Dataset Information

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.

SUBMITTER: Greiser M

PROVIDER: S-EPMC4347234 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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

Greiser Maura M Kerfant Benoît-Gilles BG Williams George S B GS Voigt Niels N Harks Erik E Dibb Katharine M KM Giese Anne A Meszaros Janos J Verheule Sander S Ravens Ursula U Allessie Maurits A MA Gammie James S JS van der Velden Jolanda J Lederer W Jonathan WJ Dobrev Dobromir D Schotten Ulrich U

The Journal of clinical investigation 20141020 11

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 ...[more]

PMID: 25329692

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Project description:Cardiac repolarization alternans is an arrhythmogenic rhythm disturbance, manifested in individual myocytes as a beat-to-beat alternation of action potential durations and intracellular calcium transient magnitudes. Recent experimental studies have reported "subcellular alternans," in which distinct regions of an individual cell are seen to have counterphase calcium alternations, but the mechanism by which this occurs is not well understood. Although previous theoretical work has proposed a possible dynamical mechanism for subcellular alternans formation, no direct evidence for this mechanism has been reported in vitro. Rather, experimental studies have generally invoked fixed subcellular heterogeneities in calcium-cycling characteristics as the mechanism of subcellular alternans formation.In this study, we have generalized the previously proposed dynamical mechanism to predict a simple pacing algorithm by which subcellular alternans can be induced in isolated cardiac myocytes in the presence or absence of fixed subcellular heterogeneity. We aimed to verify this hypothesis using computational modeling and to confirm it experimentally in isolated cardiac myocytes. Furthermore, we hypothesized that this dynamical mechanism may account for previous reports of subcellular alternans seen in statically paced, intact tissue.Using a physiologically realistic computational model of a cardiac myocyte, we show that our predicted pacing algorithm induces subcellular alternans in a manner consistent with theoretical predictions. We then use a combination of real-time electrophysiology and fluorescent calcium imaging to implement this protocol experimentally and show that it robustly induces subcellular alternans in isolated guinea pig ventricular myocytes. Finally, we use computational modeling to demonstrate that subcellular alternans can indeed be dynamically induced during static pacing of 1D fibers of myocytes during tissue-level spatially discordant alternans.Here we provide the first direct experimental evidence that subcellular alternans can be dynamically induced in cardiac myocytes. This proposed mechanism may contribute to subcellular alternans formation in the intact heart.

Dataset Information

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

Publications

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

Similar Datasets

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