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.

Heterogeneity of the action potential duration is required for sustained atrial fibrillation

“…In contrast, when the grid contained 2 APD regions with a soft boundary between the 2, extrastimuli caused sustained rotors with the singularity point fixed at the boundary between the 2 APD regions ( Figure 5M, Supplemental Video 3). Thus, similar to previously published modeling studies (11,23,24), we found that heterogeneity of the APD is sufficient to form a suitable substrate to perpetuate AF.…”

A Novel Model of the Rabbit Atrial Myocyte for the Study of Ca2+ Mediated Arrhythmia

“…Our study provides insights into the conditions for the emergence of such triggers, as well as cellular models that can be integrated into 3D atrial models to simulate such triggers. Currently, even highly detailed 3D atrial models [11,12] rely on fast pacing for the initiating of AF, and the introduction of a natural triggering mechanism will prove valuable in furthering the understanding of the complex mechanisms underlying AF. and SERCA activity is enhanced.…”

Sensitivity and Uncertainty Analysis of Two Human Atrial Cardiac Cell Models Using Gaussian Process Emulators

“…Models of the human atrial action potential are a subject of research interest and clinical relevance because heterogeneity in action potential shape and duration in different parts of the atria is associated with vulnerability to atrial fibrillation (Varela et al, 2016), and persistence of atrial fibrillation is associated with remodeling of the atrial action potential Colman et al, 2013). There are several different models of human atrial myocytes, each with different properties Wilhelms et al, 2012).…”