title: Tachycardia-induced silencing of subcellular Ca2+ signaling in atrial myocytes.
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.forename: Maura
authors.initials: M
authors.lastname: Greiser
authors.forename: Benoît-Gilles
authors.initials: BG
authors.lastname: Kerfant
authors.forename: George S B
authors.initials: GS
authors.lastname: Williams
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.forename: Erik
authors.initials: E
authors.lastname: Harks
authors.forename: Katharine M
authors.initials: KM
authors.lastname: Dibb
authors.forename: Anne
authors.initials: A
authors.lastname: Giese
authors.forename: Janos
authors.initials: J
authors.lastname: Meszaros
authors.forename: Sander
authors.initials: S
authors.lastname: Verheule
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
authors.forename: Maurits A
authors.initials: MA
authors.lastname: Allessie
authors.forename: James S
authors.initials: JS
authors.lastname: Gammie
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
authors.forename: W Jonathan
authors.initials: WJ
authors.lastname: Lederer
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schotten
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002478:Cells, Cultured; D006325:Heart Atria / Q000473:pathology*; D006339:Heart Rate; D006801:Humans; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D021381:Protein Transport; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D013610:Tachycardia / Q000378:metabolism* / Q000473:pathology
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D012964:Sodium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases