title: Significance of integrated in silico transmural ventricular wedge preparation models of human non-failing and failing hearts for safety evaluation of drug candidates.
abstract: BACKGROUND
  To evaluate the usefulness of in silico assay in predicting drug-induced QTc prolongation and ventricular proarrhythmia, we describe in this study 2-dimensional transmural ventricular wedge preparation model (2D model) of non-failing (non-FH) and failing hearts (FH) based on O'Hara-Rudy dynamic model of human ventricular myocytes.
  
  
  METHODS
  Using the prepared 2D model, we simulated ventricular action potential and recorded electrocardiogram for the non-FH and FH. The FH model was constructed based on differences in mRNA, protein, and/or current levels of ion channels between non-diseased heart and failing heart. To simulate the effects of selected drugs, we incorporated changes in ion channel conductance depending on the IC50value and Hill coefficient at unbound drug blood concentrations.
  
  
  RESULTS
  Dofetilide concentration-dependently induced QTc prolongation at therapeutic concentration in the 2D model of both non-FH and FH. The QTc prolongation in FH was longer than that in non-FH. These findings are consistent with previously reported clinical data. At supratherapeutic concentration 20nM, dofetilide induced Torsade de Pointes-like arrhythmia in the 2D non-FH model. In contrast, the single ventricular myocyte model did not quantitatively reproduce experimental data due to lack of electrotonic interaction. The simulated QTc change induced by six drugs examined in the IQ-CSRC prospective study was almost equivalent to that recorded in drug-treated healthy volunteers.
  
  
  CONCLUSIONS
  Our 2D model with or without heart failure faithfully reproduced drug-induced QT prolongation and ventricular arrhythmias, suggesting that the in silico approach is a powerful tool for predicting cardiac safety of drug candidates at preclinical stage.
authors.affiliation: Preclinical Research Laboratories, Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan; Department of Cardiovascular Medicine, Heart Rhythm Center, Shiga University of Medical Science, Otsu, Japan; Department of Physiology, Shiga University of Medical Science, Otsu, Japan. Electronic address: taeko-kubo@ds-pharma.co.jp.
authors.forename: Taeko
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Department of Cardiovascular Medicine, Heart Rhythm Center, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ashihara
authors.affiliation: Preclinical Research Laboratories, Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Tsubouchi
authors.affiliation: Department of Cardiovascular Medicine, Heart Rhythm Center, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D003198:Computer Simulation; D015507:Drugs, Investigational / Q000009:adverse effects*; D004562:Electrocardiography; D006333:Heart Failure / Q000139:chemically induced* / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology
chemical_list: D015507:Drugs, Investigational
keywords: Action potential; Arrhythmia; Computational models; Drug; Electrocardiogram; Electrophysiology; Heart failure; Ion channel; Safety pharmacology; Simulation