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

Figures

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  Figure 1. Induction of a polymorphic ventricular tachycardia after delivering two short-coupled extrastimuli (S3) under the influence of pinacidil (MAP = monophasic action potential).

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  Figure 2. Example of a polymorphic ventricular tachycardia induced by burst pacing under combined infusion of ouabain and sacubitril (MAP = monophasic action potential).

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  Figure 3. Cycle length-dependent action potential durations at 90% of repolarization ((A), APD90) and QT interval (B) under baseline conditions (◆), after administration of 1 µM pinacidil (■) and after further treatment with 5 µM sacubitril (▲). (C,D) Box plots showing the impact of 1 µM pinacidil and additive perfusion with 5 µM sacubitril on effective refractory periods (ERP, (C)) and spatial dispersion of repolarization (D). (E) Influence of pinacidil and sacubitril on ventricular arrhythmias (VA). “S2/S3” refers to the induction of arrhythmia through the delivery of premature extra stimuli, while “Burst” indicates the induction of ventricular arrhythmias (VA) through burst pacing. (# = p < 0.05 compared to baseline conditions; * = p < 0.05 compared to pinacidil).

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  Figure 4. Representative example of ECG and action potential tracings under baseline conditions, after infusion of 1 µM pinacidil and after additional treatment with 5 µM sacubitril. Hearts are stimulated at a cycle length of 900 ms (MAP monophasic action potential).

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  Figure 5. Cycle length-dependent action potential durations at 90% of repolarization ((A), APD90) and QT interval (B) under baseline conditions (◆), after administration of 0.2 µM ouabain (■) and after further treatment with 5 µM sacubitril (▲). (C,D) Box plots showing the impact of 0.2 µM ouabain and additive perfusion with 5 µM sacubitril on effective refractory periods (ERP, (C)) and spatial dispersion of repolarization (D). (E) Influence of ouabain and sacubitril on ventricular arrhythmias (VA). “S2/S3” refers to the induction of arrhythmia through the delivery of premature extra stimuli, while “Burst” indicates the induction of ventricular arrhythmias (VA) through burst pacing. (# = p < 0.05 compared to baseline conditions; * = p < 0.05 compared to ouabain).

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  Figure 6. Representative example of ECG and action potential tracings under baseline conditions, after infusion of 0.2 µM ouabaine and after additional treatment with 5 µM sacubitril. Hearts are stimulated at a cycle length of 900 ms (MAP monophasic action potential).