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.