title: Ultrastructural and functional remodeling of the coupling between Ca2+ influx and sarcoplasmic reticulum Ca2+ release in right atrial myocytes from experimental persistent atrial fibrillation.
abstract: BACKGROUND
  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.
authors.affiliation: Experimental Cardiology, KUL, Campus Gasthuisberg O/N 7th Floor, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Lenaerts
authors.forename: Virginie
authors.initials: V
authors.lastname: Bito
authors.forename: Frank R
authors.initials: FR
authors.lastname: Heinzel
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Driesen
authors.forename: Patricia
authors.initials: P
authors.lastname: Holemans
authors.forename: Jan
authors.initials: J
authors.lastname: D'hooge
authors.forename: Hein
authors.initials: H
authors.lastname: Heidbüchel
authors.forename: Karin R
authors.initials: KR
authors.lastname: Sipido
authors.forename: Rik
authors.initials: R
authors.lastname: Willems
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016280:Atrial Function, Right; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D004195:Disease Models, Animal; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006003:Glycogen / Q000378:metabolism; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008564:Membrane Potentials; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D012756:Sheep; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013997:Time Factors
chemical_list: D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger; D006003:Glycogen