Electrophysiologic effects of sacubitril in different arrhythmia models

Abstract

Background: 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.

Methods: Sacubitril was administered (3, 5, 10 μM) 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 (5 μM) 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 (5 μM) was added afterwards.

Results: 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 (- 21 ms, p < 0.01) and SDR (- 8 ms) in the LQT2-group and did not alter APD (+2 ms) but reduced SDR (-19 ms, 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).

Conclusion: Sacubitril abbreviated APD. In addition, sacubitril exhibits potential antiarrhythmic effects in LQT2 and may be beneficial in LQT3 and AF.

Keywords: Arrhythmia; Heart failure; Long QT syndrome; Sacubitril.