ABSTRACT In the United States, several hundred thousand people experience cardiac arrest each year, with the vast majority dying from this condition. Approximately two-thirds of cardiac arrest victims have previously suffered a myocardial infarction (MI), and death results from maladaptive responses to infarct healing. The healed infarct scar creates a substrate that supports malignant ventricular arrhythmias, and death results from ventricular tachycardia (VT) originating in the border zone around the infarct scar. We recently reported that the potassium channel beta subunits KCNE3 and KCNE4 are upregulated only in VT circuits, and that these proteins cause a pattern of repolarization heterogeneity that supports reentrant VT. We previously developed an epicardial gene painting method for transmural atrial gene transfer, and we have preliminary data showing that use of epicardial gene painting with adeno-associated virus vectors allows complete transmural ventricular gene transfer. In a successful STTR grant, we developed a prototype catheter that would allow epicardial gene painting without opening the chest. In this fast track SBIR proposal, we exploit these findings to develop a cure for post-infarct VT. We hypothesize that the VT circuit-specific repolarization effects create an environment conducive for reentry VT, and that normalizing repolarization will prevent VT. To test our hypothesis, we propose phase 1 experiments that finalize development of the gene painting catheter, verify ventricular- targeted transgene expression with the gene painting catheter, and evaluate biodistribution and toxicity in sinus rhythm animals. Phase 2 is a fully powered efficacy and safety study in our clinically relevant pig model of post-infarct VT. Successful completion of these aims will create a preclinical data package required to support future clinical testing of VT gene therapy.