title: Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials.
abstract: OBJECTIVE
  Understanding drug effects on the heart is key to safety pharmacology assessment and anti-arrhythmic therapy development. Here our goal is to demonstrate the ability of computational models to simulate the effect of drug action on the electrical activity of the heart, at the level of the ion-channel, cell, heart and ECG body surface potential.
  
  
  METHODS
  We use the state-of-the-art mathematical models governing the electrical activity of the heart. A drug model is introduced using an ion channel conductance block for the hERG and fast sodium channels, depending on the IC(50)  value and the drug dose. We simulate the ECG measurements at the body surface and compare biomarkers under different drug actions.
  
  
  RESULTS
  Introducing a 50% hERG-channel current block results in 8% prolongation of the APD(90)  and 6% QT interval prolongation, hERG block does not affect the QRS interval. Introducing 50% fast sodium current block prolongs the QRS and the QT intervals by 12% and 5% respectively, and delays activation times, whereas APD(90)  is not affected.
  
  
  CONCLUSIONS
  Both potassium and sodium blocks prolong the QT interval, but the underlying mechanism is different: for potassium it is due to APD prolongation; while for sodium it is due to a reduction of electrical wave velocity. This study shows the applicability of in silico models for the investigation of drug effects on the heart, from the ion channel to the ECG-based biomarkers.
authors.affiliation: Department of Computer Science, University of Oxford, Oxford, UK. nejib.zemzemi@inria.fr
authors.forename: Nejib
authors.initials: N
authors.lastname: Zemzemi
authors.forename: Miguel O
authors.initials: MO
authors.lastname: Bernabeu
authors.forename: Javier
authors.initials: J
authors.lastname: Saiz
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cooper
authors.forename: Pras
authors.initials: P
authors.lastname: Pathmanathan
authors.forename: Gary R
authors.initials: GR
authors.lastname: Mirams
authors.forename: Joe
authors.initials: J
authors.lastname: Pitt-Francis
authors.forename: Blanca
authors.initials: B
authors.lastname: Rodriguez
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D003198:Computer Simulation; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000502:physiology
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D026941:Sodium Channel Blockers; D015222:Sodium Channels