Repolarization and arrhythmia modulation by K-ATP channel activation in the porcine right ventricle

Introduction The RVOT is involved in arrhythmias in several diseases such as the Brugada syndrome (BrS). In a subpopulation of patients with BrS and early repolarization (ER) syndrome, a K-ATP gain-of-function (GOF) mutation has previously been described and was suggested to contribute to arrhythmogenicity in this context. Objective To determine the role of regional K-ATP channels expression on RV repolarization heterogeneity and in arrhythmia occurrence and modulation. Methods Pig right ventricles (RV) were perfused by both right and left coronary arteries, paced at 1 or 1.5 Hz and the electrical activity optically-mapped (di-4-ANEPPS, 20 μM). The preparation was perfused with pinacidil (PINA, 20 μM), and diazoxide (DIAZ, 100 μM), and subjected to 20 min no-flow (NF) ischemia episodes followed by 20 min reperfusion (RF). Arrhythmia susceptibility was assessed using a 20 Hz burst protocol while spontaneous arrhythmias were also recorded. Protein expression was assessed by western blot. Results PINA-induced action potential duration (APD) shortening was larger in RVOT than in the free wall (FW). DIAZ induced a slight but significant reduction in APD across the RV. SUR2A expression was greater in the RVOT epicardium vs. FW but Kir6.1/2 and SUR1 expression was similar in both regions. PINA induced spontaneous ventricular fibrillation (VF) in 80% of the preparations with higher dominant frequency (DF) and regularity index in the RVOT than the FW. DF of burst-induced VF were higher in PINA but not in DIAZ compared to CTRL VF. Similarly to PINA, NF-induced APD shortening was greater in the RVOT than in the FW. No spontaneous arrhythmia occurred during NF but slow ventricular tachycardias arose in 36% of the preparations during RF. Conclusion K-ATP activation leads to an increase in RV repolarization dispersion which is likely to contribute to arrhythmogenicity in BrS or ER patients with a K-ATP channel GOF mutation and may underlie BrS phenocopy induced by RV ischemia.