Abstract 1236: A Molecular and Functional Basis for Focal Arrhythmogenesis in Heart Failure-associated Atrial Fibrillation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Yung-Hsin Yeh ◽  
Reza Wakili ◽  
Xiao Yan Qi ◽  
Denis Chartier ◽  
Stefan Kääb ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Protein Expression ◽  
Action Potentials ◽  
Molecular Mechanisms ◽  
Potential Role ◽  
Regulatory Proteins ◽  
Related Protein ◽  
Triggered Activity ◽  
Delayed Afterdepolarizations

Introduction: Heart failure (HF) frequently causes atrial fibrillation (AF) and focal sources of unknown mechanism have been implicated. Here, we studied the potential role and molecular mechanisms of Ca 2+ handling abnormalities. Methods: Ca 2+ handling (microfluorescence, Indo-1 AM) and related protein expression (Western blot) were assessed in left atria of 20 dogs with ventricular tachypacing (240 bpm × 2 wks)-induced HF and 20 controls (CTLs). Whole-cell perforated-patch was used to record action potentials (APs), delayed afterdepolarizations (DADs) and triggered activity. Results : HF increased [Ca 2+ ] i transient amplitude from 239±24 to 444±43* nM (*P<0.05), and [Ca 2+ ] i release by 10 mM local caffeine puffs (an index of SR Ca 2+ content) from 849±71 (CTL) to 1574±169* nM (HF). Spontaneous Ca 2+ release events increased from 1.8±0.5 (CTL) to 10.7±2.1* events/run (HF). HF significantly increased APD (by ~40% at 1 Hz). DADs and triggered activity were more common in HF (15.2±2.6 triggered APs/run, vs CTL 0.4±0.2*), and were abolished by ryanodine (10 μM), but not by the I f -blocker Cs + (2 mM). HF caused profound changes in protein expression of key Ca 2+ handling and regulatory proteins (Table ). Calsequestrin, the major SR Ca 2+ -binding protein, was reduced by 32%*. Fractional RYR2 PKA (Ser2809) phosphorylation decreased by 63%*, whereas CaMKII (Ser2815) RYR2 phosphorylation increased by 221%*. The catalytic and regulatory (RII) PKA subunits were downregulated by 15%* and 73%*, whereas expression and autophosphorylation (Thr287) of CaMKIIδ were increased by 45%* and 81%* respectively. NCX1, SERCA and total, PKA and CaMKII phosphorylated SERCA-regulatory phospholamban were unchanged by HF. Conclusions: HF causes profound changes in regulation and expression of atrial Ca 2+ handling proteins, producing increased SR Ca 2+ load and release, along with DADs and triggered activity that may account for focal mechanisms that initiate and/or sustain HF-related AF.

Dependence of delayed afterdepolarizations on diastolic potentials in ischemic Purkinje fibers

1989 ◽  
Vol 257 (3) ◽  
pp. H770-H777 ◽  
Author(s):  
W. B. Gough ◽  
N. el-Sherif
Keyword(s):  
Myocardial Infarction ◽  
Action Potentials ◽  
Resting Potential ◽  
Triggered Activity ◽  
Activity Maximum ◽  
Purkinje Fibers ◽  
Sustained Activity ◽  
Delayed Afterdepolarizations ◽  
Diastolic Potential

The mechanism of focal rhythms 1 day after myocardial infarction has been ascribed to both abnormal automaticity and triggered activity arising from delayed after-depolarizations (DADs). During the course of superfusion in vitro, diastolic potentials repolarize to more negative resting potentials. The dependence of DADs and triggered activity on diastolic potentials was studied using extrinsic currents. During sustained activity (maximum diastolic potential = -61 +/- 7 mV), hyperpolarizing current decreased the DADs, rendered them subthreshold, and terminated triggered activity. During the quiescence caused by constant hyperpolarizing current, a stimulated train of action potentials produced DADs. Decreasing the current permitted augmented DADs. In quiescent preparations (resting potential = -68 +/- 7 mV), a train of stimulated action potentials was followed by subthreshold DADs. Depolarizing current increased the DAD amplitude. To exclude depolarization-induced automaticity, constant currents were applied without a previous train of stimuli. Neither DADs nor triggered activity were evoked. Therefore, DADs and triggered activity, postinfarction, depend on the diastolic potential. There is a continuity between subthreshold DADs and sustained activity. DADs may reach a magnitude in which extrinsic interventions may not adequately terminate sustained triggered activity.

