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. The prevailing paradigm focused on the role of surviving ribbons of myocardial tissue traversing the borderzone region and impaired electrical conduction as components of the arrhythmia mechanism. A problem with ascribing causation of VT entirely to those electrical conduction factors is that they occur diffusely throughout the borderzone, but VT exists in discrete circuits. 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 have also shown that gene transfer of either repolarization prolonging or conduction enhancing transgenes reduces or eliminates VT inducibility. 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 this proposal, we exploit these findings to develop a cure for post-infarct VT. We hypothesize that the VT circuit-specific repolarization effects combine with the more broadly present alterations in conduction to create an environment conducive for reentry VT, and that normalizing repolarization and/or conduction will prevent VT. To test our hypothesis, we will focus on 3 aims: (1) to homogenize repolarization in healed MI scar; (2) to normalize conduction velocity and cellular connectivity by increasing intercalated disk expression of connexin43; (3) to evaluate safety and biodistribution of the proposed interventions. Successful completion of these aims will create a preclinical data package required to support future clinical testing of VT gene therapy.