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Abstract
Acute effects of sex steroid hormones likely contribute to the observation that post-pubescent males have shorter QT intervals than females. However, the specific role for hormones in modulating cardiac electrophysiological parameters and arrhythmia vulnerability is unclear. Here we use a computational modeling approach to incorporate experimentally measured effects of physiological concentrations of testosterone, estrogen and progesterone on cardiac ion channel targets. We then study the hormone effects on ventricular cell and tissue dynamics comprised of Faber-Rudy computational models. The “female” model predicts changes in action potential duration (APD) at different stages of the menstrual cycle that are consistent with clinically observed QT interval fluctuations. The “male” model predicts shortening of APD and QT interval at physiological testosterone concentrations. The model suggests increased susceptibility to drug-induced arrhythmia when estradiol levels are high, while testosterone and progesterone are apparently protective. Simulations predict the effects of sex steroid hormones on clinically observed QT intervals and reveal mechanisms of estrogen-mediated susceptibility to prolongation of QT interval. The simulations also indicate that acute effects of estrogen are not alone sufficient to cause arrhythmia triggers and explain the increased risk of females to Torsades de Pointes. Our results suggest that acute effects of sex steroid hormones on cardiac ion channels are sufficient to account for some aspects of gender specific susceptibility to long-QT linked arrhythmias.
Highlights
In the past decade, studies have suggested that female gender is an independent risk factor for long-QT (LQT) dependent cardiac arrhythmias [1,2,3]
It is well known that female gender is an independent risk factor for some types of cardiac arrhythmias
It has been difficult to determine how much of a role physiological concentrations of circulating sex steroid hormones play in gender linked arrhythmia susceptibility because the cardiac system is so extraordinarily complex
Summary
Studies have suggested that female gender is an independent risk factor for long-QT (LQT) dependent cardiac arrhythmias [1,2,3]. A ligand-bound sex hormone receptor acts a transcription factor by binding to the promoter region of genes containing a hormone responsive element (HRE), leading to regulation of gene expression. In the heart, lipocalin-type prostaglandli D synthase (LPDGS) has been found to be transcriptionally upregulated by estradiol and estrogen receptor (ER) [10] This genomic action requires several hours before the effects can be observed. In addition to the genomic pathway, sex steroid hormones may induce a rapid activation of mitogen-activated protein kinase (MAPK) leading to transcription factor activation [11,12] as well as activation of membrane bound endothelial nitric oxide synthase (eNOS) [13,14]
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