Role of Sex Hormones in Gender Differences in Cardiac Repolarization and Arrhythmogenesis in Transgenic Long QT Syndrome 2 (LQT2) Rabbits

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The inherited long QT syndrome 2 (LQT2) is an arrhythmogenic disease with a prolonged cardiac repolarization caused by loss-of-function mutations in HERG channels (IKr). Adult women with LQT2 are at a higher risk than men for clinical events such as polymorphic ventricular tachycardia (pVT) and sudden cardiac death (SCD). In our lab we have created transgenic LQT2 rabbits over-expressing a loss-of-function mutant of HERG in the heart. My preliminary data show the same gender differences in transgenic LQT2 rabbits with a prolonged QT-index and a steeper QT/RR ratio in females. This prolonged cardiac repolarization can be mimicked by estrogen in ovariectomized rabbits. In our female LQT2 rabbits SCD only occurred after sexual maturation, partly associated with postpartum, but estrogen predisposed even prepubertal LQT2 rabbits to spontaneous pVT. I hypothesize that sex hormones modulate regional and transmural expression of cardiac ion channels, and α1- and β1-adrenergic receptors and are responsible for the gender differences in cardiac repolarization and arrhythmogenesis. I propose to elucidate the underlying mechanisms that predispose female LQT2 rabbits to cardiac arrhythmias by treating prepubertal rabbits with sex hormones and analyzing the hormone-related changes.