https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Münster Klinik für Kardiologie II - Rhythmologie Münster, Deutschland
Background: Changes of cardiac repolarization are common side effects of neurological drugs, leading to potential hazardous side effects like torsade de pointes tachycardia and sudden cardiac death. Aim of this study was to assess the safety profile of atomoxetine and amitriptyline in a sensitive whole-heart model of proarrhythmia.
Methods and results: 24 rabbit hearts of New Zealand white rabbits were explanted and retrogradely perfused employing a Langendorff apparatus. Hearts were perfused with atomoxetine (group 1, n= 12; 1 and 3 µM) or amitriptyline (group 2, n=12; 1 and 5 µM). A predefined pacing protocol was used to determine action potential duration (APD90), QT interval, spatial dispersion of repolarization and effective refractory periods. Premature extra stimuli and burst stimulation were employed to assess ventricular vulnerability. In addition, bradycardiac AV-blocked hearts were perfused with a hypokalemic solution to facilitate triggered activity.
Administration of atomoxetine had a dose-dependent effect on cardiac repolarization. At the lower concentration, atomoxetine significantly abbreviated QT and APD90 whereas cardiac repolarization was prolonged with 5 µM. The configuration of action potentials remained stable. Spatial dispersion remained stable and no significant effect on refractory periods could be observed. Though atomoxetine had no significant proarrhythmic effect during programmed stimulation, an episode of torsade de pointes tachycardia occurred under hypokalemic conditions.
Infusion of amitriptyline led to a significant reduction of cardiac repolarization duration (APD90 and QT interval) and reduced spatial dispersion of repolarization at the lower concentration. The APD90/APD50 ratio was reduced by amitriptyline, indicating a more rectangular action potential configuration. Effective refractory periods were significantly abbreviated. No significant proarrhythmic effects were observed, neither after programmed stimulation nor under hypokalemic conditions.
Conclusion: Atomoxetine exhibitis a concentration-dependent effect on cardiac electrophysiology with a reduction of repolarization duration at the lower concentration and a prolongation of APD90 and QT interval with the higher dose. Consequently, an episode of torsade de pointes was observed with 5 µM atomoxetine. In contrast, amitriptyline abbreviated cardiac repolarization duration and had no significant proarrhythmic effect.