scholarly journals Human Atrial Fibrillation Is Not Associated With Remodeling of Ryanodine Receptor Clusters

2021 ◽  
Vol 9 ◽  
Author(s):  
Michelle L. Munro ◽  
Isabelle van Hout ◽  
Hamish M. Aitken-Buck ◽  
Ramanen Sugunesegran ◽  
Krishna Bhagwat ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ryanodine Receptor ◽  
Cardiac Disease ◽  
Spatial Organization ◽  
Super Resolution ◽  
Underlying Mechanism ◽  
Right Atrial ◽  
Cardiomyocyte Hypertrophy ◽  
Human Cardiomyocytes ◽  
Human Atrial Fibrillation

The release of Ca2+ by ryanodine receptor (RyR2) channels is critical for cardiac function. However, abnormal RyR2 activity has been linked to the development of arrhythmias, including increased spontaneous Ca2+ release in human atrial fibrillation (AF). Clustering properties of RyR2 have been suggested to alter the activity of the channel, with remodeling of RyR2 clusters identified in pre-clinical models of AF and heart failure. Whether such remodeling occurs in human cardiac disease remains unclear. This study aimed to investigate the nanoscale organization of RyR2 clusters in AF patients – the first known study to examine this potential remodeling in diseased human cardiomyocytes. Right atrial appendage from cardiac surgery patients with paroxysmal or persistent AF, or without AF (non-AF) were examined using super-resolution (dSTORM) imaging. Significant atrial dilation and cardiomyocyte hypertrophy was observed in persistent AF patients compared to non-AF, with these two parameters significantly correlated. Interestingly, the clustering properties of RyR2 were remarkably unaltered in the AF patients. No significant differences were identified in cluster size (mean ∼18 RyR2 channels), density or channel packing within clusters between patient groups. The spatial organization of clusters throughout the cardiomyocyte was also unchanged across the groups. RyR2 clustering properties did not significantly correlate with patient characteristics. In this first study to examine nanoscale RyR2 organization in human cardiac disease, these findings indicate that RyR2 cluster remodeling is not an underlying mechanism contributing to altered channel function and subsequent arrhythmogenesis in human AF.

scholarly journals Pathological phosphorylation of the ryanodine receptor at s2808 increases the number of individual clusters activated per calcium spark and the calcium released per cluster

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Nolla-Colomer ◽  
C Tarifa ◽  
A Llach ◽  
V Jimenez-Sabado ◽  
A Vallmitjana ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ryanodine Receptor ◽  
Calcium Release ◽  
Region Of Interest ◽  
Fold Increase ◽  
Frame Rate ◽  
Right Atrial ◽  
Funding Source ◽  
Calcium Spark ◽  
Custom Made

Abstract Background Atrial fibrillation (AF) has been associated with an increase in ryanodine receptor (RyR2) phosphorylation and local calcium release (sparks), but it is not known how calcium dynamics of individual RyR2 clusters affect spark dimensions and properties. Purpose This study aimed to test the hypothesis that pathological alterations in the phosphorylation of individual RyR2 clusters at s2808 facilitate the fusion of spontaneous calcium release events from neighboring RyR2 clusters. Methods Cardiomyocytes from mice with GFP-tagged RyR2 or human right atrial tissue were subjected to confocal calcium imaging or immunofluorescent labelling of total and s2808 phosphorylated RyR2. Calcium signals were measured at a frame rate of 240 Hz in a 0.5 x 0.5 μm region of interest (ROI) for each GFP-tagged RyR2 cluster and spontaneous calcium release events were detected using a custom-made algorithm. Results Calcium sparks recorded in 41 myocytes with GFP-tagged RyR2s was due to the spontaneous opening of a single RyR2 cluster in 91.2±2.2% of the cells and two neighbouring clusters in (6.2±1.6%) of the cells. Events with two clusters had bigger amplitude (0.14±0.01 vs. 0.10±0.01, p<0.05), were wider (1.43±0.03 vs. 1.13±0.04 μm, p<0.05), and lasted longer at half maximum (59.8±5.2 vs. 44.4±2.4 ms, p<0.01). Consequently, the calcium spark mass, measured as the time integral of the spark in each ROI increased from 9.2±1.6 for 1 cluster to 17.8±3.5 a.u. for 2 clusters (p<0.01). Interestingly, sparks lasted longer (79±5 vs. 61±4 ms, p<0.001) were wider (3.0±0.2 vs. 2.2±0.1 μm, p>0.001) and had bigger mass (31.5±3.3 vs. 21.9±3.3 a.u, p<0.01) in atrial myocytes from 21 patients with AF than in 27 without. Because phosphorylation of RyR2 clusters at s2808 (s2808/total RyR2) was higher in patients with than without AF (0.80±0.19 vs. 0.44±0.03, p<0.05), we tested how stimulation of RyR2 phosphorylation at s2808 with the β2-adrenergic agonist fenoterol (3μM) affected calcium release in individual RyR2 clusters. Fenoterol increased s2808 phosphoryaltion from 0.39±0.05 to 0.79±0.16 (p<0.05, n=9). It also increased the mass of sparks with 1 RyR2 cluster (from 9.2±1.1 to 16.0±2.3 a.u., p<0.01) and sparks with 2 clusters from 17.8±3.5 to 23.6±2.7 a.u. Moreover, it increased the fraction of sparks with 2 clusters from 6.2±1.6% to 19.3±3.3% (p<0.01) and sparks with 3 clusters reached 6.3±1.9% in the presence of fenoterol. Conclusions The calcium spark mass recorded in patients without AF is comparable to that recorded during activation of calcium release from one or two GFP-tagged RyR2 clusters. The larger mass and slower kinetics of sparks recorded in patients with AF is compatible with an increase in the calcium released from each RyR2 cluster and a 3-fold increase in sparks with 2 or 3 RyR2 clusters observed in GFP-tagged RyR2s when phosphorylation at s2808 is increased to levels observed in atrial fibrillation. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Spanish Ministry of Science and Innovation; Generatlitat de Catalunya

