title: Evolution and pharmacological modulation of the arrhythmogenic wave dynamics in canine pulmonary vein model.
abstract: OBJECTIVE
  Atrial fibrillation (AF), the commonest cardiac arrhythmia, has been strongly linked with arrhythmogenic sources near the pulmonary veins (PVs), but underlying mechanisms are not fully understood. We aim to study the generation and sustenance of wave sources in a model of the PV tissue.
  
  
  RESULTS
  A previously developed biophysically detailed three-dimensional canine atrial model is applied. Effects of AF-induced electrical remodelling are introduced based on published experimental data, as changes of ion channel currents (ICaL, IK1, Ito, and IKur), the action potential (AP) and cell-to-cell coupling levels. Pharmacological effects are introduced by blocking specific ion channel currents. A combination of electrical heterogeneity (AP tissue gradients of 5-12 ms) and anisotropy (conduction velocities of 0.75-1.25 and 0.21-0.31 m/s along and transverse to atrial fibres) can results in the generation of wave breaks in the PV region. However, a long wavelength (171 mm) prevents the wave breaks from developing into re-entry. Electrical remodelling leads to decreases in the AP duration, conduction velocity and wavelength (to 49 mm), such that re-entry becomes sustained. Pharmacological effects on the tissue heterogeneity and vulnerability (to wave breaks and re-entry) are quantified to show that drugs that increase the wavelength and stop re-entry (IK1 and IKur blockers) can also increase the heterogeneity (AP gradients of 26-27 ms) and the likelihood of wave breaks.
  
  
  CONCLUSIONS
  Biophysical modelling reveals large conduction block areas near the PVs, which are due to discontinuous fibre arrangement enhanced by electrical heterogeneity. Vulnerability to re-entry in such areas can be modulated by pharmacological interventions.
authors.affiliation: Biological Physics Group, School of Physics & Astronomy, University of Manchester, Manchester M13 9PL, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Colman
authors.forename: Marta
authors.initials: M
authors.lastname: Varela
authors.forename: Jules C
authors.initials: JC
authors.lastname: Hancox
authors.forename: Henggui
authors.initials: H
authors.lastname: Zhang
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Aslanidi
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage*; D001683:Biological Clocks / Q000187:drug effects*; D003198:Computer Simulation; D004195:Disease Models, Animal; D004285:Dogs; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008955:Models, Cardiovascular; D011667:Pulmonary Veins / Q000187:drug effects / Q000503:physiopathology*
chemical_list: D000889:Anti-Arrhythmia Agents
keywords: Atrial arrhythmias; Computational modelling; Drug effects; Pulmonary veins; Re-entrant waves