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. 2014 Mar;16(3):416-23.
doi: 10.1093/europace/eut349.

Evolution and Pharmacological Modulation of the Arrhythmogenic Wave Dynamics in Canine Pulmonary Vein Model

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Free PMC article

Evolution and Pharmacological Modulation of the Arrhythmogenic Wave Dynamics in Canine Pulmonary Vein Model

Michael A Colman et al. Europace. .
Free PMC article

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.

Keywords: Atrial arrhythmias; Computational modelling; Drug effects; Pulmonary veins; Re-entrant waves.

Figures

Figure 1
Figure 1
Model of the canine PV region. (A) Three-dimensional segmented geometry, the PV and LA regions are indicated by different colours and labelled. (B) Segmentation-specific APs in the LA and PV regions. (C) Fibre orientation in the PV region, atrial fibres are tracked and coloured according to the main local fibre orientation component along the anterior-posterior direction. (D) Fibre discontinuities near the LSPV ostium. PV, pulmonary veins, LSPV, left superior pulmonary vein; LIPV, left inferior pulmonary vein; RSPV, right superior pulmonary vein; RIPV, right inferior pulmonary vein.
Figure 2
Figure 2
Generation of conduction blocks in the PV region. Simulated activation patterns following the LSPV pacing are shown for different conditions. (A) Control, (B) full remodelling, (C) cell-to-cell coupling reduction only, (D) ion channel remodelling only, (E) full remodelling without heterogeneity, (F) full remodelling without anisotropy. All activation times are measured from the time of the applied S2 stimulus. Regions coloured in black indicate areas in which excitation failed to propagate. The asterisk indicates the location of the applied stimuli.
Figure 3
Figure 3
Generation of sustained re-entry in the PV region. Snapshots of re-entrant waves and the resultant activation patterns are shown. (A) and (B) Initiation and sustenance of re-entry. Timings indicated are following the S2 stimulus. Arrows indicate direction of wavefront propagation. (C) Activation patterns during the transient (i) and sustained (ii) rotations of a stable re-entrant wave.

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