ABSTRACT

   There is an ever-increasing awareness of the importance of differences between men and women, in adulthood and preadolescence, in the physiology and pathophysiology of the cardiovascular system. One of the most important differences between men and women regarding sex and arrhythmia is the greater risk in women of a polymorphic ventricular tachycardia known as Torsade de Pointes (TdP), induced by drugs that prolong repolarization. Additionally, female gender is an independent risk ventricular factor for syncope and sudden death in the congenital long QT syndrome (LQTS), whilst prepubertal males have higher risk of lethal cardiac events than prepubertal females.
   In this work, have been formulated  new computational models that allow to simulate sex- and age-related differences in mammals: adult male, adult female, prepubertal male and prepubertal female models comprising electrophysiological characteristics of epicardial, midmiocardial and endocardial cells making possible the simulation of transmural ventricular heterogeneity. A model of dofetilide, an antiarrhythmic drug, was developed with markovian formulation and incorporated into aforementionated ventricular cell models, which include cardiomyocytes as hERG channel cells, wild type and mutations, in normal and pathological conditions.
   The results shown how dofetilide reduced the rapid component of delayed rectifier current which contributed to longer prolongation of action potencial duration (APD), higher incidence of early postdepolarizations (EAD) and increasing the transmural dispersion of repolarization (DOR) in all models. Based results on sex- and age-related differences regarding hERG mutations (congenital LQTS) and dofetilide application  (acquired LQTS or induced by drugs) pointed out that adult females have higher prevalence than adult males in both LQTS. Prepubertal results shown that males and females had similar effects on APD prolongation, EADs and DOR, however, prepubertal males had certain prevalence than females, on electrophysiological effects in some mutations and several concentrations of dofetilide making reversible the sex related differences compared with adults.
   Keywords: mathematical models, computational simulations, antiarrhythmic drugs, dofetilide, long QT syndrome, sex, age, action potential duration, early postdepolarizations, transmural dispersion of repolarization.