Edible Salt Plus D-Gal Accelerate Aging Progress

2014 ◽  
Vol 955-959 ◽  
pp. 326-334 ◽  
Author(s):  
Peng Wan ◽  
Cheng Xi Wei ◽  
Jian Long Wu ◽  
Qing Hua Jin
Keyword(s):  
Protein Expression ◽  
Spatial Memory ◽  
Morris Water Maze ◽  
Water Maze ◽  
Molecular Mechanisms ◽  
Potential Role ◽  
Memory Function ◽  
Accelerate Aging ◽  
Cox 2

Edible salt (ES) is also thought to exacerbate the symptoms of Alzheimer, however, the in vivo function of ES remains poorly understand. In this work, we investigated the phenomenon using the model of Alzheimer induced by D-gal. The behavious examination results exhibited that D-gal plus ES can weaken spatial memory function in the Morris water maze; the activities of T-SOD, GSH-Px and the CAT level in both hippocampus and cortex showed that D-gal plus ES decreased the expression of T-SOD and GSH-Px, but the expression of CAT increased, the protein expression determined in both of the hippocampus and cortex demonstrated that COX-2, iNOS, NFκ-B-p65-N proteins were significantly increased. It is possible that ES acts through several mechanisms, mediating a potential role in memory damage in mice. These results suggest that further study is necessary to evaluate the effect of salt on damage of memory and to determine the molecular mechanisms.

scholarly journals Simulation of Arrhythmogenic Effect of Rogue RyRs in Failing Heart by Using a Coupled Model

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Luyao Lu ◽  
Ling Xia ◽  
Xiuwei Zhu
Keyword(s):  
Heart Failure ◽  
Membrane Potential ◽  
Action Potentials ◽  
Coupled Model ◽  
Reaction Diffusion ◽  
Cellular Level ◽  
Cardiac Cells ◽  
Failing Heart ◽  
Arrhythmogenic Effect ◽  
Delayed Afterdepolarizations

Cardiac cells with heart failure are usually characterized by impairment of Ca2+handling with smaller SR Ca2+store and high risk of triggered activities. In this study, we developed a coupled model by integrating the spatiotemporal Ca2+reaction-diffusion system into the cellular electrophysiological model. With the coupled model, the subcellular Ca2+dynamics and global cellular electrophysiology could be simultaneously traced. The proposed coupled model was then applied to study the effects of rogue RyRs on Ca2+cycling and membrane potential in failing heart. The simulation results suggested that, in the presence of rogue RyRs, Ca2+dynamics is unstable and Ca2+waves are prone to be initiated spontaneously. These release events would elevate the membrane potential substantially which might induce delayed afterdepolarizations or triggered action potentials. Moreover, the variation of membrane potential depolarization is indicated to be dependent on the distribution density of rogue RyR channels. This study provides a new possible arrhythmogenic mechanism for heart failure from subcellular to cellular level.

scholarly journals Investigation into the Protective Effects of Hypaconitine and Glycyrrhetinic Acid Against Chronic Heart Failure of the Rats

2021 ◽  
Author(s):  
Liqin Wang ◽  
Haiming Deng ◽  
Tengyu Wang ◽  
Yun Qiao ◽  
Jianbing Zhu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Factor ◽  
Chronic Heart Failure ◽  
Protein Expression ◽  
Molecular Mechanisms ◽  
Isonicotinic Acid ◽  
Glycyrrhetinic Acid ◽  
Protective Effects ◽  
Mediated Effects ◽  
Enos Protein

Abstract BackgroundThe present study aimed to determine the protective effects of hypaconitine (HA) and glycyrrhetinic acid (GA) against chronic heart failure (CHF) in the rats and to explore the underlying molecular mechanisms.Methods The CHF rat model was established by transverse-aortic constriction (TAC) operation. The total cholesterol (TCHO) and triglyceride (TG) levels were determined by ELISA assay. The protein expression of fibroblast growth factor 2 (FGF2), vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS) in the rat ventricular tissues was determined by immunohistochemistry. The serum metabolites were determined by LC-MS/MS assay.ResultsHA + GA treatment significantly reduced the plasma levels of TCHO and TG in the CHF rats. The expression of FGF2 and VEGFA protein was up-regulated and the expression of eNOS protein was down-regulated in the ventricular tissues of CHF rats, which was significantly restored after HA + GA treatment. HA + GA treatment down-regulated serum isonicotinic acid, phosphatidylcholine, cardiolipin, estrogen glucuronide, and glycocholic acid, up-regulated serum sphingosine and deoxycholic acid in the CHF rats.ConclusionIn conclusion, HA +GA showed protective effects on CHF in the rats, and the HA + GA may exert protective effects by reducing lipid levels, up-regulating the expression of FGF2 and VEGFA proteins, attenuating eNOS protein expression, and modulating metabolic pathways. However, the molecular mechanisms underlying HA + GA-mediated effects still require further examination.

