Atrial Heterogeneity Generates Re-entrant Substrate during Atrial Fibrillation and Anti-arrhythmic Drug Action: Mechanistic Insights from Canine Atrial Models

Abstract

Anti-arrhythmic drug therapy is a frontline treatment for atrial fibrillation (AF), but its success rates are highly variable. This is due to incomplete understanding of the mechanisms of action of specific drugs on the atrial substrate at different stages of AF progression. We aimed to elucidate the role of cellular, tissue and organ level atrial heterogeneities in the generation of a re-entrant substrate during AF progression, and their modulation by the acute action of selected anti-arrhythmic drugs. To explore the complex cell-to-organ mechanisms, a detailed biophysical models of the entire 3D canine atria was developed. The model incorporated atrial geometry and fibre orientation from high-resolution micro-computed tomography, region-specific atrial cell electrophysiology and the effects of progressive AF-induced remodelling. The actions of multi-channel class III anti-arrhythmic agents vernakalant and amiodarone were introduced in the model by inhibiting appropriate ionic channel currents according to experimentally reported concentration-response relationships. AF was initiated by applied ectopic pacing in the pulmonary veins, which led to the generation of localized sustained re-entrant waves (rotors), followed by progressive wave breakdown and rotor multiplication in both atria. The simulated AF scenarios were in agreement with observations in canine models and patients. The 3D atrial simulations revealed that a re-entrant substrate was typically provided by tissue regions of high heterogeneity of action potential duration (APD). Amiodarone increased atrial APD and reduced APD heterogeneity and was more effective in terminating AF than vernakalant, which increased both APD and APD dispersion. In summary, the initiation and sustenance of rotors in AF is linked to atrial APD heterogeneity and APD reduction due to progressive remodelling. Our results suggest that anti-arrhythmic strategies that increase atrial APD without increasing its dispersion are effective in terminating AF.

Fig 1. Electrophysiological properties of ionic channel currents in the canine atria.

In created atrial single cell models, the properties (lines) are validated against experimental data from the dog (symbols) [11]. a), b) L-type calcium current, I_CaL: a) Steady-state values of the voltage-dependent activation (d) and inactivation (f) variables as a function of membrane potential; b) Current-voltage relationship in the LA and PV models. c) Inward rectifier current, I_K1: Current-voltage relationships.

Fig 2. Heterogeneous ionic channel and cellular properties in the canine atria.

Created atrial single cell models (bars) are validated against experimental data from the dog (symbols). a), b), c) Absolute values of the current densities of three main ionic currents: I_to (at +20 mV), I_CaL (+10 mV), I_K1 (-100 mV). Dashed lines join data obtained in the same experimental study. d) APD₉₀ (1 Hz) for all regional models at different stages of ionic remodelling and the RNC model [9]. e) Multiplicative factors for each listed current for models of moderate and advanced ionic remodelling. Only ionic currents that are remodelled with AF are shown. f) Blockade factors for amiodarone (A) at concentrations of 5 and 10 μM and vernakalant (V) at 10 and 30 μM for each listed current. Only ionic currents that are affected by the considered drug actions are shown. All sources of experimental data are summarised in S3 and S4 Tables.

Fig 3. High-resolution 3D canine atrial geometry and corresponding myofibre orientation.

a) Posterior-superior view; b) Inferior-anterior view. The atrial geometry was segmented into four major regions, which are described by the respective electrophysiological atrial cell models: RA (orange), LA (pink), BB-CT (yellow) and PV (blue). Atrial fibres are coloured according to the local fibre orientation component along the anterior-posterior direction.

Fig 4. Heterogeneous APs in canine atrial cell models and their changes due to remodelling.

a) APs (pacing frequency: 2 Hz) for baseline, moderate and advanced ionic remodelling and equivalent canine experimental data when available (insets). b) APs for each of the atrial regional models (2 Hz), above intracellular calcium transients (CaT) and each of the models’ currents in relative units. All sources of experimental data are summarised in S3 Table.

Fig 5. Generation and multiplication of re-entrant waves in the heterogeneous atria.

All panels show an anterior-inferior view (left) and a posterior-superior view (right) of the 3D voltage maps at indicated time points. Rotors are represented by black arrows and conduction block by white lines.

Fig 6. Drug effects on APD₉₀ heterogeneity in the 3D canine atrial model.

a) Whole-atria APD₉₀ maps, measured after pacing the atria at 2 Hz from the sinoatrial node at baseline (B) and under the action of amiodarone at 10 μM concentrations and vernakalant at 30 μM. b) Boxplots showing mean, standard deviation and spread of APD₉₀ measured in each of the major regions of the 3D atria. c) Histograms of APD₉₀ across the entire atria.

Fig 7. CV restitution curves and ERP calculated with 1D models for the PV and LA.

Conditions of moderate (left) and advanced (right) remodelling, at baseline (top) and under the action of 10 μM amiodarone (middle) and 30 μM vernakalant (bottom panels) are shown. The numbers in each panel show ERP in ms (defined as the earliest BCL that does not lead to conduction block) for each tissue type.

Fig 8. Drug effects on CV heterogeneity in the 3D atria model.

Whole-atria CV maps, measured after fast pacing from the LSPV at BCL = 150 ms in moderate remodelling and CV reduction conditions a) at baseline; under the actions of: b) 10 μM amiodarone and c) 30 μM vernakalant. Patchy red regions correspond to zones of decreased CV, which can also be seen in the corresponding histograms in panel d), as a slow-conduction left tail, which is most prominent in the presence of vernakalant.