title: Simulation of early after-depolarisation in non-failing human ventricular myocytes: can this help cardiac safety pharmacology?
abstract: BACKGROUND
  Identified as being the primary mechanism involved in the induction of torsades de pointes (TdP), early after-depolarisation (EAD) formation is an important parameter in cardiac safety pharmacology. Easily observed experimentally at the cellular or tissue level, EAD can also be simulated by computer algorithms using animal or human models. During the last decade, confidence in these algorithms has greatly increased. We investigated the putative usefulness of EAD simulation for cardiac safety pharmacology.
  
  
  METHODS
  EAD simulations were performed in non-failing human ventricular myocytes using the O'Hara-Rudy dynamic model. The role of each cardiac current was investigated by modifying the amplitude of its activity in the model. Prediction of EAD induction by drugs was based on the ratio of their 50% inhibitory concentration values for various cardiac ionic currents to their maximal effective free therapeutic plasma concentration (EFTPCmax).
  
  
  RESULTS
  In the ventricular endocardial myocytes, EAD was only induced by at least 85% inhibition of the rapid delayed rectifier K(+) current (IKr). The other currents can either induce or prevent EAD under sub- (80% IKr inhibition) or up-threshold conditions (87% IKr inhibition) of EAD. The study of the ability of drugs to induce EAD resulted in a classification which was in agreement with the Tdp risk classification.
  
  
  CONCLUSIONS
  Based on EAD computer simulation within the human situation, the present study identified the role of various cardiac currents in the EAD formation and suggested that prediction of EAD formation can be useful for early cardiac safety pharmacology.
authors.affiliation: SCAP Test, rue d'Albroux, 10 - B-1367 Grand Rosière Hottomont, Belgium. bchristophe@scaptest.com.
authors.forename: Bernard
authors.initials: B
authors.lastname: Christophe
mesh_terms: D000200:Action Potentials; D000465:Algorithms; D003198:Computer Simulation; D051668:Delayed Rectifier Potassium Channels / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D051668:Delayed Rectifier Potassium Channels; D011188:Potassium