B-po04-005 anteroposterior repolarization gradient is determined by regional ion channel expression and the activation sequence in the porcine right ventricle

The right ventricular outflow tract (RVOT) is a common origin of life-threatening arrhythmias. The contribution of right ventricular (RV) intrinsic repolarization heterogeneity to RVOT arrhythmogenicity is unclear. We sought to characterize RV repolarization and its modulation by the activation sequence. The electrical activity of isolated pig RVs (N=21) was optically mapped (di-4-ANEPPS), both on epicardial (EPI) and endocardial (ENDO) surfaces. Repolarization features were globally and regionally estimated in wedges paced (1 Hz) in the RV free wall ENDO (RVFWENDO), RVFWEPI and RVOTEPI. Action potentials (APs) were also recorded in EPI cardiomyocytes isolated from the RVFW and the RVOT using the patch-clamp technique. Finally, ion channels expression profile was determined by western blot. Activation time (AT) was always the longest in the surface from which pacing was initiated (P<0.001). Thus, EPI pacing reversed ENDO-EPI ΔAT found in RVFWENDO pacing. AP duration (APD80) was longer in the ENDO than EPI (P<0.001), maintaining the ENDO-EPI ΔAPD80 for all pacing protocols. Repolarization times (RTs) were also longer in the ENDO than EPI, irrespective of the pacing site. Surface RTs were the longest when the pacing originated from the RVOTEPI (EPI RT : 405 ± 20 ms in RVOTEPI pacing, vs 367 ± 21 ms and 349 ± 30 ms in RVFWEPI and RVFWENDO pacing respectively), because ATs were dramatically prolonged in this condition. Local APD80 was always longer in the RVFW compared to the RVOT in both EPI and ENDO surfaces (P<0.001), defining an anteroposterior APD80 gradient. RVOTEPI pacing exacerbated RT heterogeneity (P<0.001) because of the persistent anteroposterior APD80 gradient and AT slowing which reversed AT-APD relationship. EPI cardiomyocytes isolated from the RVOT also exhibited shorter APD80s (533 ± 83 ms) than in the RVFW (583 ± 80 ms, P<0.05). This correlated with a higher Kv11.1 level in the RVOT (P<0.05), and suggested a role for IKr in defining RV anteroposterior APD gradient in pigs. RV anteroposterior repolarization is determined by specific regional electrophysiological signatures due to local ion channel expression. This intrinsic substrate may be arrhythmogenic when an ectopic beat is initiated in the RVOT.