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

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.

In female transgenic LQT2 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 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 I_Ks-tail and I_Ks-steady (−25.5%, oxytocin; −13.3%, prolactin, P < 0.05) in CHO-cells and LQT2-cardiomyocytes. I_Kr currents were not altered. This oxytocin-/prolactin-induced I_Ks reduction caused APD₉₀ prolongation (+11.9%/+13%, P < 0.05) in the context of reduced/absent I_Kr in LQT2 cardiomyocytes. Hormones had no effect on I_K1 and I_Ca,L in cardiomyocytes. Protein and mRNA levels of CACNA1C/Ca_v1.2 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 I_Ks and by increasing Ca_v1.2 and RyR2 expression/transcription, thereby contributing to the increased postpartal arrhythmic risk in LQT2.