Mechanisms of postpartum-related arrhythmogenesis in long-QT syndrome
Final Report Abstract
Sudden cardiac death (SCD) in younger, apparently healthy individuals, most often occurs secondary to rare inherited arrhythmogenic channelopathies. The inherited long-QT syndrome type 2 (LQT2) is one of these arrhythmogenic diseases, in which loss-of-function mutations in the gene of repolarizing HERG ion channel prolong cardiac repolarization and increase the risk for ventricular tachyarrhythmia, syncope and SCD. Adult women with LQT2 have a higher risk for lethal arrhythmia than men. During the postpartum phase, this risk is further increased by 4-fold. Despite this clinical observation, no studies have investigated whether and how oxytocin and prolactin that are secreted during the postpartum phase have pro-arrhythmic effects. We hypothesize that oxytocin and prolactin contribute to the heightened postpartal arrhythmogenic risk by modulating the arrhythmogenic substrate (regionally heterogeneous prolongation of cardiac repolarization) as well as the susceptibility to pro-arrhythmic sympathetic stimuli. We have generated transgenic LQT2 rabbit models (HERG-G628S) mimicking the human LQT2 phenotype with QT interval prolongation, spontaneous ventricular tachycardia and sudden cardiac death - and similarly as in human subjects - a particularly high mortality during the postpartum phase due to lethal ventricular arrhythmia. These transgenic LQT2 rabbits are thus useful tools to investigate mechanisms of postpartumrelated arrhythmogenesis on in vivo, ex vivo whole heart, tissue, cellular and molecular levels. In this project, we have utilized transgenic LQT2 rabbits to investigate how oxytocin and prolactin affect arrhythmogenesis, (regional) cardiac repolarization and the expression and function of cardiac ion channels and transporters. To assess mechanisms of postpartum arrhythmia on multiple levels, we have used in vivo ECG monitoring, ex vivo monophasic action potential measurements, real-time PCR and western blot analyses of mRNA and protein expression of cardiac ion channels and Ca2+-handling proteins, and patch clamping. The experimental data were then integrated into an in silico LQT2 heart model to test whether the hormone-induced changes predispose to arrhythmia. 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 oxytocinand 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- and 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 RyR 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 1:1 capture and early afterdepolarization formation. Conclusions: Postpartum hormones oxytocin and prolactin prolong QT/APD in LQT2 by reducing IKs and by increasing Cav1.2 and RyR expression / transcription, thereby contributing to the increased postpartal arrhythmic risk in LQT2.
Publications
- Good feeling, bad heart? – Ambiguity of "cuddling" hormone oxytocin in therapeutic use due to repolarization prolonging effects in the context of anti-psychotic and anti-depressant drug-treatment. 41th Meeting of the ESC Working Group on Cardiac Cellular Electrophysiology, June 2017, Vienna
P. Kreifels, G. Franke, S. Perez-Feliz, I. Bodi, C. Bode, K.E. Odening
- Oxytocin has harmful cardiac repolarization prolonging effects - particularly in context of druginduced LQTS. “Annual Meeting of the European Society of Cardiology”, Aug 2018, Munich
P. Kreifels, G. Franke, S. Perez-Feliz, I. Bodi, A. Castiglione, D. Ziupa, M. Brunner, C. Bode, K.E. Odening
- Oxytocin blocks IKs and IK1 - thus exerting harmful cardiac repolarization prolonging effects particularly in context of drug-induced LQTS. EHRA / EWGCCE Meeting, Mar 2019, Lisbon
P. Kreifels, I. Bodi, G. Franke, S. Perez-Feliz, A. Castiglione, D. Ziupa, M. Brunner, C. Bode, K.E. Odening
