title: Effects of L-type calcium channel and human ether-a-go-go related gene blockers on the electrical activity of the human heart: a simulation study.
abstract: OBJECTIVE
  Class III and IV drugs affect cardiac human ether-a-go-go related gene (IKr) and L-type calcium (ICaL) channels, resulting in complex alterations in repolarization with both anti- and pro-arrhythmic consequences. Interpretation of their effects on cellular and electrocardiogram (ECG)-based biomarkers for risk stratification is challenging. As pharmaceutical compounds often exhibit multiple ion channel effects, our goal is to investigate the simultaneous effect of ICaL and IKr block on human ventricular electrophysiology from ionic to ECG level.
  
  
  RESULTS
  Simulations are conducted using a human body torso bidomain model, which includes realistic representation of human membrane kinetics, anatomy, and fibre orientation. A simple block pore model is incorporated to simulate drug-induced ICaL and IKr blocks, for drug dose = 0, IC50, 2× IC50, 10× IC50, and 30× IC50. Drug effects on human ventricular activity are quantified for different degrees and combinations of ICaL and IKr blocks from the ionic to the body surface ECG level. Electrocardiogram simulations show that ICaL block results in shortening of the QT interval, ST elevation, and reduced T-wave amplitude, caused by reduction in action potential duration and action potential amplitude during the plateau phase, and in repolarization times. In contrast, IKr block results in QT prolongation and reduced T-wave amplitude. When ICaL and IKr blocks are combined, the degree of ICaL block strongly determines QT interval whereas the effect of IKr block is more pronounced on the T-wave amplitude.
  
  
  CONCLUSIONS
  Our simulation study provides new insights into the combined effect of ICaL and IKr blocks on human ventricular activity using a multiscale computational human torso model.
authors.affiliation: Carmen team, INRIA Bordeaux Sud-Ouest, 200 avenue de la vieille tour, Talence Cedex 33405, France nejib.zemzemi@inria.fr.
authors.forename: Nejib
authors.initials: N
authors.lastname: Zemzemi
authors.affiliation: Department of Computer Science, University of Oxford, Oxford OX1 3QD, UK.
authors.forename: Blanca
authors.initials: B
authors.lastname: Rodriguez
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism; D003198:Computer Simulation; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008955:Models, Cardiovascular
chemical_list: D000889:Anti-Arrhythmia Agents; D020746:Calcium Channels, L-Type; D051638:Ether-A-Go-Go Potassium Channels
keywords: Computer simulation; Dispersion of repolarization; ECG modelling; L-type calcium block; QT interval; hERG block