Tachycardia-induced silencing of subcellular [Ca.sup.2+] signaling in atrial myocytes

Atrial fibrillation (AF) is characterized by sustained high atrial activation rates and arrhythmogenic cellular [Ca.sup.2+] signaling Instability; however, it is not clear how a high atrial rate and [Ca.sup.2+] instability may be related. Here, we characterized subcellular [Ca.sup.2+] 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 [Ca.sup.2+] signaling. [Ca.sup.2+] sparks, arrhythmogenic [Ca.sup.2+] waves, sarcoplasmic reticulum (SR) [Ca.sup.2+] leak, and SR [Ca.sup.2+] content were largely unaltered. Based on computational analysis, these findings were consistent with a higher [Ca.sup.2+] leak due to PKA-dependent phosphorylation of SR [Ca.sup.2+] channels (RyR2s), fewer RyR2s, and smaller RyR2 clusters in the SR. We determined that less [Ca.sup.2+] release per [[Ca.sup.2+]] transient, increased [Ca.sup.2+] buffering strength, shortened action potentials, and reduced L-type [Ca.sup.2+] 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 [[[Ca.sup.2+]].sub.i] signal to the myocyte center. We conclude that sustained high atrial rates alone silence [Ca.sup.2+] signaling and do not produce [Ca.sup.2+] signaling instability, consistent with an adaptive molecular and cellular response to atrial tachycardia.