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- Title
Tachycardia-induced silencing of subcellular Ca<sup>2+</sup> signaling in atrial myocytes.
- Authors
Greiser, Maura; Kerfant, Benoît-Gilles; Williams, George S. B.; Voigt, Niels; Harks, Erik; Dibb, Katharine M.; Giese, Anne; Meszaros, Janos; Verheule, Sander; Ravens, Ursula; Allessie, Maurits A.; Gammie, James S.; van der Velden, Jolanda; Lederer, W. Jonathan; Dobrev, Dobromir; Schotten, Ulrich
- Abstract
A trial fibrillation (AF) is characterized by sustained high atrial activation rates and arrhythmogenic cellular Ca2+ signaling instability; however, it is not clear how a high atrial rate and Ca2+ instability may be related. Here, we characterized subcellular Ca2+ signaling after 5 days of high atrial rates in a rabbit model. While some changes were similar to those in persistent AF, we identified a distinct pattern of stabilized subcellular Ca2+ signaling. Ca2+ sparks, arrhythmogenic Ca2+ waves, sarcoplasmic reticulum (SR) Ca2+ leak, and SR Ca2+ content were largely unaltered. Based on computational analysis, these findings were consistent with a higher Ca2+ leak due to PKA-dependent phosphorylation of SRCa2+ channels (RyR2s), fewer RyR2s, and smaller RyR2 clusters in the SR. We determined that less Ca2+ release per [Ca2+] transient, increased Ca2+ buffering strength, shortened action potentials, and reduced L-type Ca2+ current contribute to a stunning reduction of intracellular Na+ concentration following rapid atrial pacing. In both patients with AF and in our rabbit model, this silencing led to failed propagation of the [Ca2+] signal to the myocyte center. We conclude that sustained high atrial rates alone silence Ca2+ signaling and do not produce Ca2+ signaling instability, consistent with an adaptive molecular and cellular response to atrial tachycardia.
- Subjects
INTRACELLULAR calcium; TACHYCARDIA; ATRIAL fibrillation; HUMAN cellular signal transduction; MUSCLE cells
- Publication
Journal of Clinical Investigation, 2014, Vol 124, Issue 11, p4759
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI70102