scholarly journals Peroxisome Proliferator-Activated ReceptorαReduces Endothelin-1-Caused Cardiomyocyte Hypertrophy by Inhibiting Nuclear Factor-κB and Adiponectin

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Hsu-Lung Jen ◽  
Po-Len Liu ◽  
Yung-Hsiang Chen ◽  
Wei-Hsian Yin ◽  
Jaw-Wen Chen ◽  
...  
Keyword(s):  
Cell Size ◽  
Underlying Mechanism ◽  
Nuclear Factor Κb ◽  
Cardiomyocyte Hypertrophy ◽  
Peroxisome Proliferator ◽  
Nuclear Factor ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Human Cardiomyocytes ◽  
Endothelin 1

Peroxisome proliferator-activated receptorα(PPARα) plays a role in the pathogenesis of cardiac hypertrophy, although its underlying mechanism remains unclear. The purpose of this study was to evaluate the effect of PPARαactivation on endothelin-1- (ET-1-) caused cardiomyocyte hypertrophy and explore its underlying mechanisms. Human cardiomyocytes (HCMs) were cultured with or without ET-1, whereafter the inhibitory effects of fenofibrate, a PPARαactivator, on cell size and adiponectin protein were tested. We examined the activation of extracellular signal-regulated kinase (ERK) and p38 proteins caused by ET-1 and the inhibition of the ERK and p38 pathways on ET-1-induced cell size and adiponectin expression. Moreover, we investigated the interaction of PPARαwith adiponectin and nuclear factor-κB (NF-κB) by electrophoretic mobility shift assays and coimmunoprecipitation. ET-1 treatment significantly increased cell size, suppressed PPARαexpression, and enhanced the expression of adiponectin. Pretreatment with fenofibrate inhibited the increase in cell size and enhancement of adiponectin expression. ET-1 significantly activated the ERK and p38 pathways, whereas PD98059 and SB205380, respectively, inhibited them. Our results suggest that activated PPARαcan decrease activation of adiponectin and NF-κB and inhibit ET-1-induced cardiomyocyte hypertrophy.

Ranolazine Prevents Levosimendan-Induced Atrial Fibrillation

Pharmacology ◽  
2018 ◽  
Vol 102 (3-4) ◽  
pp. 138-141 ◽  
Author(s):  
Christian Ellermann ◽  
Anja Kohnke ◽  
Dirk G. Dechering ◽  
Simon Kochhäuser ◽  
Florian Reinke ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Acute Decompensated Heart Failure ◽  
Experimental Studies ◽  
Decompensated Heart Failure ◽  
Underlying Mechanism ◽  
Limited Range ◽  
Antiarrhythmic Effect ◽  
Additional Treatment ◽  
Right Atrial ◽  
Positive Inotropic Drug

