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

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

Genesis of Atrial Fibrillation Under Different Diffuse Fibrosis Density Related with Atmospheric Pollution. In-Silico Study

Atrial remodeling is a widely acknowledged process that accelerates the susceptibility to and progression of atrial fibrillation. An increasingly recognized structural component is atrial fibrosis. Recent studies have shown that air pollution increases the risk of heart arrhythmias, where the exposure to particulate matter (PM) contributes to the generation of myocardial fibrosis, increasing the cardiovascular risk. The density and patterns of fibrosis (interstitial, compact and diffuse) are relevant in abnormal conduction and vulnerability to cardiac arrhythmias. Taking into account that fibrosis has been widely reported as one of the consequences of PM exposure, in this work, we evaluated the effects of low and high diffuse fibrosis density on conduction velocity and arrhythmic propagation patterns. For this purpose, cellular models of atrial myocyte and fibroblast were implemented in a 3D model of the human atria. Low (6.25%) and high (25%) fibrosis densities were simulated in the left atrium and its effect on conduction velocity and fibrillatory dynamics was evaluated. Results showed a conduction velocity reduction of 71% associated with a high fibrosis density. At low fibrosis density, few reentries were observed. On the other hand, at high fibrosis density, irregular propagation patterns, characterized by multiple wavelets and rotors, were observed. Our results suggest that high diffuse fibrosis density is associated with a significant conduction velocity reduction and with chaotic propagation patterns during atrial fibrillation. © 2020, Springer Nature Switzerland AG