scholarly journals Transverse tubules are a common feature in large mammalian atrial myocytes including human

2011 ◽  
Vol 301 (5) ◽  
pp. H1996-H2005 ◽  
Author(s):  
M. A. Richards ◽  
J. D. Clarke ◽  
P. Saravanan ◽  
N. Voigt ◽  
D. Dobrev ◽  
...  
Keyword(s):  
Calcium Release ◽  
Surface Membrane ◽  
Atrial Myocytes ◽  
Close Coupling ◽  
Human Atrial Myocytes ◽  
Temporal Properties ◽  
Ventricular Cells ◽  
T Tubules ◽  
Spatio Temporal ◽  
Cellular Dysfunction

Transverse (t) tubules are surface membrane invaginations that are present in all mammalian cardiac ventricular cells. The apposition of L-type Ca2+ channels on t tubules with the sarcoplasmic reticulum (SR) constitutes a “calcium release unit” and allows close coupling of excitation to the rise in systolic Ca2+. T tubules are virtually absent in the atria of small mammals, and therefore Ca2+ release from the SR occurs initially at the periphery of the cell and then propagates into the interior. Recent work has, however, shown the occurrence of t tubules in atrial myocytes from sheep. As in the ventricle, Ca2+ release in these cells occurs simultaneously in central and peripheral regions. T tubules in both the atria and the ventricle are lost in disease, contributing to cellular dysfunction. The aim of this study was to determine if the occurrence of t tubules in the atrium is restricted to sheep or is a more general property of larger mammals including humans. In atrial tissue sections from human, horse, cow, and sheep, membranes were labeled using wheat germ agglutinin. As previously shown in sheep, extensive t-tubule networks were present in horse, cow, and human atrial myocytes. Analysis shows half the volume of the cell lies within 0.64 ± 0.03, 0.77 ± 0.03, 0.84 ± 0.03, and 1.56 ± 0.19 μm of t-tubule membrane in horse, cow, sheep, and human atrial myocytes, respectively. The presence of t tubules in the human atria may play an important role in determining the spatio-temporal properties of the systolic Ca2+ transient and how this is perturbed in disease.

P3830Carvedilol treatment diminishes spontaneous calcium release and electrical activity in human atrial myocytes

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
V Jimenez-Sabado ◽  
T Lu ◽  
S Casabella ◽  
C Tarifa ◽  
A Herraiz-Martinez ◽  
...  
Keyword(s):  
Electrical Activity ◽  
Adrenergic Receptors ◽  
Calcium Release ◽  
Calcium Waves ◽  
Atrial Myocytes ◽  
Patch Clamp Technique ◽  
Human Atrial Myocytes ◽  
Site Density ◽  
Inward Currents ◽  
Beta 2

Abstract Background Atrial fibrillation (AF) has been associated with an increase in spontaneous calcium release induced electrical activity, which could potentially be reversed by carvedilol, a nonselective beta-blocker that also inhibits the cardiac ryanodine receptor (RyR2). Interestingly the enantiomer R-carvedilol inhibits the RyR2 but not beta-adrenergic receptors, allowing it to effectively prevent calcium release-induced spontaneous electrical activity without inducing bradycardia and hypotension. Purpose The purpose of this study was to determine how carvedilol treatment affects calcium release-induced transient inward currents (ITI) in human atrial myocytes from patients with AF; and to test the effects of R-carvedilol on spontaneous calcium release in order to assess its therapeutical utility. Methods Human atrial myocytes were isolated from patients undergoing cardiac surgery and subjected to patch-clamp technique (n=60) or confocal calcium imaging (n=6). Beta-2 adrenergic receptors were activated with the selective agonist fenoterol (3μM) and 1μM R-carvedilol was used to inhibit spontaneous calcium release events. Results Recordings of calcium release-induced transient inward currents (ITI) revealed that carvedilol treatment reduced the ITI frequency in patients with AF from 2.2±0.4 events/min in untreated patients to 0.59±0.35 events/min (p<0.01), which was even lower than the incidence in patients without AF (1.0±0.1 events/min; p<0.01). To assess the effects of R-carvedilol, myocytes were first simulated with fenoterol. This increased the calcium spark frequency from 23±15 to 960±336 events/s/1000μm2 in 16 cells from 6 patients (p<0.05). This was due to an increase in the spark site density (from 0.50±0.24 to 12.1±2.4 sites/1000μm2, p<0.001) rather than in the firing rate (0.068±0.14 vs. 0.035±0.012 sparks/s in control, p=0.14). Fenoterol also increased the spark duration from 50.9±5.4 to 77.3±4.1ms (p<0.001) without affecting the amplitude. Importantly, fenoterol also induced global calcium release events such as calcium waves and transients (2.8±1.1 vs. 0 events/min in control, p<0.05). When R-carvedilol was added, the effects of fenoterol were abolished, reducing the incidence of calcium sparks to 69±51 events/s/1000μm2 (p<0.05), the spark site density to 1.68±1.04 sites/1000μm2 (p<0.01), the spark duration to 63.4±4.3ms (p<0.05), and calcium waves and transients were reduced to 0.21±0.14 events/min (p<0.05). Conclusions Carvedilol treatment reduces the ITI frequency in patients with AF to levels below that observed at baseline in patients without AF. Furthermore, the non-beta-blocking R-carvedilol enantiomer abolishes spontaneous calcium release events induced by beta-2 adrenergic stimulation in human atrial myocytes, proposing a therapeutical utility for this compound in patients with AF linked to excessive spontaneous calcium release. Acknowledgement/Funding SAF2017-88019; Marato2015-20-30; SGR2017-1769; CIBERCV

