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(Circulation Research. 2009;105:876.)
© 2009 American Heart Association, Inc.

Cellular Biology

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

Ilse Lenaerts, Virginie Bito, Frank R. Heinzel, Ronald B. Driesen, Patricia Holemans, Jan D'hooge, Hein Heidbüchel, Karin R. Sipido, Rik Willems

From the Divisions of Experimental Cardiology (I.L., V.B., R.B.D., P.H., K.R.S., R.W.) and Cardiac Imaging (J.D.), Department of Cardiovascular Medicine; Division of Clinical Cardiology (H.H., R.W.), UZ Gasthuisberg, University of Leuven, Belgium; and Department of Cardiology (F.R.H.), Medical University of Graz, Austria.

Correspondence to Karin R. Sipido, MD, PhD, Experimental Cardiology, KUL, Campus Gasthuisberg O/N 7th Floor, Herestraat 49, B-3000 Leuven, Belgium. E-mail Karin.Sipido{at}med.kuleuven.be

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.

Key Words: atrial fibrillation • sarcoplasmic reticulum • Na⁺/Ca²⁺ exchange • ryanodine receptor • T-tubules