Heterogeneous action potential duration response to ischemia in the pig right ventricle

Abstract

The right ventricular outflow tract (RVOT) has a distinct embryonic development leading to specific electrophysiological properties in the healthy adult heart. These include shorter action potential duration (APD), which is likely to contribute to RVOT high susceptibility to arrhythmias in idiopathic and pathological conditions. How these differences are altered in ischemia remains unknown. We sought to determine whether RVOT repolarization undergoes a specific adaptation to ischemia. Pig right ventricles (RV) were perfused by both right and left anterior descending coronary arteries, paced at 1.5 Hz and the electrical activity optically-mapped on epicardial (EPI) and endocardial (ENDO) surfaces (di-4-ANEPPS, 20 μM). The preparation was perfused with pinacidil (PINA, 20 μM), diazoxide (DIAZ, 100 μM) and glibenclamide (GLIB, 10 μM), and subjected to 20 min no-flow ischemia episodes followed by 20 min reperfusion. Protein expression was assessed by western blot and localization by immunohistochemistry. Ischemia significantly shortened APD across the whole wedge, with a larger effect in RVOT than RVFW EPI (−50.94% ± 9.58% vs. −36.18% ± 8.38% P < 0.01) and ENDO ( P < 0.05). GLIB partially prevented ischemia-induced APD shortening. Although APD shortening remained larger in the RVOT EPI, GLIB effect was more pronounced in the RVOT than RVFW EPI ( P < 0.01) but not in the ENDO. PINA shortened APD to the same extent as ischemia with similar regional effects, while DIAZ had little effect on all regions. Kir6.1 and Kir6.2 localized at the t-tubules in all regions but their expression level was similar. RVOT repolarization seems to be more sensitive to ischemia than the RVFW. Katp channels are involved in this difference despite similar Kir6.1 and Kir6.2 expression, suggesting a role for sulphonylurea receptors. This increase in repolarization heterogeneity is likely to facilitate re-entrant arrhythmias in this context.