Ultrastructural and functional remodeling of the coupling between Ca2+ influx and sarcoplasmic reticulum Ca2+ release in right atrial myocytes from experimental persistent atrial fibrillation.
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.
Lenaerts
Ilse
I
Experimental Cardiology, KUL, Campus Gasthuisberg O/N 7th Floor, Herestraat 49, B-3000 Leuven, Belgium.
Bito
Virginie
V
Heinzel
Frank R
FR
Driesen
Ronald B
RB
Holemans
Patricia
P
D'hooge
Jan
J
Heidbüchel
Hein
H
Sipido
Karin R
KR
Willems
Rik
R
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
D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger; D006003:Glycogen