Electrophysiological Remodelling of Right Atria in Atrial Fibrillation Sheep Model and Role of Succinate in Electrophysiological Properties

Introduction: Atrial fibrillation (AF) is the most common arrhythmia and is associated with deleterious remodelling processes. In AF patients, the plasmatic succinate content increases, indicating a potential role for metabolic remodelling in AF progression. Objective: To assess the impact of succinate on the electrophysiological properties of right atria (RA) in a persistent AF sheep model. Methods: Optical mapping experiments were performed in ex vivo RA from a burst pacing AF sheep model (SHAM=5; AF=5). The right coronary artery was perfused with Tyrode solution initially containing glucose (5.6mM), subsequently replaced by succinate (5mM). Action potential durations at 80% of repolarization (APD80) and mean conduction velocities (CV) were assessed from 2 to 5Hz pacing frequency and during sinus rhythm (SR). An S1S2 protocol was used to determine effective refractory period (ERP) and a burst pacing procotol (20Hz) to assess ex vivo AF vulnerability. Finally, an organ donation program allowed us to investigate these properties in a human RA from an AF patient. Results: SR frequency was higher in AF than SHAM sheep (2.0 vs. 1.6 Hz; p=0.19). Succinate perfusion decreased SR frequency by 18% in SHAM sheep (1.7 vs. 1.4 Hz; p=0.12) and by 43% in AF sheep (2.0 vs. 1.2 Hz; p=0.009). The ERP was lower in AF than SHAM sheep (184 vs. 210 ms; p=0.5) and succinate induced a significant increase of 136% in SHAM sheep (210 vs. 286 ms; p=0.06) and of 188% in AF sheep (184 vs. 346 ms; p=0.0008). Epicardial APD80 was lower when pacing at 2.5Hz in AF than SHAM sheep (165 vs. 197 ms ; p=0.3). Succinate increased APD80 in both SHAM and AF RA (191 to 224 ms; 165 to 231 ms) but its effect was more important in AF than SHAM sheep (148 vs. 117 %; p=0.1). Mean CV was slower in AF sheep than SHAM sheep (110 vs. 130 cm/s; p=0.47). Succinate slowed mean CV on AF sheep (110 vs. 76; p=0.4) but did not affect SHAM RA. In the human RA, APD80 (257 vs; 309 ms) and total activation time were increased by succinate. Conclusions: Our results indicate that succinate alters atrial electrophysiological properties, most likely through the associated ROS overproduction. Importantly, AF sheep showed an increased sensitivity to succinate perfusion. Preliminary data in a human RA are in line with these observations.