Abstract 1079: Increased Susceptibility to Atrial Fibrillation in FKBP12.6 Deficient Mice
Introduction: Atrial fibrillation (AF) is a common cardiac arrhythmia associated with significant morbidity and mortality. Cardiac remodeling plays an important role in the pathogenesis of AF and is associated with changes in the structure and function of atrial ion channels. Previous studies have demonstrated PKA hyperphosphorylation of the cardiac ryanodine receptor (RyR2) and decreased binding of the regulatory subunit FKBP12.6 in patients with AF. Dissociation of FKBP12.6 from the RyR2 complex is thought to promote excess leakage of Ca2+ from the sarcoplasmic reticulum (SR) and trigger arrhythmias. Aim of this study was to test the hypothesis that FKBP12.6 deficiency increases the susceptibility to AF in mice due to enhanced diastolic SR Ca2+ leak.
Methods: Surface and intracardiac electrophysiology studies were performed in wildtype (WT) and FKBP12.6 deficient (FKBP12.6-/-) mice. Right atrial programmed stimulation was performed before and after infusion of 50μg/kg carbachol (i.p.).
Results: Under baseline conditions, there were no differences in electrophysiological parameters comparing WT and FKBP12.6-/- mice: RR 146±12 vs 140±15 ms; PR 43±2 vs 43±4 ms; QRS 17±3 vs 19±2 ms, and QTc interval 26±8 vs 35±7 ms, respectively. After carbachol injection, AF was induced in 3 of 6 FKBP12.6-/- mice, whereas AF was not observed in 0 of 6 WT mice. The mean duration of AF episodes, confirmed by rapid and irregular P waves on intra-atrial electrograms, was 6.3±2.3 s.
Conclusion: The results of the present study show an increased susceptibility to AF in FKBP12.6-/- mice. This suggests that intracellular Ca2+ leak through ryanodine receptors may initiate or sustain atrial arrhythmias. Future studies may exploit this model to identify novel pharmacological agents for the treatment of atrial fibrillation.