Po-01-159 role of the succinate pathway in atrial fibrillation mechanisms

Atrial fibrillation (AF) is the most common arrhythmia and is associated with increased morbidity and mortality. The mechanisms underlying the transition from paroxysmal to persistent AF are still a matter of debate. Recent studies indicate a potential role for metabolic remodelling in the AF stabilization process and increased levels of a specific metabolic substrate, succinate, have been found in blood plasma of AF patients. While succinate is known to increase reactive oxygen species (ROS) production, the role of the succinate receptor (GPR91) in atrial function is unknown. To assess the impact of the succinate pathway on AF vulnerability in a sheep model. GPR91 expression levels were quantified by Western Blot (WB) in a previously described sheep model of persistent AF induced by burst-pacing. Optical experiments were subsequently performed in ex vivo right atria (RA) from control sheep (N=5). RA were perfused by Tyrode solution, then supplemented with the cis-epoxysuccinic acid (cESA), a specific activator of GPR91 (150μM) to study its involvement in atrial electrophysiology and AF. Action potential duration at 80% of repolarization (APD80) were assessed from 2 to 5Hz pacing frequency. 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. WB experiments revealed an increase in GPR91 expression in AF sheep compared to sham sheep. Interestingly, in resistant sheep (no AF after 90 days of burst pacing), expression levels were decreased compared to sham. During cESA perfusion in control sheep RA, sinus rhythm (119 vs 95 bpm; p=0,03) and ERP (202 vs 178 ms; p=0,36) were decreased when compared to baseline. We also observed a decrease in APD80 (199 vs 177 ms; p=0.009) and in CV (127 vs 115 cm/sec; p=0.01). These electrophysiological perturbations led to an increase in AF vulnerability by burst pacing (0% vs 60%) and an increase in spontaneous arrhythmias. These results were corroborated in the human RA were cESA decreased APD80 (265 vs 241 ms), ERP (240 vs 220 ms), and CV (119 vs 94 cm/sec) and increased arrhythmia vulnerability. For the first time, we demonstrated that GPR91 is expressed in atrial tissue and that its activation through succinate can play a major role in AF mechanisms.