2019 - Postpartum hormones oxytocin and prolactin cause pro-arrhythmic prolongation of cardiac repolarization in long QT syndrome type 2
Port-a Patch Publication in EP Europace (2019)
Authors:
Bodi I., Sorge J., Castiglione A., Glatz S.M., Wuelfers E.M., Franke G., Perez-Feliz S., Koren G., Zehender M., Bugger H., Seemann G., Brunner M., Bode C., Odening K.E.
Journal:
EP Europace (2019) euz037, https://doi.org/10.1093/europace/euz037
Abstract:
Aims
Women with long QT syndrome 2 (LQT
2) 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 LQT
2 rabbits (HERG-G628S, loss of I
Kr), 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 LQT
2 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 APD
75 in LQT
2 hearts. Prolactin prolonged APD
75 at high concentrations. As underlying mechanisms, we identified an oxytocin- and prolactin-induced acute reduction of I
Ks-tail and I
Ks-steady (−25.5%, oxytocin; −13.3%, prolactin, P < 0.05) in CHO-cells and LQT
2-cardiomyocytes. I
Kr currents were not altered. This oxytocin-/prolactin-induced I
Ks reduction caused APD
90 prolongation (+11.9%/+13%, P < 0.05) in the context of reduced/absent I
Kr in LQT
2 cardiomyocytes. Hormones had no effect on I
K1 and I
Ca,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.
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