scholarly journals Molecular Mechanisms of Atrial Fibrillation Induced Heart Failure

2012 ◽  
Vol 21 ◽  
pp. S86
Author(s):  
M. Byrne ◽  
L. Ling ◽  
O. Khammy ◽  
D. Williams ◽  
D. Kaye
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Molecular Mechanisms

scholarly journals Common chromosomal imbalances and stemness-related protein expression markers in endometriotic lesions from different anatomical sites: the potential role of stem cells

2012 ◽  
Vol 27 (11) ◽  
pp. 3187-3197 ◽  
Author(s):  
Cássia G.T. Silveira ◽  
Mauricio S. Abrão ◽  
João A. Dias ◽  
Renata A. Coudry ◽  
Fernando A. Soares ◽  
...  
Keyword(s):  
Stem Cells ◽  
Protein Expression ◽  
Potential Role ◽  
Related Protein ◽  
Chromosomal Imbalances

scholarly journals RNA-seq profiling of the atrial transcriptome reveals gender-specific patterns and interactions with atrial fibrillation and heart failure

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
D Balamurali ◽  
S Zeemering ◽  
MF Sinner ◽  
R Wakili ◽  
S Hatem ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Molecular Mechanisms ◽  
Right Atrial ◽  
Rna Seq ◽  
Horizon 2020 ◽  
Research And Innovation ◽  
The Right ◽  
Gender Specific ◽  
Right Atria

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): TRAIN-HEART Innovative Training Network, funded by the European Union’s Horizon 2020 research and innovation program (under the Marie Sklodowska-Curie grant agreement no. 813716) Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly (CATCH ME), funded by the European Union’s Horizon 2020 research and innovation program (under the grant agreement no. 633196) Background Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with heart failure (HF) and stroke. Clinical and experimental data from previous studies suggest gender differences in mechanisms and phenotypes of AF: women may have more atrial fibrosis, worse outcomes after catheter ablation, and some women carry a higher risk for thromboembolic complications than men. The molecular mechanisms underlying these differences are still poorly understood. Methods Gender-based transcriptional patterns were assessed using paired-end, directional RNA sequencing data generated from atrial tissue biopsies in 199 patients either in sinus rhythm or with paroxysmal or persistent AF as part of the CATCH-ME project. Transcript counts were compared between genders separately in the left and right atria using the DESeq2 package in R. The models were adjusted for potential sources of confounding (age, atrial fibrillation status, heart failure status and sequencing batch). Interaction models were implemented using DESeq2 to compare gender*morbidity interactions for persistent AF and HF. Significance was assessed using likelihood ratio tests comparing models with and without the interaction terms. Results with an adjusted P-value  0.05 were considered significant and utilized for subsequent downstream assessments. Differentially expressed (DE) genes were tested for enrichment of gene ontology (GO) terms and KEGG pathways using the WebGestalt toolkit. Results Transcriptome-wide profiling across the cohort identified 33 sex-differentiated genes in the left atria and 51 in the right atrial samples, with 21 of these showing bilateral differences. Interestingly, 36 (44%) of the results from these analyses were comprised of non-coding transcripts, including long non-coding RNAs (lncRNAs), antisense RNAs and pseudogenes. GO and pathway enrichment analyses for these genes revealed their involvement in critical pathways such as the complement and coagulation cascades and RNA transport.  Interaction analyses between gender and AF identified two genes (MPP2 & GNAS-AS1) that were differentially transcribed in the right atria and one gene (MYL2) that was DE in the left atria by gender in persistent AF samples. A similar analysis comparing gender*HF morbidity also revealed evidence of DE. Four transcripts (HLA-DQB1-AS1, EIF1AY, UTY and ZFY-AS1) showed gender-specific differences in expression by HF status in left atria, while HLA-DQB1-AS1 was differentially regulated by gender and HF status in right atrial samples. Conclusions These RNA-seq analyses provide novel insights into gender-related differences in the transcriptional landscape of right and left adult human atrial appendages. Moreover, interaction analyses identified three genes DE in female atria in persistent AF and four DE genes in female atria in heart failure, providing a molecular anchor for the observed differences in atrial diseases phenotypes between men and women.

