Postpartum hormones oxytocin and prolactin cause pro-arrhythmic prolongation of cardiac repolarization in long QT syndrome type 2

Ilona Bodi; Jonathan Sorge; Alessandro Castiglione; Sylva M Glatz; Eike M Wuelfers; Gerlind Franke; Stefanie Perez-Feliz; Gideon Koren; Manfred Zehender; Heiko Bugger; Gunnar Seemann; Michael Brunner; Christoph Bode; Katja E Odening

doi:10.1093/europace/euz037

Postpartum hormones oxytocin and prolactin cause pro-arrhythmic prolongation of cardiac repolarization in long QT syndrome type 2

Europace. 2019 Jul 1;21(7):1126-1138. doi: 10.1093/europace/euz037.

Authors

Ilona Bodi^{1

2

3}, Jonathan Sorge^{1

2}, Alessandro Castiglione^{1

2

3}, Sylva M Glatz^{1

2}, Eike M Wuelfers^{2

3}, Gerlind Franke^{1

2}, Stefanie Perez-Feliz^{1

2

3}, Gideon Koren⁴, Manfred Zehender^{1

2}, Heiko Bugger^{1

2}, Gunnar Seemann^{2

3}, Michael Brunner^{1

2

5}, Christoph Bode^{1

2}, Katja E Odening^{1

2

3}

Affiliations

¹ Department of Cardiology and Angiology I, Heart Center University of Freiburg, Hugstetter Str. 55, Freiburg, Germany.
² Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³ Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg - Bad Krozingen and Medical Center - University of Freiburg, Freiburg, Germany.
⁴ Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
⁵ Department of Cardiology and Medical Intensive Care, St. Josefskrankenhaus, Freiburg, Germany.

PMID: 30938413
DOI: 10.1093/europace/euz037

Abstract

Aims: Women with long QT syndrome 2 (LQT2) have a particularly high postpartal risk for lethal arrhythmias. We aimed at investigating whether oxytocin and prolactin contribute to this risk by affecting repolarization.

Methods and results: In female transgenic LQT2 rabbits (HERG-G628S, loss of IKr), hormone effects on QT/action potential duration (APD) were assessed (0.2-200 ng/L). Hormone effects (200 ng/L) on ion currents and cellular APD were determined in transfected cells and LQT2 cardiomyocytes. Hormone effects on ion channels were assessed with qPCR and western blot. Experimental data were incorporated into in silico models to determine the pro-arrhythmic potential. Oxytocin prolonged QTc and steepened QT/RR-slope in vivo and prolonged ex vivo APD75 in LQT2 hearts. Prolactin prolonged APD75 at high concentrations. As underlying mechanisms, we identified an oxytocin- and prolactin-induced acute reduction of IKs-tail and IKs-steady (-25.5%, oxytocin; -13.3%, prolactin, P < 0.05) in CHO-cells and LQT2-cardiomyocytes. IKr currents were not altered. This oxytocin-/prolactin-induced IKs reduction caused APD90 prolongation (+11.9%/+13%, P < 0.05) in the context of reduced/absent IKr in LQT2 cardiomyocytes. Hormones had no effect on IK1 and ICa,L in cardiomyocytes. Protein and mRNA levels of CACNA1C/Cav1.2 and RyR2 were enhanced by oxytocin and prolactin. Incorporating these hormone effects into computational models resulted in reduced repolarization reserve and increased propensity to pro-arrhythmic permanent depolarization, lack of capture and early afterdepolarizations formation.

Conclusions: Postpartum hormones oxytocin and prolactin prolong QT/APD in LQT2 by reducing IKs and by increasing Cav1.2 and RyR2 expression/transcription, thereby contributing to the increased postpartal arrhythmic risk in LQT2.

Keywords: Pro-arrhythmia; Hormones; Ion currents; Long QT syndrome; Oxytocine; Postpartum hormones; Prolactin; Repolarization.

MeSH terms

Action Potentials
Animals
Disease Models, Animal
Female
Heart Conduction System / drug effects*
Long QT Syndrome / chemically induced*
Myocytes, Cardiac / drug effects
Oxytocin / metabolism*
Postpartum Period
Prolactin / metabolism*
Rabbits

Substances

Oxytocin
Prolactin

Supplementary concepts

Long Qt Syndrome 2