Oxytocin exerts harmful cardiac repolarization prolonging effects in drug-induced LQTS

Paul Kreifels; Ilona Bodi; Tibor Hornyik; Gerlind Franke; Stefanie Perez-Feliz; R Lewetag; Robin Moss; Alessandro Castiglione; David Ziupa; Manfred Zehender; Michael Brunner; Christoph Bode; Katja E Odening

doi:10.1016/j.ijcha.2022.101001

Oxytocin exerts harmful cardiac repolarization prolonging effects in drug-induced LQTS

Int J Cardiol Heart Vasc. 2022 Apr 3:40:101001. doi: 10.1016/j.ijcha.2022.101001. eCollection 2022 Jun.

Authors

Paul Kreifels^{1

2}, Ilona Bodi^{1

2

3}, Tibor Hornyik^{1

2

3}, Gerlind Franke^{1

2}, Stefanie Perez-Feliz^{1

2}, R Lewetag^{1

2}, Robin Moss², Alessandro Castiglione^{1

3}, David Ziupa¹, Manfred Zehender¹, Michael Brunner⁴, Christoph Bode¹, Katja E Odening^{1

2

3}

Affiliations

¹ Department of Cardiology and Angiology I, University Heart Center Freiburg, Medical Faculty, University of Freiburg, Freiburg, Germany.
² Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg • Bad Krozingen, and Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³ Translational Cardiology, Department of Cardiology, Inselspital, University Hospital Bern, and Institute of Physiology, University of Bern, Bern, Switzerland.
⁴ Department of Cardiology and Medical Intensive Care, St. Josef Hospital, Freiburg, Germany.

Abstract

Background: Oxytocin is used therapeutically in psychiatric patients. Many of these also receive anti-depressant or anti-psychotic drugs causing acquired long-QT-syndrome (LQTS) by blocking HERG/I_Kr. We previously identified an oxytocin-induced QT-prolongation in LQT2 rabbits, indicating potential harmful effects of combined therapy. We thus aimed to analyze the effects of dual therapy with oxytocin and fluoxetine/risperidone on cardiac repolarization.

Methods: Effects of risperidone, fluoxetine and oxytocin on QT/QTc, short-term variability (STV) of QT, and APD were assessed in rabbits using in vivo ECG and ex vivo monophasic AP recordings in Langendorff-perfused hearts. Underlying mechanisms were assessed using patch clamp in isolated cardiomyocytes.

Results: Oxytocin, fluoxetine and risperidone prolonged QTc and APD in whole hearts. The combination of fluoxetine + oxytocin resulted in further QTc- and APD-prolongation, risperidone + oxytocin tended to increase QTc and APD compared to monotherapy. Temporal QT instability, STV_QTc was increased by oxytocin, fluoxetine / fluoxetine + oxytocin and risperidone / risperidone + oxytocin. Similar APD-prolonging effects were confirmed in isolated cardiomyocytes due to differential effects of the compounds on repolarizing ion currents: Oxytocin reduced I_Ks, fluoxetine and risperidone reduced I_Kr, resulting in additive effects on I_Ktotal-tail. In addition, oxytocin reduced I_K1, further reducing the repolarization reserve.

Conclusion: Oxytocin, risperidone and fluoxetine prolong QTc / APD. Combined treatment further prolongs QTc/APD due to differential effects on I_Ks and I_K1 (block by oxytocin) and I_Kr (block by risperidone and fluoxetine), leading to pronounced impairment of repolarization reserve. Oxytocin should be used with caution in patients in the context of acquired LQTS.

Keywords: Acquired long-QT syndrome; Arrhythmia mechanisms; Drug induced QT-prolongation; Ion channels.