Evolution and pharmacological modulation of the arrhythmogenic wave dynamics in canine pulmonary vein model

Michael A Colman, Marta Varela, Jules C Hancox, Henggui Zhang, Oleg V Aslanidi

Research output: Contribution to journalArticle (Academic Journal)

31 Citations (Scopus)

Abstract

AIMS: 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.

METHODS AND 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.

CONCLUSION: 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.

Original languageEnglish
Pages (from-to)416-23
Number of pages8
JournalEP-Europace
Volume16
Issue number3
DOIs
Publication statusPublished - Mar 2014

Keywords

  • Action Potentials
  • Animals
  • Anti-Arrhythmia Agents
  • Biological Clocks
  • Computer Simulation
  • Disease Models, Animal
  • Dogs
  • Heart Conduction System
  • Heart Rate
  • Humans
  • Models, Cardiovascular
  • Pulmonary Veins

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