safety of VE when used in combination with RF ablation compared with RF ablation alone -Venous Ethanol for Left Ventricular Ischemic VEntricular Tachycardia -VELVET clinical trial. The trial will include an investigational new drug (IND) authorization by the FDA. Patients with ischemic VT will be randomized to conventional endocardial ablation alone, vs combined with VE in the infarct-related vein. In Aim 2 -R33 phase- we will enroll a total of 156 patients, and collect efficacy, safety and procedural data on the impact of VE added to catheter ablation. This trial will allow for a wealth of new imaging data to be collected that will characterize the extent of myocardial scar and innervation before and after VE -compared to endocardial RF alone. In Aim 3 -R33 phase- we will collect multi-modality imaging data characterizing the VT substrate before and after ablation -with catheter ablation alone vs combined with VE. Cardiac magnetic resonance, venous CT angiograms and regional adrenergic innervation maps with positron emission tomography (PET) scans of innervation tracers (11C hydroxyephedrine, 11C-HED) will provide a complete structural assessment of the VT substrate, before and after ablation. If completed, the project will validate a new procedu...