Abstract 1534: Structural and Functional Remodeling of the Coupling between Sarcolemmal Ca 2+ Channels and the Ryanodine Receptor in Atrial Fibrillation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ilse Lenaerts ◽  
Virginie Bito ◽  
Patricia Holemans ◽  
Hein Heidbüchel ◽  
Karin R. Sipido ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Protein Expression ◽  
Ryanodine Receptor ◽  
Cell Voltage ◽  
Atrial Myocytes ◽  
Cell Shortening ◽  
Ventricular Cells ◽  
Functional Remodeling ◽  
T Tubules ◽  
And Control

Background: Permanent atrial fibrillation (AF) in humans has been associated with structural and electrical remodelling. Data on contractile remodelling and control of sarcoplasmic reticulum (SR) Ca 2+ release via the ryanodine receptor (RyR) in permanent AF are however limited. Methods : Ewes were atrially paced at 600 bmp for a median of 23 weeks resulting in permanent AF (mean of 89.6±6 days, N=13) and compared to matched, non-instrumented control animals (CTRL, N=17). Atrial myocytes were isolated and cell shortening (field stimulation), membrane currents (whole cell voltage clamp) and [Ca 2+ ] i (Fluo-3) were measured. Protein expression was analyzed by immunoblotting. T-tubule density was quantified from confocal Z-stack images of cells stained with di-8-ANEPPS. Data are shown as mean±SEM of at least 17 cells and 5 animals. Results: Myocyte shortening and underlying [Ca 2+ ] i transients were profoundly reduced in AF (by 54.8% and 62%, p<0.01). This reduced cell shortening could be corrected by increasing [Ca 2+ ] i during caffeine-induced Ca 2+ release from the SR (L/L 0 9.7±0.5% in AF vs. 10.8±0.5% in CTRL). SR Ca 2+ content (integrated Na + /Ca 2+ exchange current during caffeine application) was not different (CTRL 1.9±0.3 pC/pF vs. AF 2±0.4 pC/pF), but calculated fractional SR Ca 2+ release during a depolarizing step to +10 mV was reduced in AF (by 20.6%, p<0.05). Peak Ca 2+ current density was modestly decreased (at <10 mV by 23.9%, p<0.01). T-tubules were present in the CTRL atrial myocytes though their density was much lower than in ventricular cells (11.4% vs. 20.6%, p<0.05). T-tubule density was robustly reduced in AF vs. CTRL (by 45%, p<0.01) with a reduction of myocyte surface:volume ratio (by 26%, p<0.01). The organization of RyR was apparently unchanged but protein expression was reduced (by 18.6%, p<0.05). Conclusion: In permanent AF, reduced SR Ca 2+ release is a major factor in the reduced cell contraction. Loss of T-tubules contributes to uncoupling of sarcolemmal Ca 2+ channels to RyR and reduced fractional SR Ca 2+ release despite preserved SR Ca 2+ content.

scholarly journals Atrial Fibrillation Is Associated With Increased Spontaneous Calcium Release From the Sarcoplasmic Reticulum in Human Atrial Myocytes

Circulation ◽  
2004 ◽  
Vol 110 (11) ◽  
pp. 1358-1363 ◽  
Author(s):  
Leif Hove-Madsen ◽  
Anna Llach ◽  
Antoni Bayes-Genís ◽  
Santiago Roura ◽  
Enrique Rodriguez Font ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Sarcoplasmic Reticulum ◽  
Calcium Release ◽  
Atrial Myocytes ◽  
Human Atrial Myocytes

The proarrhythmic antihistaminic drug terfenadine increases spontaneous calcium release in human atrial myocytes

