52 research outputs found
Microdomain-specific beta-adrenergic regulation of calcium signaling in tachycardia-induced atrial fibrillation
No full textTo our knowledge, no studies have been performed to investigate microdomain-specific protein kinase A (PKA)-dependent-phosphorylation of ryanodine receptors (RyR) during '-adrenergic modulation in atrial fibrillation (AF). Therefore, atrial myocytes from sham-operated- (SHAM) and rapid atrial paced (RAP; 5 days at 10 Hz) rabbits were stimulated under baseline or after '-adrenergic stimulation (Isoproterenol, 300 nM). Ca2+ transients were measured confocally during field stimulation (1 Hz, 37 °C). PKA-dependent RyR phosphorylation was analyzed by immunostaining and assigned to the nearest membrane. Confocal images were analyzed using ImageJ. Statistical significance (p<0.05) was evaluated with Student's t-test, Mann-Whitney U test, or ANOVA. At global level in atrial RAP cells, amplitude of Ca2+ transients and RyR phosphorylation were significantly reduced at baseline, but normalized after '-adrenergic stimulation. At microdomain level in atrial RAP cells, '-adrenergic rescue of RyR phosphorylation involved equal recruitment of RyR at uncoupled, subsarcolemmal and axial regions. In atrial myocytes, level of PKA-dependent RyR phosphorylation depends on the subcellular location. Atrial remodeling due to rapid pacing causes RyR hypophosphorylation that can be reversed by '-adrenergic stimulation. This mechanism could, at least partly, contribute to the '-adrenergic rescue of Ca2+ transients in AF improving contractility, but could adversely increase the likelihood of arrhythmias
Microdomain-specific beta-adrenergic regulation of calcium signaling in tachycardia-induced atrial fibrillation
No full textTo our knowledge, no studies have been performed to investigate microdomain-specific protein kinase A (PKA)-dependent-phosphorylation of ryanodine receptors (RyR) during '-adrenergic modulation in atrial fibrillation (AF). Therefore, atrial myocytes from sham-operated- (SHAM) and rapid atrial paced (RAP; 5 days at 10 Hz) rabbits were stimulated under baseline or after '-adrenergic stimulation (Isoproterenol, 300 nM). Ca2+ transients were measured confocally during field stimulation (1 Hz, 37 °C). PKA-dependent RyR phosphorylation was analyzed by immunostaining and assigned to the nearest membrane. Confocal images were analyzed using ImageJ. Statistical significance (p<0.05) was evaluated with Student's t-test, Mann-Whitney U test, or ANOVA. At global level in atrial RAP cells, amplitude of Ca2+ transients and RyR phosphorylation were significantly reduced at baseline, but normalized after '-adrenergic stimulation. At microdomain level in atrial RAP cells, '-adrenergic rescue of RyR phosphorylation involved equal recruitment of RyR at uncoupled, subsarcolemmal and axial regions. In atrial myocytes, level of PKA-dependent RyR phosphorylation depends on the subcellular location. Atrial remodeling due to rapid pacing causes RyR hypophosphorylation that can be reversed by '-adrenergic stimulation. This mechanism could, at least partly, contribute to the '-adrenergic rescue of Ca2+ transients in AF improving contractility, but could adversely increase the likelihood of arrhythmias
The role of microdomains in regulating ryanodine receptors (RyRs) and the alterations after myocardial infarction in cardiomyocytes
No full textstatus: Publishe
Repolarization variability and early afterdepolarizations in long QT syndrome type 2: is labile calcium the common denominator?
