Background: Observational clinical data suggest a direct effect of sacubitril on cardiac electrophysiology. However, data concerning the impact of combination of sacubitril with antiarrhythmic drug therapy is sparse. Thus, we aimed at characterizing the electrophysiologic effects of a combination therapy of sacubitril with the class III-drug sotalol and the class IB-agent mexiletine in a sensitive, experimental whole-heart model.

Methods and results: 25 rabbit hearts were excised and retrogradely perfused using a Langendorff-setup. Hearts were treated with mexiletine (25 µM, 13 hearts) or sotalol (100 µM, 12 hearts) after generating baseline data. Eight endo- and epicardial monophasic action potentials and ECG recordings demonstrated an abbreviation of action potential duration (APD₉₀, -21 ms, p<0.01) and no significant changes of QT interval (+10ms, p=ns) after administration of mexiletine. Spatial dispersion of repolarization remained stable after mexiletine treatment (+6 ms, p=ns) whereas effective refractory periods (ERP) were significantly prolonged (+80 ms, p<0.01). Sotalol prolonged cardiac repolarization (APD₉₀: +1 ms, p=ns; QT: +24 ms, p<0.01) and amplified spatial dispersion (+ 19 ms, p<0.01) without changing ERP (+ 8 ms, p=ns). Additional treatment with sacubitril (5 µM) led to a significant reduction of APD₉₀ (- 12 ms, p<0.01), QT interval (-20 ms, p<0.01) and ERP (- 23 ms, p<0.01) in the presence of a stable dispersion of repolarization (- 4ms, p=ns) in the mexiletine group. In the sotalol group, additional administration of sacubitril abbreviated cardiac repolarization duration (APD₉₀: -9 ms, p<0.05; QT -13 ms, p<0.01) and reduced ERP (- 18 ms, p<0.01) without affecting spatial dispersion (-3 ms, p=ns). Ventricular vulnerability was assessed by a predefined pacing protocol employing premature extra stimuli and burst stimulation. After lowering the potassium concentration, 30 episodes of torsade de pointes tachycardia were observed after sotalol treatment (vs. 0 episodes under baseline, p<0.05). Additional sacubitril treatment significantly suppressed torsade de pointes tachycardia (8 episodes, p<0.05) in the sotalol-group.

No proarrhythmic effect was observed after mexiletine treatment (8 episodes vs. 3 episodes under baseline conditions, p=ns). Additional sacubitril treatment did not increase ventricular vulnerability (32 episods, p=ns).