Electrophysiologic effects of sacubitril in different arrhythmia models

Abstract

Previous studies report conflicting data regarding anti- or proarrhythmic effects of sacubitril. Aim of this study was to assess the impact of acute sacubitril treatment in different arrhythmia models. Sacubitril was administered (3, 5, 10μM) in 12 isolated rabbit hearts. Further 12 hearts were treated with erythromycin to simulate long-QT-syndrome-2 (LQT2). Other 12 hearts were perfused with veratridine to mimic long-QT-syndrome-3 (LQT3). Both LQT-groups were treated with sacubitril (5μM) additionally. Ventricular vulnerability was assessed by a pacing protocol. AV-blocked bradycardic hearts were perfused with a hypokalemic solution to trigger torsade de pointes (TdP). In further 13 hearts, AF was induced by a combination of acetylcholine and isoproterenol and sacubitril (5μM) was added afterwards. With sacubitril, action potential duration (APD) was abbreviated whereas spatial dispersion of repolarisation (SDR) remained stable. In both LQT groups, APD and SDR were increased. Infusion of sacubitril reduced APD (- 21ms, p<0.01) and SDR (- 8ms) in the LQT2-group and did not alter APD (+2ms) but reduced SDR (-19ms, p<0.01) in the LQT3-group. Ventricular vulnerability was not altered by sacubitril. No TdP were observed with sacubitril or under baseline conditions in any group. Sacubitril significantly suppressed TdP in the LQT2-group (3 vs. 43 episodes, p<0.05) but not in the LQT3-group (10 vs. 16 episodes, p=ns). Sacubitril reduced inducibility of AF (9 vs. 31 episodes). Sacubitril abbreviated APD. In addition, sacubitril exhibits potential antiarrhythmic effects in LQT2 and may be beneficial in LQT3 and AF.