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

Abstract

AimsAtrial 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 resultsA 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.ConclusionBiophysical 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.

The Efficacy of Class III Anti-arrhythmic Drug Action in 3D Canine Atrial Models: Is the Blockade of IKCa Pro- or Anti-arrhythmic?

“…In this study we used the 3D canine model successfully employed to study the efficacy of AADs in atrial fibrillation [8], [9]. This model includes a realistic canine atrial geometry and myofibre orientations derived from micro computed tomography [10].…”

“…Conditions mimicking AF were obtained by pacing with an S1-S2 protocol near the pulmonary veins (PV) in the presence of moderate or severe ionic remodelling (see [8], [9] for details). We additionally studied a situation of moderate remodelling in the presence of IKCa, according to the new mathematical formulation of this current presented below.…”

Effect of Heart Failure:induced Electrical Remodeling on the Initiation of Atrial Arrhythmias

“…In simulations, standard S1-S2 pacing protocol was applied to the tissue regions of the CT/PM junction, following the same approach as used in Colman et al [10,11]. Three S1 stimuli were applied at a cycle length of 500 ms for control and HF models, followed by a shorter-coupled S2 stimulus.…”

Recent progress in multi-scale models of the human atria

“…Data from [29,30]. (b) The canine atria and pulmonary vein region reconstructed from micro-CT data (i) (data from [32]) is of sufficient resolution to reconstruct orientation demonstrating the complexity of fibres in the pulmonary veins (ii) (data from [45,47]). RA = right atrium, LA = left atrium, PV = pulmonary veins, LSPV = left superior pulmonary vein.…”

“…Biophysically detailed models of the atria which account for regional variation in action potential properties ('Regional variation in atrial electrical properties' section) and complex fibre structure ('Reconstructing complex atrial structure' section) have been used to provide further understanding into some of the mechanisms governing the initiation and evolution of re-entrant activity during AF (e.g. [15,29,45]). …”