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.
Highlights
Atrial fibrillation (AF) is the most common cardiac arrhythmia, imposing a large socio-economic burden on society [1]
Note that at the borders between tissue types, the action potential duration (APD) gradients introduced by the division of atrial tissue into regions with sharp boundaries are greatly smoothed by electrotonic effects (S7 Fig)
This study demonstrates how in silico 3D atrial models can be created from highly detailed ionic channel-to-organ electrophysiological and imaging data and applied to improve the mechanistic understanding of arrhythmogenesis and anti-arrhythmic drug action in atrial fibrillation (AF)
Summary
Atrial fibrillation (AF) is the most common cardiac arrhythmia, imposing a large socio-economic burden on society [1]. AF is associated with high morbidity and is often progressive, with electrical and structural remodelling of the atria leading to a substrate that facilitates the self-perpetuation and resistance to treatment of the arrhythmia [1]. Available anti-arrhythmic drugs have major limitations, including poor long-term effectiveness and, for some, high pro-arrhythmic risk [1,3]. Multiple studies have suggested that AF can be sustained by re-entrant waves propagating in an abnormal atrial substrate [2,3]. Heterogeneous atrial tissue is more susceptible to re-entry leading to conduction block in regions with gradients in refractoriness, high conduction anisotropy, or a combination of these [4]. Experiments have provided evidence that channel blockers aimed at producing anti-arrhythmic effects can instead result in re-entry linked with increased atrial heterogeneity [5]
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