Background In addition to extrasystoles of pulmonary vein (PV) origin, those arising from the superior vena cava (SVC) can precipitate atrial fibrillation (AF). The present study evaluates the electrophysiological properties of canine SVC sleeve preparations and the effect of ranolazine on late phase 3 early and delayed afterdepolarization (EAD and DAD)-induced triggered activity in SVC sleeves, and compares SVC and PV sleeve electrophysiologic properties. Methods and Results Action potentials (APs) were recorded from superfused SVC and PV sleeves using microelectrode techniques. Acetylcholine (1 μM), isoproterenol (1 μM), high calcium ([Ca2+]o=5.4 mM), or a combination were used to induce EADs, DADs and triggered activity. A marked diversity of action potential characteristics was observed in the SVC sleeve, including action potentials with short and long APs, with and without phase 4 depolarization. Rapid pacing induced hyperpolarization, accentuating the slope of phase 4 depolarization. Phase 4 depolarization and rapid pacing-induced hyperpolarization were reduced or eliminated following atropine (10 μM) or ranolazine (10 μM). APs displaying phase 4 depolarization (n=19) had longer APDs, smaller amplitude and Vmax, and a more positive take-off potential than APs lacking phase 4 depolarization (n=15). Ranolazine (5–10 μM) eliminated late phase 3 EADs and DAD-induced triggered activity as well as isoproterenol-induced automaticity elicited in SVC sleeves. Compared to PV, SVC sleeves display phase 4 depolarization, smaller Vmax and longer APs. Conclusions Autonomic influences promote spontaneous automaticity and triggered activity in SVC sleeves, thus generating extrasystolic activity capable of initiating atrial arrhythmias. Ranolazine can effectively suppress these triggers.

AVE0118’s action to prolong effective refractory period (ERP) in atria but not ventricles is thought to be due to its inhibition of IKur. However, in non-remodeled atria, AVE0118 prolongs ERP but not action potential duration (APD70-90), which can be explained with inhibition of sodium, but not potassium channel current. ERP, APD, and the maximum rate of rise of the AP upstroke (Vmax) were measured in canine isolated coronary-perfused right atrial and in superfused ventricular tissue preparations. Whole-cell patch-clamp techniques were used to measure sodium channel current (INa) in HEK293 cells stably expressing SCN5A. AVE0118 (5–10 μM) prolonged ERP (p<0.001), but not APD70 and decreased Vmax (by 15%, 10 μM, p<0.05; n=10 for each). Ventricular ERP, APD90, and Vmax were not changed significantly by 10 μM AVE0118 (all p=ns; n=7). AVE0118 effectively suppressed acetylcholine-mediated persistent atrial fibrillation (AF). AVE0118 (10 μM) reduced peak current amplitude of SCN5A-WT current by 36.5±6.6% (p<0.01; n=7) and shifted half-inactivation voltage (V0.5) of the steady- state inactivation curve from -89.9±0.5 to -96.0±0.9 mV (p<0.01; n=7). Our data suggest that AVE0118-induced prolongation of atrial, but not ventricular ERP, is due largely to atrial- selective depression of INa, which likely contributes to the effectiveness of AVE0118 to suppress AF.