Opposing effects of bepridil on ventricular repolarization in humans - Inhomogeneous prolongation of the action potential duration vs flattening of its restitution kinetics

Abstract

Background: Bepridil is highly effective in the treatment of atrial fibrillation, but its clinical usefulness is limited by a potential risk for the drug-induced Torsades de pointes (TdP) in association with its Class D1 action. Methods and Results: Monophasic action potentials (MAPs) were recorded from the right ventricular outflow tract (RVOT) and apex (RVA) in 9 patients treated with bepridil (172±26 mg/day) and 10 control patients. Bepridil significantly increased the steady-state MAP durations at 90% repolarization (MAPD90S) in a rate-independent manner at pacing cycle lengths ranging from 330 to 750 ms. The bepridil-induced prolongation of the MAPD 90 was greater in RVOT (∼13%) than RVA (∼8%). Bepridil flattened the MAPD90 restitution slope estimated by an S1-S2 protocol in both the RVOT (0.65±0.22 vs 0.95±0.38) and RVA (0.65±0.14 vs 0.94±0.29). The Tpeak-end interval in the ECG was increased by bepridil for S1 but not S2 at the shortest diastolic interval to produce a ventricular response. Conclusions: Bepridil produces an inhomogeneous prolongation of the MAPDs, but flattens their restitution kinetics in the human ventricle. The former effect would favor the functional reentry predisposing to TdP, whereas the latter one would counteract that by reducing the dynamic instability of the repolarization.