Ultrastructural and Functional Remodeling of the Coupling Between Ca2+ Influx and Sarcoplasmic Reticulum Ca2+ Release in Right Atrial Myocytes From Experimental Persistent Atrial Fibrillation

Rationale: Persistent atrial fibrillation (AF) has been associated with structural and electric remodeling and reduced contractile function. \ Objective: To unravel mechanisms underlying reduced sarcoplasmic reticulum (SR) Ca2+ release in persistent AF. Methods: We studied cell shortening, membrane currents, and [Ca2+](i) in right atrial myocytes isolated from sheep with persistent AF (duration 129+/-39 days, N=16), compared to matched control animals (N=21). T-tubule density, ryanodine receptor (RyR) distribution, and local [Ca2+](i) transients were examined in confocal imaging. Results: Myocyte shortening and underlying [Ca2+](i) transients were profoundly reduced in AF (by 54.8% and 62%, P<0.01). This reduced cell shortening could be corrected by increasing [Ca2+](i). SR Ca2+ content was not different. Calculated fractional SR Ca2+ release was reduced in AF (by 20.6%, P<0.05). Peak Ca2+ current density was modestly decreased (by 23.9%, P<0.01). T-tubules were present in the control atrial myocytes at low density and strongly reduced in AF (by 45%, P<0.01), whereas the regular distribution of RyR was unchanged. Synchrony of SR Ca2+ release in AF was significantly reduced with increased areas of delayed Ca2+ release. Propagation between RyR was unaffected but Ca2+ release at subsarcolemmal sites was reduced. Rate of Ca2+ extrusion by Na+/Ca2+ exchanger was increased. Conclusions: In persistent AF, reduced SR Ca2+ release despite preserved SR Ca2+ content is a major factor in contractile dysfunction. Fewer Ca2+ channel-RyR couplings and reduced efficiency of the coupling at subsarcolemmal sites, possibly related to increased Na+/Ca2+ exchanger, underlie the reduction in Ca2+ release. (Circ Res. 2009; 105: 876-885.)