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.

抗心律失常药物治疗是心房颤动（atrial fibrillation, AF）的一线治疗方案，但其临床成功率差异极大。该现象源于学界对特定药物在房颤进展不同阶段作用于心房基质的具体作用机制仍缺乏充分认知。本研究旨在阐明细胞、组织与器官水平的心房异质性在房颤进展过程中折返基质形成中的作用，以及选定抗心律失常药物的急性作用对其的调控效应。为探究复杂的细胞-器官层面调控机制，我们构建了完整的三维犬心房精细生物物理模型。该模型整合了源自高分辨率显微计算机断层扫描（micro-computed tomography）的心房几何结构与纤维走行方向、区域特异性心房细胞电生理特性，以及进行性房颤诱导的心肌重构效应。根据已发表实验报道的浓度-反应关系，通过抑制对应离子通道电流，将多通道III类抗心律失常药物维纳卡兰与胺碘酮的作用纳入模型。通过在肺静脉区域施加异位起搏启动房颤，可诱发出局灶性持续折返波（转子），随后双侧心房出现进行性波碎裂与转子增殖现象。模拟的房颤场景与犬模型及临床患者的观测结果高度一致。三维心房模拟结果显示，折返基质通常由动作电位时程（action potential duration, APD）高度异质性的组织区域构成。胺碘酮可延长心房动作电位时程并降低其异质性，其终止房颤的效果优于仅同时延长动作电位时程与动作电位时程离散度的维纳卡兰。综上，房颤转子的启动与维持与心房动作电位时程异质性及进行性重构导致的动作电位时程缩短密切相关。本研究结果提示，能够延长心房动作电位时程而不增加其离散度的抗心律失常策略，可有效终止房颤。