An in Silico Study of Female Susceptibility to Arousal-Induced Arrhythmias

Abstract

Female sex is a dominant risk factor for arousal-triggered arrhythmia in the long-QT syndrome. We undertook a combined experimental and computational approach to predict if there exists ‘a perfect storm’ of hormone concentration, genetic anomaly, and sympathetic stimulation promotes arrhythmia in females with hERG pore loop mutations.We first probed the interactions of estradiol (E2) with the hERG K channel using a molecular induced fit docking modeling approach. We then developed mathematical models of acquired and inherited Long-QT Syndrome in male and female ventricular human heart myocytes by combining dofetilide or naturally occurring hERG mutations with male and female O’Hara-Rudy model myocytes that incorporate genomic differences and effects of sex steroid hormones. These “male” and “female” model myocytes and tissues then were used to predict how various sex-based differences underlie arrhythmia risk in the setting of acute sympathetic nervous system discharge. Finally, we used molecular scale models to explore interactions between the pore loop mutation G604S and E2 in hERG. The models predicted that female sex increase susceptibility to reentrant arrhythmia following acute sympathetic nervous system stimulation in the setting of both acquired and inherited LQT2 syndrome. The model also suggested that males were protected at physiological testosterone levels. These predictions might inform future risk stratification for drug design and screening.