Objectives: Levosimendan is a calcium sensitizer that is used as positive inotropic drug in acute decompensated heart failure. An increased incidence of atrial fibrillation after levosimendan-treatment was observed in clinical and experimental studies. Due to the limited range of antiarrhythmic drugs, the aim of the present study was to assess potential antiarrhythmic effects of ranolazine in levosimendan-pretreated isolated rabbit hearts. Methods: Twelve rabbit hearts were excised and retrogradely perfused employing the Langendorff setup. Left and right atrial catheters were used to record monophasic action potentials and to obtain cycle length-dependent atrial action potential durations (aAPD90) and effective refractory periods (aERP). After obtaining baseline data, 0.5 µmol/L levosimendan was infused. Subsequently, 10 µmol/L ranolazine was administered. Results: Infusion of levosimendan led to a reduction of aAPD90 (–9 ms, p < 0.05) and aERP (–13 ms, p < 0.05). Additional treatment with ranolazine prolonged aAPD90 (+23 ms, p < 0.01) and aERP (+30 ms, p < 0.05). Under baseline conditions, a predefined pacing protocol induced 77 episodes of atrial fibrillation. Infusion of levosimendan enhanced the vulnerability to atrial fibrillation (132 episodes, p = 0.14). Further treatment with ranolazine had a significant antiarrhythmic effect (61 episodes, p < 0.05). Conclusions: In this study, ranolazine seems to prevent atrial fibrillation in levosimendan-pretreated hearts. Underlying mechanism is a prolongation of atrial repolarization and aERP.

Effect of pulmonary vein isolation on the left-to-right atrial dominant frequency gradient in human atrial fibrillation

Heart Rhythm ◽  
2006 ◽  
Vol 3 (8) ◽  
pp. 889-895 ◽  
Author(s):  
Sorin Lazar ◽  
Sanjay Dixit ◽  
David J. Callans ◽  
David Lin ◽  
Francis E. Marchlinski ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Pulmonary Vein ◽  
Pulmonary Vein Isolation ◽  
Dominant Frequency ◽  
Right Atrial ◽  
Frequency Gradient ◽  
Human Atrial Fibrillation

Abstract 18427: Rotors and Focal Sources for Human Atrial Fibrillation Are Spatially and Temporally Stable

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Vijay Swarup ◽  
Tina Baykaner ◽  
Junaid Zaman ◽  
James Daubert ◽  
John Hummel ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Left Atrial ◽  
Science Studies ◽  
Right Atrial ◽  
Spiral Arms ◽  
Physiological Analysis ◽  
Rotor Core ◽  
The Stability ◽  
Contact Electrodes ◽  
Human Atrial Fibrillation

Introduction: Several groups now report electrical rotors or focal sources sustaining human atrial fibrillation (AF) after it has been triggered. However, some groups report stable sources while others report transient rotational activity. Hypothesis: We hypothesized that AF rotors would be spatially stable in a large multi center experience, using phase mapping. Methods: We prospectively mapped AF in 277 patients (181 persistent, 61±12 years) at 6 centers in the FIRM-registry, using basket catheters with 64 contact electrodes per atrium. AF was mapped by RhythmView (Topera Inc) before ablation. FIRM uses phase analysis and dynamic physiological analysis of repolarization and conduction. AF propagation movies were interpreted by each operator to assess the stability and dynamics of AF sources in multiple maps over tens of minutes prior to ablation. Results: Sources were identified in 258 of 260 of patients in whom AF was mapped (99%), for 2.8±1.4 sources/patient. Patients showed 1.8±1.1 left atrial and 1.1±0.8 right atrial sources. On FIRM mapping, each source was stable for 4196±6360 cycles, with no difference between patients with paroxysmal vs persistent AF (4290±5847 vs 4150±6604, p=0.78), or right vs left atrial sources (p=0.26) (Figure). Rotors showed precession ('wobble') in ~2 cm2 areas, and spiral arms disorganized (‘fibrillatory conduction)’ beyond a spatial domain that varied around each rotor core for each patient, and between patients. Conclusions: Rotors and focal sources for human AF are stable for thousands of cycles during mapping using FIRM. These data show that AF rotors are distinct from macro-reentry. Notably, rotors precess within small atrial regions, and emanating spiral arms disorganize variably into the fibrillatory milieu in agreement with basic science studies. These results provide a rationale for FIRM-guided ablation at AF sources, and explain why rotors have been difficult to detect using traditional mapping approaches.

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