Sex Modulates the Arrhythmogenic Substrate in Prepubertal Rabbit Hearts with Long QT 2

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Abstract
Females have a greater susceptibility to Torsade de Pointes in congenital and drug-induced long QT syndrome (LQTS) that has been attributed to the modulation of ion channel expression by sex hormones. However, little is known regarding sex differences in pre-puberty, that is, before the surge of sexual hormones. In patients with congenital LQTS types 1 and 2, male children tend to have a greater occurrence of adverse events, especially in 10-15 year olds, than their female counterpart. To evaluate whether the rabbit model of drug-acquired LQTS exhibits similar age dependences, hearts of prepubertal rabbits were perfused, mapped optically to record action potentials (APs) and treated with an I(Kr) blocker, E4031 to elicit LQTS2. As expected, AP durations (APD) were significantly longer in female (n = 18) than male hearts (n = 10), at long cycle length. Surprisingly, E4031 (50-250 nM) induced a greater prolongation of APDs in male than in female hearts, and in both genders reversed the direction of repolarization (apex --> base to base --> apex), enhancing dispersions of repolarization. Furthermore, in male hearts, E4031 (0.5 microM) elicited early afterdepolarizations (EADs) that progressed to polymorphic ventricular tachycardia (PVT) (n = 7/10) and were interrupted by isoproterenol (40 nM) and prevented by propranolol (0.5-2.5 microM). In female hearts, E4031 (0.5 microM) produced marked prolongations of APDs yet few EADs with no progression to PVT (n = 16/18). Thus, sex differences are opposite in prepubertal versus adult rabbits with respect to E4031-induced APD prolongation, EADs and PVT, underscoring the fact that APD prolongation alone is insufficient to predict arrhythmia susceptibility.