2006 ◽  
Vol 553 (1-3) ◽  
pp. 215-221 ◽  
Author(s):  
Leif Hove-Madsen ◽  
Anna Llach ◽  
Cristina E. Molina ◽  
Cristina Prat-Vidal ◽  
Jordi Farré ◽  
...  
Keyword(s):  
Calcium Release ◽  
Atrial Myocytes ◽  
Human Atrial Myocytes ◽  
Antihistaminic Drug

scholarly journals Hypokalemia Promotes Arrhythmia by Distinct Mechanisms in Atrial and Ventricular Myocytes

2020 ◽  
Vol 126 (7) ◽  
pp. 889-906 ◽  
Author(s):  
Kiarash Tazmini ◽  
Michael Frisk ◽  
Alexandre Lewalle ◽  
Martin Laasmaa ◽  
Stefano Morotti ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Atrial Myocytes ◽  
Early Afterdepolarizations ◽  
Membrane Hyperpolarization ◽  
Atrial Cells ◽  
Ventricular Cells ◽  
Rat Myocytes ◽  
Delayed Afterdepolarizations ◽  
T Tubules ◽  
A Current

Rationale: Hypokalemia occurs in up to 20% of hospitalized patients and is associated with increased incidence of ventricular and atrial fibrillation. It is unclear whether these differing types of arrhythmia result from direct and perhaps distinct effects of hypokalemia on cardiomyocytes. Objective: To investigate proarrhythmic mechanisms of hypokalemia in ventricular and atrial myocytes. Methods and Results: Experiments were performed in isolated rat myocytes exposed to simulated hypokalemia conditions (reduction of extracellular [K + ] from 5.0 to 2.7 mmol/L) and supported by mathematical modeling studies. Ventricular cells subjected to hypokalemia exhibited Ca 2+ overload and increased generation of both spontaneous Ca 2+ waves and delayed afterdepolarizations. However, similar Ca 2+ -dependent spontaneous activity during hypokalemia was only observed in a minority of atrial cells that were observed to contain t-tubules. This effect was attributed to close functional pairing of the Na + -K + ATPase and Na + -Ca 2+ exchanger proteins within these structures, as reduction in Na + pump activity locally inhibited Ca 2+ extrusion. Ventricular myocytes and tubulated atrial myocytes additionally exhibited early afterdepolarizations during hypokalemia, associated with Ca 2+ overload. However, early afterdepolarizations also occurred in untubulated atrial cells, despite Ca 2+ quiescence. These phase-3 early afterdepolarizations were rather linked to reactivation of nonequilibrium Na + current, as they were rapidly blocked by tetrodotoxin. Na + current-driven early afterdepolarizations in untubulated atrial cells were enabled by membrane hyperpolarization during hypokalemia and short action potential configurations. Brief action potentials were in turn maintained by ultra-rapid K + current (I Kur ); a current which was found to be absent in tubulated atrial myocytes and ventricular myocytes. Conclusions: Distinct mechanisms underlie hypokalemia-induced arrhythmia in the ventricle and atrium but also vary between atrial myocytes depending on subcellular structure and electrophysiology.

scholarly journals A spatio-temporal specification language and its completeness & decidability

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Tengfei Li ◽  
Jing Liu ◽  
Haiying Sun ◽  
Xiang Chen ◽  
Lipeng Zhang ◽  
...  
Keyword(s):  
Intelligent Transportation System ◽  
Cyber Physical Systems ◽  
Specification Language ◽  
Finite Model ◽  
Critical Systems ◽  
Physical Systems ◽  
Spatial Objects ◽  
Temporal Properties ◽  
Spatio Temporal ◽  
Temporal Specification

AbstractIn the past few years, significant progress has been made on spatio-temporal cyber-physical systems in achieving spatio-temporal properties on several long-standing tasks. With the broader specification of spatio-temporal properties on various applications, the concerns over their spatio-temporal logics have been raised in public, especially after the widely reported safety-critical systems involving self-driving cars, intelligent transportation system, image processing. In this paper, we present a spatio-temporal specification language, STSL PC, by combining Signal Temporal Logic (STL) with a spatial logic S4 u, to characterize spatio-temporal dynamic behaviors of cyber-physical systems. This language is highly expressive: it allows the description of quantitative signals, by expressing spatio-temporal traces over real valued signals in dense time, and Boolean signals, by constraining values of spatial objects across threshold predicates. STSL PC combines the power of temporal modalities and spatial operators, and enjoys important properties such as finite model property. We provide a Hilbert-style axiomatization for the proposed STSL PC and prove the soundness and completeness by the spatio-temporal extension of maximal consistent set and canonical model. Further, we demonstrate the decidability of STSL PC and analyze the complexity of STSL PC. Besides, we generalize STSL to the evolution of spatial objects over time, called STSL OC, and provide the proof of its axiomatization system and decidability.

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