Mechanisms of postpartum-related arrhythmogenesis in long-QT syndrome

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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 channels 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 LQTS phenotype with QT interval prolongations, 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 LQT rabbits are thus useful tools to investigate mechanisms of postpartum-related arrhythmogenesis on in vivo, ex vivo whole heart, tissue, cellular and molecular levels.In this project, we will utilize transgenic LQT2 rabbits to investigate how oxytocin and prolactin affect arrhythmogenesis, (regional) cardiac repolarization and the expression, phosphorylation and function of cardiac ion channels and transporters. To assess mechanisms of postpartum arrhythmia on multiple levels, we will use 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 cellular patch clamping. The experimental data will finally be integrated into an in silico LQT2 heart model to test whether the hormone-induced changes predispose to arrhythmia.Our longterm goal is to translate our findings on the mechanisms of postpartum-related arrhythmogenesis into clinical (diagnostic and therapeutic) routines, specifically, use these findings for recommendations regarding breastfeeding and oxytocin administration in LQTS patients.