BS-526-02 ROLE OF THE SUCCINATE PATHWAY IN THE ELECTROPHYSIOLOGICAL PROPERTIES OF RIGHT ATRIA IN A PERSISTENT ATRIAL FIBRILLATION SHEEP MODEL

Abstract

The progression from paroxysmal to persistent atrial fibrillation (AF) is still a poorly understood process. Succinate levels are increased in AF patients indicating a potential role for metabolic remodeling in this transition process. To assess the impact of the succinate pathway on the electrophysiological properties of right atria (RA) in a persistent AF sheep model. Optical mapping was performed on ex vivo RA from a burst pacing AF sheep model, including 8 sham, 7 persistent AF, and 3 resistant animals. RA were perfused by Tyrode solution with glucose (5.6mM), subsequently replaced by succinate (10mM), known to increase mitochondrial Reactive Oxygen Species (ROS). An activator of the succinate β-adrenergic receptor (GPR91), cis-epoxysuccinic acid (300μM), was also used to study the GPR91 involvement in atrial electrophysiology and AF (N=6). Action potential duration at 80% of repolarization (APD80) were assessed from 2 to 5Hz pacing frequency and during sinus rhythm (SR). We used an S1S2 pacing protocol to determine effective refractory period (ERP) and a burst pacing protocol (30Hz) 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 and decrease in frequencies at which alternans was observed. These results appear to be confirmed in a human AF RA where succinate increased APD80 (257 vs 309 ms), ERP (260 vs 330 ms) and the occurrence of spontaneous arrhythmias. Finally, in sheep, 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. Succinate induces significant electrophysiological modifications, especially in persistent AF, and increases vulnerability to AF. We have shown that the GPR91 pathway is involved in atrial electrophysiology and succinate-induced arrhythmogenesis, most likely in combination with increased ROS production.