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A multiscale computational modelling approach predicts mechanisms of female sex risk in the setting of arousal‐induced arrhythmias

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The Journal of Physiology

Published online on


Female sex is a risk factor for inherited and acquired Long‐QT associated Torsade de Pointes (TdP) arrhythmias, and sympathetic discharge is a major factor in triggering TdP in female Long‐QT syndrome patients. We used a combined experimental and computational approach to predict ‘the perfect storm’ of hormone concentration, IKr block, and sympathetic stimulation that induces arrhythmia in females with inherited and acquired Long‐QT. More specifically, we developed mathematical models of acquired and inherited Long‐QT syndrome in male and female ventricular human myocytes by combining effects of a hormone and a hERG blocker dofetilide or hERG mutations. 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. The model predicted increased risk for arrhythmia in females when acute sympathetic nervous system discharge was applied in the settings of both inherited and acquired Long‐QT syndrome. Females were predicted to have protection from arrhythmia induction when progesterone is high. Males were protected by the presence of testosterone. Structural modelling points towards two plausible and distinct mechanisms of estrogen action enhancing torsadogenic effects: Models suggest estradiol interaction with hERG mutations in the pore loop containing G604, or by interaction with common TdP‐related blockers in the intra‐cavity binding site. Our study presents findings that constitute the first evidence linking structure to function mechanisms underlying female dominance of arousal induced arrhythmias. This article is protected by copyright. All rights reserved