Divergent Electrophysiologic Effects of Sacubitril in Digitalis- and Pinacidil-Related Shortened Repolarization: Experimental Evidence for Harmful Effects of Digitalis Glycosides

<b>Background</b>: Recent studies reported an abbreviation of cardiac repolarization induced by sacubitril. Thus, the purpose of this study was to evaluate the electrophysiologic effects of sacubitril in the presence of drugs that shorten the QT interval. <b>Methods and Results</b>: 25 rabbit hearts were retrogradely perfused. After generating baseline data, hearts were allocated to two groups. In the first group (<i>n</i> = 12), the I_K,ATP opener pinacidil (1 µM) significantly reduced action potential duration at 90% of repolarization (APD₉₀), QT intervals and effective refractory periods (ERP). Additional administration of sacubitril (5 µM) slightly reduced APD₉₀. The digitalis glycoside ouabain (0.2 µM) significantly shortened repolarization duration and refractory periods. Additional infusion of sacubitril abbreviated repolarization duration and ERP. Ventricular vulnerability was assessed by delivering premature extra stimuli and burst stimulation. Significantly more ventricular arrhythmias occurred with pinacidil (26 episodes vs. 5 episodes under baseline conditions, <i>p</i> < 0.05). Additional sacubitril treatment had no significant proarrhythmic effect (24 episodes). Ouabain alone did not provoke ventricular arrhythmias (6 episodes vs. 3 under baseline conditions, <i>p</i> = ns) whereas additional sacubitril treatment significantly increased the occurrence of VT episodes (29 episodes, <i>p</i> < 0.01). <b>Conclusions</b>: Sacubitril abbreviates cardiac repolarization in ouabain-pretreated hearts. While sacubitril had no proarrhythmic effect in the presence of pinacidil, the combination of sacubitril and ouabain amplified the arrhythmic risk. The underlying mechanism is a further abbreviation of refractory periods and cardiac repolarization that facilitate ventricular arrhythmias. These findings add further evidence to the proarrhythmic capacity of digitalis glycosides in the presence of other drugs that influence cardiac repolarization.