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)
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.
EP Europace (2019) euz037, https://doi.org/10.1093/europace/euz037
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
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
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
cardiomyocytes. Hormones had no effect on IK1
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.
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.