title: Acute effects of sex steroid hormones on susceptibility to cardiac arrhythmias: a simulation study.
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.
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, California, United States of America.
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Yang
authors.forename: Junko
authors.initials: J
authors.lastname: Kurokawa
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Furukawa
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Clancy
mesh_terms: D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D002478:Cells, Cultured; D003198:Computer Simulation; D004198:Disease Susceptibility; D004562:Electrocardiography; D004967:Estrogens / Q000378:metabolism; D005260:Female; D012739:Gonadal Steroid Hormones / Q000378:metabolism*; D006168:Guinea Pigs; D008297:Male; D008390:Markov Chains; D008597:Menstrual Cycle / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D015221:Potassium Channels; D011374:Progesterone / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D013739:Testosterone / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D004967:Estrogens; D012739:Gonadal Steroid Hormones; D010880:Piperidines; D015221:Potassium Channels; D011725:Pyridines; C063968:E 4031; D013739:Testosterone; D011374:Progesterone