scholarly journals Association Between C1q/TNF-Related Protein-1 Levels in Human Plasma and Epicardial Adipose Tissues and Congestive Heart Failure

2017 ◽  
Vol 42 (5) ◽  
pp. 2130-2143 ◽  
Author(s):  
Ying Yang ◽  
Si Liu ◽  
Rong-Yi Zhang ◽  
Hui Luo ◽  
Ling Chen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Molecular Mechanisms ◽  
Mrna Level ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Related Protein ◽  
Tissue Samples ◽  
Protein Levels ◽  
Mitogen Activated Protein

Background/Aims: C1q and tumour necrosis factor-related protein 1 (CTRP1) possesses anti-atherogenic and anti-inflammatory effects. This study investigated whether the CTRP1 levels in the plasma and epicardial adipose tissue (EAT) were associated with congestive heart failure (CHF) and to disclose possible molecular mechanisms. Methods: Plasma and tissue samples were obtained from subjects with or without CHF. Plasma levels of CTRP1 were measured by ELISA. The mRNA levels of CTRP1 and inflammatory cytokines were detected by RT-PCR. The protein levels of CTRP1, aldosterone synthase (CYP11B2) and mitogen-activated protein kinase were examined by Western blotting. Results: The levels of CTRP1 in the plasma and EAT were higher in the CHF patients than those in the controls. There were no differences in the CTRP1 levels in cardiomyocytes between the CHF group and the non-CHF group. An exploratory survival analysis showed that higher CTRP1 values at admission were associated with a worse prognosis after discharge. CTRP1 increased the IL-6 mRNA level in H295R cells. CTRP1 recruited ERK1/2 and Jak-2 for aldosterone release by modulating the CYP11B2 protein level, and brain natriuretic peptide repressed the CTRP1-induced aldosterone release through the JAK2-STAT3 signalling pathways. Conclusion: The CTRP1 levels in the plasma and EAT were increased in the CHF patients. CTRP1 is involved in the pathogenesis of CHF by modulating IL-6 levels and aldosterone release.

scholarly journals Atrial Fibrillation in Heart Failure Is Associated with High Levels of Circulating microRNA-199a-5p and 22–5p and a Defective Regulation of Intracellular Calcium and Cell-to-Cell Communication

2021 ◽  
Vol 22 (19) ◽  
pp. 10377
Author(s):  
Anna Garcia-Elias ◽  
Marta Tajes ◽  
Laia Yañez-Bisbe ◽  
Cristina Enjuanes ◽  
Josep Comín-Colet ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Potential Role ◽  
Cell Communication ◽  
Circulating Microrna ◽  
Atrial Remodeling ◽  
Reduced Ejection Fraction ◽  
Protein Levels ◽  
Moderate Reduction ◽  
Inward Currents

MicroRNAs (miRNAs) participate in atrial remodeling and atrial fibrillation (AF) promotion. We determined the circulating miRNA profile in patients with AF and heart failure with reduced ejection fraction (HFrEF), and its potential role in promoting the arrhythmia. In plasma of 98 patients with HFrEF (49 with AF and 49 in sinus rhythm, SR), differential miRNA expression was determined by high-throughput microarray analysis followed by replication of selected candidates. Validated miRNAs were determined in human atrial samples, and potential arrhythmogenic mechanisms studied in HL-1 cells. Circulating miR-199a-5p and miR-22-5p were significantly increased in HFrEF patients with AF versus those with HFrEF in SR. Both miRNAs, but particularly miR-199a-5p, were increased in atrial samples of patients with AF. Overexpression of both miRNAs in HL-1 cells resulted in decreased protein levels of L-type Ca2+ channel, NCX and connexin-40, leading to lower basal intracellular Ca2+ levels, fewer inward currents, a moderate reduction in Ca2+ buffering post-caffeine exposure, and a deficient cell-to-cell communication. In conclusion, circulating miR-199a-5p and miR-22-5p are higher in HFrEF patients with AF, with similar findings in human atrial samples of AF patients. Cells exposed to both miRNAs exhibited altered Ca2+ handling and defective cell-to-cell communication, both findings being potential arrhythmogenic mechanisms.

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