Background:
Recent preclinical studies reported an abbreviation of cardiac repolarization after sacubitril treatment. Thus, purpose of this study was to evaluate the electrophysiologic effects of sacubitril in the presence of drugs that shorten the QT interval.

Methods and results:
25 rabbit hearts of New Zealand white rabbits were explanted and Langendorff-perfused. Monophasic action potentials were recorded employing eight epi- and endocardially placed catheters. Hearts were stimulated at seven different cycle lengths (300-900ms), thus obtaining cycle-length dependent action potential duration at 90% of repolarization (APD₉₀). Spatial dispersion of repolarization was defined as the difference of the maximum and minimum of APD₉₀. After generating baseline data, hearts were allocated to two groups.

In the first group (n=12), the I_K,ATP opener pinacidil (1 µM) led to a significant abbreviation of APD₉₀ (-28 ms, p<0.01), QT interval (-43 ms, p<0.01) and effective refractory periods (ERP: -21 ms, p<0.01) without significantly altering spatial dispersion (+6 ms, p=ns). Additional administration of sacubitril (5 µM) slightly reduced APD₉₀ (-3 ms, p<0.01) and ERP (-14 ms, p<0.01) without altering QT interval (+ 4ms, p=ns) or spatial dispersion (+ 2 ms, p=ns).

The second group (n=13) was treated with the digitalis glycoside ouabain (0.2 µM). Ouabain also significantly abbreviated repolarization duration and refractory periods (APD₉₀: -18 ms, p<0.01; QT: -26 ms, p<0.01; ERP: -27 ms, p<0.01). Additional treatment with sacubitril (5 µM) further reduced repolarization duration and ERP (APD₉₀: -34 ms, p<0.01; QT: -32 ms, p<0.01; ERP: -37 ms, p<0.01). Spatial dispersion remained stable with ouabain alone and with the combination of both drugs. Ventricular vulnerability was tested by a predefined pacing protocol employing premature extra stimuli and burst stimulation. After pinacidil treatment, significantly more ventricular arrhythmias (VA) were observed (26 episodes vs. 5 episodes under baseline conditions, p<0.05). Additional sacubitril treatment had no significant effect (24 episodes, p=ns). Ouabain did not provoke ventricular arrhythmias (6 episodes vs. 3 under baseline conditions, p=ns) whereas additional sacubitril treatment significantly increased the occurrence of VT episodes (29 episodes, p<0.01).

Conclusion:
Sacubitril shortens cardiac repolarization in the presence of QT-abbreviating drugs. While sacubitril had no proarrhythmic effect in the presence of the I_K,ATP-opener pinacidil, sacubitril  significantly increased the occurrence of VA in combination with the digitalis glycoside ouabain. The underlying mechanism is likely a further reduction of cardiac repolarization duration and refractory periods that facilitate re-entry and the occurrence of arrhythmias.

These findings add further evidence to the arrhythmogenic capacity of digitalis glycosides in the presence of other drugs that influence cardiac repolarization.