Therapeutic Target For Atrial Fibrillation Research Articles

Circulating exosome long non-coding RNAs are associated with atrial structural remodeling by increasing systemic inflammation in atrial fibrillation patients.

Atrial fibrillation (AF) is the most common cardiac arrhythmia with severe clinical sequelae, but its genetic characteristic implicated in pathogenesis has not been completely clarified. Accumulating evidence has indicated that circulating exosomes and their carried cargoes, such as long non-coding RNAs (lncRNAs), involve in the progress of multiple cardiovascular diseases. However, their potential role as clinical biomarkers in AF diagnosis and prognosis remains unknown. Herein, we conducted the sequence and bioinformatic analysis of circulating exosomes harvested from AF and sinus rhythm patients. A total of 53 differentially expressed lncRNAs were identified, and a total of 6 significantly changed lncRNAs (fold change > 2.0), including NR0046235, NR003045, NONHSAT167247.1, NONHSAT202361.1, NONHSAT205820.1 and NONHSAT200958.1, were verified by qRT-PCR in 215 participants. Moreover, these circulating exosome lncRNA levels were different between paroxysmal and persistent AF patients, which were dramatically associated with abnormal hemodynamics and atrial diameter. Furthermore, we observed that the area under ROC curve (AUC) of six lncRNAs combination for diagnosis of persistent AF was 80.34%. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment pathway analysis indicated these exosome lncRNAs mainly concerning response to chemokine-chemokine receptor interaction, which induced activated inflammation and structural remodeling. In addition, increased plasma levels of CXCR3 ligands, including CXCL4, CXCL9, CXCL10 and CXCL11, were accumulated in AF patient tissues. Our study provides the transcriptome profile revealing pattern of circulating exosome lncRNAs in atrial structural remodeling, which bring valuable insights into improving prognosis and therapeutic targets for AF.

Retracted: Multiomics Analysis of Genetics and Epigenetics Reveals Pathogenesis and Therapeutic Targets for Atrial Fibrillation.

[This retracts the article DOI: 10.1155/2021/6644827.].

Abstract 15017: Chromatin Regulators as Potential Players in Atrial Fibrillation: Locus Analysis and Regulatory Role Investigation

Background: Atrial fibrillation (AF), a prevalent cardiac arrhythmia, has multiple biomarkers identified, yet their roles remain partially understood. Research Questions and Aims: The study sought to investigate the expression and prognostic value of Chromatin Regulators (CRs) in AF, their correlation with the immune microenvironment, and to identify potential prognostic markers, therapeutic drugs, and miRNAs. Methods: We filtered three GEO database datasets containing AF and normal samples, identifying 23 differentially expressed CRs. Sequence analysis and protein-protein interaction (PPI) network construction led to the identification of 10 AF prognosis-related CRs. The biological roles and potential pathways of these CRs were analyzed through Gene Ontology (GO) and ssGSEA algorithm. Moreover, we examined the correlation between hub genes and immune cells/immune function, identifying the top 5 immunity-relevant CRs. Results: Ten CRs linked to AF prognosis were identified, achieving an AUC of 0.901997 in a nomogram model. GO analysis demonstrated the involvement of these CRs in processes associated with cardiovascular diseases. The ssGSEA algorithm showed a connection between the identified CRs and immune infiltration. The study also identified the top 5 immunity-related CRs, and potential drugs and miRNAs for AF therapy. Conclusions: This study elucidates the role of specific CRs in AF, presenting a promising risk model and potential therapeutic targets. Further validation and evaluation of potential therapeutic targets' efficacy and safety are required. This underscores CRs as potential biomarkers and therapeutic targets for AF.

Downregulation of fibromodulin attenuates inflammatory signaling and atrial fibrosis in spontaneously hypertensive rats with atrial fibrillation via inhibiting TLR4/NLRP3 signaling pathway.