No full textMechanosensitivity of microdomain calcium signalling in the heart
No full textIn cardiac myocytes, calcium (Ca2+) signalling is tightly controlled in dedicated microdomains. At the dyad, i.e. the narrow cleft between t-tubules and junctional sarcoplasmic reticulum (SR), many signalling pathways combine to control Ca2+-induced Ca2+ release during contraction. Local Ca2+ gradients also exist in regions where SR and mitochondria are in close contact to regulate energetic demands. Loss of microdomain structures, or dysregulation of local Ca2+ fluxes in cardiac disease, is often associated with oxidative stress, contractile dysfunction and arrhythmias. Ca2+ signalling at these microdomains is highly mechanosensitive. Recent work has demonstrated that increasing mechanical load triggers rapid local Ca2+ releases that are not reflected by changes in global Ca2+. Key mechanisms involve rapid mechanotransduction with reactive oxygen species or nitric oxide as primary signalling molecules targeting SR or mitochondria microdomains depending on the nature of the mechanical stimulus. This review summarizes the most recent insights in rapid Ca2+ microdomain mechanosensitivity and re-evaluates its (patho)physiological significance in the context of historical data on the macroscopic role of Ca2+ in acute force adaptation and mechanically-induced arrhythmias. We distinguish between preload and afterload mediated effects on local Ca2+ release, and highlight differences between atrial and ventricular myocytes. Finally, we provide an outlook for further investigation in chronic models of abnormal mechanics (eg post-myocardial infarction, atrial fibrillation), to identify the clinical significance of disturbed Ca2+ mechanosensitivity for arrhythmogenesis. (C) 2017 Published by Elsevier Ltd
Dynamic regulation of subcellular calcium handling in the atria:modifying effects of stretch and adrenergic stimulation
No full textAtrial fibrillation is the fast and irregular heart rate that occurs when the upper chambers of the heart experience chaotic electrical activation. Three main factors contribute to the development of this disease: triggers, substrate and modifying factors. An arrhythmia is thus like a fire that needs a spark (Trigger) to ignite a pile of wood (Substrate) and depends on the humidity or accelerants (modifying factors) to burn faster or slower. This body of work takes a closer look at such modifying factors. The major finding of this thesis is that stretching atrial heart muscle cells releases Calcium ions from storage spaces within each cell. If these Calcium release events get frequent enough they can act as triggers for the arrhythmia. The thickness of the atrial muscle is heterogeneous, thus filling the atrium with blood distends thinner parts stronger than ticker portions. The varying degree of stretch might stimulate Calcium release predominantly from myocytes in thinner regions of the atria. This heterogeneity in spontaneous Calcium release can modify also the substrate. A comparable effect of stretch was previously described in the heart’s main chambers. However, it appears that the in the atria it depends on another mechanism, which could serve as a treatment target that mainly acts on the atria without negatively affecting the ventricle
Arrhythmogenic mechanisms in heart failure:linking Beta-Adrenergic stimulation, stretch and calcium
No full textHeart failure (HF) is associated with elevated sympathetic tone and mechanical load. Both systems activate signaling transduction pathways that increase cardiac output, but eventually become part of the disease process itself leading to further worsening of cardiac function. These alterations can adversely contribute to electrical instability, at least in part due to the modulation of Ca2+ handling at the level of the single cardiac myocyte. The major aim of this review is to provide a definitive overview of the links and cross talk between β-adrenergic stimulation, mechanical load, and arrhythmogenesis in the setting of HF. We will initially review the role of Ca2+ in the induction of both early and delayed afterdepolarizations, the role that β-adrenergic stimulation plays in the initiation of these and how the propensity for these may be altered in HF. We will then go onto reviewing the current data with regards to the link between mechanical load and afterdepolarizations, the associated mechano-sensitivity of the ryanodine receptor and other stretch activated channels that may be associated with HF-associated arrhythmias. Furthermore, we will discuss how alterations in local Ca2+ microdomains during the remodeling process associated the HF may contribute to the increased disposition for β-adrenergic or stretch induced arrhythmogenic triggers. Finally, the potential mechanisms linking β-adrenergic stimulation and mechanical stretch will be clarified, with the aim of finding common modalities of arrhythmogenesis that could be targeted by novel therapeutic agents in the setting of HF
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