Role of the succinate pathway in the electrophysiological properties of right atria in a persistent atrial fibrillation sheep model

Atrial fibrillation (AF) is the most sustained arrhythmia and increases morbidity and mortality. However, development and maintenance of AF is a still poorly understood process. Metabolic remodelling could induce transition from paroxysmal to persistent AF. Succinate levels are increased in AF patients indicating a potential role for metabolic remodelling. To assess the impact of the succinate pathway on the electrophysiological properties of right atria (RA) in persistent AF sheep model. Optical experiments were performed in ex vivo RA from a burst pacing AF sheep model. RA were perfused by Tyrode solution with glucose (5.6 mM), subsequently replaced by succinate (10 mM) to increase mitochondrial reactive oxygen species (ROS) production which are known to modulate excitation-contraction coupling (ECC) and study metabolic remodelling. An activator of the succinate β-adrenergic receptor (GPR91), cis-epoxysuccinic acid (300 μM), was used to study the GPR91 involvement in atrial electrophysiology and AF. Action potential duration at 80% of repolarization (APD80) were assessed from 2 to 5 Hz pacing frequency and during sinus rhythm (SR). We used an S1S2 pacing protocol to determine effective refractory period (ERP) and a burst pacing protocol (30 Hz) 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. During succinate perfusion SR is decreased in Sham (1,5 vs 1,2 Hz; P = 0,03), AF (1,5 vs 1 Hz; P = 0,003) and resistant (1,3 vs 1 Hz; P = 0,01) sheep, ERP is increased in AF sheep (184 vs 344 ms; P = 0,0007) and APD80 is increased in Sham (217 vs 264 ms; P = 0,0004) and AF sheep (195 vs 275 ms; P = 0,003). We also observed an increase in amplitude alternans which can induce re-entries and therefore be pro-arrhythmic. These results seems to be confirmed on human AF RA by increasing APD80 (257 vs 309 ms), ERP (260 vs 330 ms) and spontaneous arrhythmias. GPR91 activation led to a slowing of SR (1,7 vs 1,3 Hz; P = 0,03), a shortening of APD80 (200 vs 170 ms; P = 0,007) and an increase in spontaneous arrhythmias. A dysregulation of ECC could explain our results consistently with the ROS involvement and metabolic remodelling in AF. For the first time, we also demonstrated that GPR91 pathway is involved in atrial electrophysiology and could be involved in AF mechanisms.