Substrate-Dependent Pro- and Antiarrhythmic Action of Omecamtiv Mecarbil at the Ventricular and Atrial Level: Insights from a Langendorff-Perfused Rabbit Heart Model

Abstract Omecamtiv mecarbil is a cardiac-selective myosin activator and potential heart failure treatment, but its electrophysiological profile remains incompletely characterized. We investigated omecamtiv mecarbil in a Langendorff-perfused rabbit heart model. Forty-eight rabbit hearts were retrogradely perfused; twenty-four in a ventricular and twenty-four in an atrial setup. In the ventricular setup, action potential duration at 90% repolarization (APD 90 ), QT interval, and dispersion of repolarization were assessed during pacing at seven cycle lengths. After baseline recordings, Group 1 ( n = 12) received 1, 5 and 10 µM omecamtiv mecarbil sequentially, while Group 2 ( n = 12) received 100 µM sotalol followed by 5 µM omecamtiv mecarbil. In the atrial setup, Group 3 ( n = 12) received 5 and 10 µM omecamtiv mecarbil, and Group 4 ( n = 12) received isoproterenol/acetylcholine (IsoACh) to increase atrial fibrillation (AF) susceptibility, followed by 5 µM omecamtiv mecarbil. Omecamtiv mecarbil alone shortened ventricular APD 90 and QT interval, increased dispersion of repolarization, and raised ventricular arrhythmia incidence. Sotalol prolonged APD 90 , QT interval, and dispersion, with a marked rise in VT episodes; additional omecamtiv mecarbil did not further prolong repolarization but increased arrhythmia susceptibility further. In the atrial setup, omecamtiv mecarbil alone prolonged conduction time and increased AF inducibility. Under IsoACh, which shortened atrial APD and refractoriness and increased AF episodes, additional omecamtiv mecarbil slowed atrial conduction and markedly suppressed AF. In summary, omecamtiv mecarbil was proarrhythmic at the ventricular level, particularly under reduced repolarization reserve, but showed antiarrhythmic effects in an IsoACh-induced AF model and proarrhythmic properties in the healthy atrium, indicating a substrate-dependent electrophysiological profile.