Abstract 1347: Increased Sarcoplasmic Reticulum Calcium Leak In FKBP12.6 Mice Associated With Atrial Fibrillation
Introduction: Previous studies in patients with atrial fibrillation (AF) demonstrated decreased binding of the regulatory subunit FKBP12.6 to cardiac ryanodine receptors (RyR2). Dissociation of FKBP12.6 from RyR2 produces Ca2+ leakage from the sarcoplasmic reticulum (SR) that induces ventricular tachyarrhythmias. We hypothesized that FKBP12.6 deficiency increases the susceptibility to experimentally induced AF.
Methods: Intracardiac programmed electrical stimulation was used to study the vulnerability of FKBP12.6-deficient (−/−) mice to AF, in the absence or presence of tetracaine (a blocker of SR Ca2+ leak). Atrial myocytes were isolated from wildtype (WT) and FKBP12.6−/− mice, and stimulated Ca2+ transients were visualized using fluo-4AM. Presence of spontaneous SR Ca2+ release events was assessed immediately after 30-s pacing at 1 Hz, in the absence or presence of tetracaine (5 Î1/4M).
Results: FKBP12.6−/− mice were more susceptible to pacing-induced AF compared with WT mice (87% vs. 6%; P<0.05). Tetracaine prevented AF in FKBP12.6−/− mice (8/8; 100%), although ECG parameters were not affected otherwise. Isolated FKBP12.6−/− atrial myocytes exhibited non-triggered Ca2+ oscillations during diastole more frequently (60% of cells) than WT myocytes (9%; p<0.05). Tetracaine reduced the incidence of spontaneous SR Ca2+ releases in FKBP12.6−/− myocytes to 16% (Figure⇓).
Conclusion: These studies implicate that depletion of FKBP12.6 in the RyR2 macromolecular complex promotes development of a substrate for AF, and suggest that normalizing aberrant RyR2-mediated SR Ca2+ release events in AF patients might constitute a promising target for the treatment of AF.