Ultrastructural and Functional Remodeling of the Coupling Between Ca 2+ Influx and Sarcoplasmic Reticulum Ca 2+ Release in Right Atrial Myocytes From Experimental Persistent Atrial Fibrillation

Abstract

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) Ca 2+ release in persistent AF. Methods : We studied cell shortening, membrane currents, and [Ca 2+ ] 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 [Ca 2+ ] i transients were examined in confocal imaging. Results : Myocyte shortening and underlying [Ca 2+ ] i transients were profoundly reduced in AF (by 54.8% and 62%, P <0.01). This reduced cell shortening could be corrected by increasing [Ca 2+ ] i . SR Ca 2+ content was not different. Calculated fractional SR Ca 2+ release was reduced in AF (by 20.6%, P <0.05). Peak Ca 2+ 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 Ca 2+ release in AF was significantly reduced with increased areas of delayed Ca 2+ release. Propagation between RyR was unaffected but Ca 2+ release at subsarcolemmal sites was reduced. Rate of Ca 2+ extrusion by Na + /Ca 2+ exchanger was increased. Conclusions : In persistent AF, reduced SR Ca 2+ release despite preserved SR Ca 2+ content is a major factor in contractile dysfunction. Fewer Ca 2+ channel–RyR couplings and reduced efficiency of the coupling at subsarcolemmal sites, possibly related to increased Na + /Ca 2+ exchanger, underlie the reduction in Ca 2+ release.