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

• DOI: 10.1371/journal.pcbi.1005245
• Publication Date: 2016-12-16T22:50:45Z
• Authors: Marta Varela; Michael A. Colman; Jules C. Hancox; Oleg V. Aslanidi
• Keywords: Atrial action potential; Atrium (architecture); Reentry

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