Abstract 18255: Atrial Fibrillation in RyR2-R2474S Mice
Background: Atrial fibrillation (AF) is one of the most common arrhythmias. Despite a wealth of information on the electrical abnormalities present in the working atrial muscle, a detailed understanding of the cellular events that underlie AF is lacking.
Methods: To explore the role of ryanodine receptor (RyR2) in triggering AF, we executed in vivo intra-esophageal burst pacing induced AF and in vitro atrial myocyte SR Ca2+ leak measurements in WT and RyR2-R2474S+/- mice.
Results: With the in vivo stimulation protocol, 70% of RyR2-R2474S+/- mice could be stimulated into AF whereas WT mice showed no AF (WT: n = 33, R2474S: n = 10, P < 0.05). Confocal Ca2+ imaging in isolated atrial myocytes from these mice showed that atrial myocytes from RyR2-R2474S+/- mice exhibited a 152% increase in SR Ca2+ leak compared to WT (WT: n = 25, R2474S: n=20, P < 0.01). Further, pretreatment of RyR2-R2474S+/- atrial myocytes for 2 hours with 10 µM S107, a 1,4-benzothiazepine derivative that stabilizes RyR2 by inhibiting depletion of the stabilizing subunit calstabin2 (FKBP12.6) from the RyR2 channel (thereby reducing SR Ca2+ leak), resulted in a 68% decrease in diastolic SR Ca2+ leak AF (n = 23, P < 0.05). Administration of S107 treatment via drinking water (20mg/kg/day) for two weeks in RyR2-R2474S+/- mice prevented burst pacing induced-AF (from 70% to 0%) (n = 10 in both groups, P < 0.05).
Conclusions: Thus, SR Ca2+ leak via RyR2 plays a critical role in the pathogenesis of AF and may be a novel therapeutic target for AF in humans.
- © 2011 by American Heart Association, Inc.