Tachycardia-induced silencing of subcellular Ca2+ signaling in atrial myocytes.

Maura Greiser, Benoît-Gilles Kerfant, George S B Williams, Niels Voigt, Erik Harks, Katharine M Dibb, Anne Giese, Janos Meszaros, Sander Verheule, Ursula Ravens, Maurits A Allessie, James S Gammie, Jolanda van der Velden, W Jonathan Lederer, Dobromir Dobrev, Ulrich Schotten

    Research output: Contribution to journalArticlepeer-review


    Atrial 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 SR Ca2+ channels (RyR2s), fewer RyR2s, and smaller RyR2 clusters in the SR. We determined that less Ca2+ release per [Ca2+]i 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+]i 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.
    Original languageEnglish
    Pages (from-to)4759-4772
    Number of pages14
    JournalThe Journal of clinical investigation
    Issue number11
    Publication statusPublished - 3 Nov 2014


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