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

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Abstract

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.

Authors

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