Abstract 2630: Cellular and Molecular Determinants of Altered Atrial Ca2+ Signaling in Patients With Chronic Atrial Fibrillation
Background: Chronic atrial fibrillation (cAF) is associated with abnormal atrial Ca2+ signalling, causing remodeling, contractile dysfunction and triggered activity. The poorly understood molecular basis of impaired atrial Ca2+ signaling in cAF was the object of this study.
Methods: Membrane currents (whole-cell voltage clamp) and [Ca2+]i (Fluo-3) were measured in right atrial myocytes from sinus rhythm (Ctl) and cAF patients. Protein expression was quantified by immunoblotting.
Results: In cAF L-type Ca2+ current density and [Ca2+]i transient amplitude were 43% and 46% lower than in Ctl, whereas diastolic [Ca2+]i was unchanged (Figure⇓). Despite reduced protein expression of Serca2a, sarcoplasmic reticulum (SR) Ca2+ content calculated by integrating Na+ -Ca2+ exchange current (INCX) during caffeine-induced Ca2+ release was preserved in cAF, likely because of attenuated Serca2a inhibition by hyperphoshorylated phospholamban. The phosphorylation of ryanodine receptor channels at Ser2809 was 140% higher in cAF compared to Ctl, without protein changes in the major SR Ca2+ buffer calsequestrin. The decay of the caffeine-evoked Ca2+ transient is attributable to Ca2+ transport by NCX and was 100% faster in cAF, consistent with the greater INCX amplitude in cAF. In addition, a given Ca2+ release produced larger INCX current, possibly as a result of NCX protein upregulation.
Conclusions: We conclude that reduced SR Ca2+ release and enhanced NCX activity both contribute to atrial hypocontractility in cAF. The generation of a larger depolarising INCX for a given SR Ca2+ release may cause delayed afterdepolarisations and triggered activity, contributing to AF maintenance.