title: Effects of human atrial ionic remodelling by β-blocker therapy on mechanisms of atrial fibrillation: a computer simulation.
abstract: OBJECTIVE
  Atrial anti-arrhythmic effects of β-adrenoceptor antagonists (β-blockers) may involve both a suppression of pro-arrhythmic effects of catecholamines, and an adaptational electrophysiological response to chronic β-blocker use; so-called 'pharmacological remodelling'. In human atrium, such remodelling decreases the transient outward (Ito) and inward rectifier (IK1) K(+) currents, and increases the cellular action potential duration (APD) and effective refractory period (ERP). However, the consequences of these changes on mechanisms of genesis and maintenance of atrial fibrillation (AF) are unknown. Using mathematical modelling, we tested the hypothesis that the long-term adaptational decrease in human atrial Ito and IK1 caused by chronic β-blocker therapy, i.e. independent of acute electrophysiological effects of β-blockers, in an otherwise un-remodelled atrium, could suppress AF.
  
  
  RESULTS
  Contemporarily, biophysically detailed human atrial cell and tissue models were used to investigate effects of the β-blocker-based pharmacological remodelling. Chronic β-blockade remodelling prolonged atrial cell APD and ERP. The incidence of small amplitude APD alternans in the CRN model was reduced. At the 1D tissue level, β-blocker remodelling decreased the maximum pacing rate at which APs could be conducted. At the three-dimensional organ level, β-blocker remodelling reduced the life span of re-entry scroll waves.
  
  
  CONCLUSIONS
  This study improves our understanding of the electrophysiological mechanisms of AF suppression by chronic β-blocker therapy. Atrial fibrillation suppression may involve a reduced propensity for maintenance of re-entrant excitation waves, as a consequence of increased APD and ERP.
authors.affiliation: College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, EX4 4QF, UK Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester M13 9PL, UK.
authors.forename: Sanjay R
authors.initials: SR
authors.lastname: Kharche
authors.affiliation: College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, EX4 4QF, UK.
authors.forename: Tomas
authors.initials: T
authors.lastname: Stary
authors.affiliation: Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester M13 9PL, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Colman
authors.affiliation: Department of Computer Sciences, University of Liverpool, Liverpool, L69 3BX, UK.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Biktasheva
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK Henggui.Zhang@manchester.ac.uk Antony.Workman@glasgow.ac.uk.
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Workman
authors.affiliation: School of Medicine, University of Glasgow, Glasgow, G12 8QQ, UK.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Rankin
authors.affiliation: School of Biomedical Sciences, University of Leeds, Leeds, LS6 9JT, UK.
authors.forename: Arun V
authors.initials: AV
authors.lastname: Holden
authors.affiliation: Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester M13 9PL, UK Henggui.Zhang@manchester.ac.uk Antony.Workman@glasgow.ac.uk.
authors.forename: Henggui
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D064752:Atrial Remodeling; D003198:Computer Simulation; D006801:Humans; D007473:Ion Channels / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D007473:Ion Channels
keywords: Arrhythmia; Atrial fibrillation; Computer simulation; Ion channel; β-Blockers
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