Oxytocin and prolactin prolonged QT and action potential duration in LQT2 models by reducing IKs (-25.5% and -13.3%, respectively; P<0.05) and increasing Cav1.2 and RyR2 expression.
Postpartum hormones oxytocin and prolactin prolong QT and action potential duration in LQT2 models by reducing IKs and increasing Cav1.2 and RyR2 expression, providing a mechanistic basis for the increased postpartum arrhythmic risk in LQT2 patients.
p-value: p=<0.05
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.
Bódi et al. (Thu,) conducted a other in Long QT syndrome type 2. Oxytocin and prolactin was evaluated on Reduction of IKs-tail and IKs-steady and APD90 prolongation (p=<0.05). Oxytocin and prolactin prolonged QT and action potential duration in LQT2 models by reducing IKs (-25.5% and -13.3%, respectively; P<0.05) and increasing Cav1.2 and RyR2 expression.