title: Sex and age related differences in drug induced QT prolongation by dofetilide under reduced repolarization reserve in simulated ventricular cells.
abstract: The aim of this study was to investigate sex and age related differences in drug induced QT prolongation by dofetilide under reduced repolarization reserve in simulated ventricular cells. Left ventricular endocardial action potentials were simulated using a modified Luo Rudy model. Sex, age and regional differences in currents I(CaL), IK(r), IK(s), and I(to) were incorporated into the model by modifying the equations representing them. A model of dofetilide, a class III antiarrhythmic drug, was developed and included into a ventricular cell models. The reduced repolarization reserve was reproduced decreasing the IKs current. Our results shown that the adult female cells had longer action potentials, a steeper APD-BCL relationship and a higher susceptibility to EADs than adult male cells, under control, drug induced and reduced repolarization reserve conditions. On the other hand, young female and young male cells had similar action potentials under control conditions. However, young male cells had longer action potentials and higher susceptibility to EADs than young female cells under drug induced and reduced repolarization reserve conditions. Sex and age dependent differences in I(CaL), IKr, IKs, and Ito may explain the age and sex disparities in prolongation of APD by the action of dofetilide.
authors.affiliation: Departamento de Ingeniería Electrónica, Instituto Tecnológico de Morelia, Mexico. rodogonzalez@ieee.org
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Gonzalez
authors.forename: Julio
authors.initials: J
authors.lastname: Gomis-Tena
authors.forename: Alberto
authors.initials: A
authors.lastname: Corrias
authors.forename: Jose Maria
authors.initials: JM
authors.lastname: Ferrero
authors.forename: Blanca
authors.initials: B
authors.lastname: Rodriguez
authors.forename: Javier
authors.initials: J
authors.lastname: Saiz
mesh_terms: D000200:Action Potentials; D000375:Aging; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects; D003198:Computer Simulation; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology*; D008297:Male; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010627:Phenethylamines / Q000009:adverse effects*; D012737:Sex Factors; D013449:Sulfonamides / Q000009:adverse effects*
chemical_list: D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; C063533:dofetilide