Myocardial fibrosis is an important factor in the induction and maintenance of atrial fibrillation (AF). Fibromodulin (FMOD) promotes fibrotic gene expression. However, its specific role in spontaneously hypertensive rats (SHR)-AF remains unclear. We analyzed FMOD mRNA and protein expression in rat atrial tissues using RT-qPCR, Western blot analysis, and immunohistochemistry. Histopathological examination of atrial tissues was performed using hematoxylin and eosin (H&E), Masson's trichrome, and Picrosirius red staining. The levels of inflammatory and fibrosis-related proteins were measured using Western blot analysis. FMOD relative mRNA and protein expression levels were notably upregulated in atrial tissues of both AF groups (normal-AF and SHR-AF groups) than that in atrial tissues of the no-AF group (normal and SHR group). This effect was particularly pronounced in the SHR-AF group. Pathological changes revealed that the extracellular matrix, collagen, collagen fibers, and left atrial diameter were notably increased in the atrial tissues from the SHR-AF group compared to those in the atrial tissues from the SHR group, whereas the left ventricular fractional shortening and left ventricular ejection fraction were notably lower. Expression of TLR4, MyD88, NLRP3, TGF-β1, collagen I, and collagen II mRNA were clearly higher in atrial tissues from the SHR-AF group than in those from the SHR group. Protein levels of TLR4, MyD88, NLRP3, Cleavage-Caspase-1, Cleavage-IL-1β, TGF-β1, p-Smad2, collagen I, and collagen II were clearly higher in atrial tissues from the SHR-AF group than in those from the SHR group. FMOD knockdown inhibited atrial fibrosis, collagen accumulation, and the TLR4/MyD88/NLRP3 signaling pathway. Downregulation of FMOD attenuated inflammatory signaling and atrial fibrosis in SHR-AF by inhibiting the TLR4/NLRP3 signaling pathway. Therefore, FMOD may be a promising therapeutic target in AF.

Beyond the Rhythm: In Silico Identification of Key Genes and Therapeutic Targets in Atrial Fibrillation.

Atrial fibrillation (AF) is a prevalent cardiac arrhythmia worldwide and is characterized by a high risk of thromboembolism, ischemic stroke, and fatality. The precise molecular mechanisms of AF pathogenesis remain unclear. The purpose of this study was to use bioinformatics tools to identify novel key genes in AF, provide deeper insights into the molecular pathogenesis of AF, and uncover potential therapeutic targets. Four publicly available raw RNA-Seq datasets obtained through the ENA Browser, as well as proteomic analysis results, both derived from atrial tissues, were used in this analysis. Differential gene expression analysis was performed and cross-validated with proteomics results to identify common genes/proteins between them. A functional enrichment pathway analysis was performed. Cross-validation analysis revealed five differentially expressed genes, namely FGL2, IGFBP5, NNMT, PLA2G2A, and TNC, in patients with AF compared with those with sinus rhythm (SR). These genes play crucial roles in various cardiovascular functions and may be part of the molecular signature of AF. Furthermore, functional enrichment analysis revealed several pathways related to the extracellular matrix, inflammation, and structural remodeling. This study highlighted five key genes that constitute promising candidates for further experimental exploration as biomarkers as well as therapeutic targets for AF.

Neutrophil Extracellular Traps: Potential Prothrombotic State Markers and Therapeutic Targets for Atrial Fibrillation.

Recently, the mechanism of thrombogenesis has taken a new direction with the involvement of neutrophil extracellular traps (NETs). However, little is known about the relationship between NETs and thrombogenesis in atrial fibrillation (AF). Our study aimed to evaluate NETs in AF patients and their potential association with thrombogenesis. In addition, we studied the effect of NETs on thrombogenesis in rat models. A total of 125 AF patients and 172 controls were studied. Spontaneous echo contrast (SEC) was examined using transesophageal echocardiography to assess the prothrombotic state. We used rapid atrial pacing (RAP) rat models to study NETs' formation and their effects on thrombogenesis. The levels of NETs were analyzed by flow cytometry. To deeply understand the regulatory mechanism of NET formation, the transcriptional characteristics of the left atrial appendage (LAA) tissue from RAP rats were analyzed. We found that NETs were increased significantly in AF patients and positively correlated with SEC grades. And inserting the NET level could significantly enhance the predictivity of CHA2DS2-VASc scores for the AF prothrombotic state. In the RAP models, we observed that NET levels increased significantly in the LAA and promoted thrombosis. Meanwhile, we found that these changes could be suppressed by the NET formation inhibitor. Transcriptomic analysis of the LAA tissue from RAP rats suggested that RAP might stimulate the NET formation by promoting the expression of inflammatory cytokine and adhesion genes. NETs may constitute useful thrombogenesis risk markers in AF patients and provide a potential therapeutic strategy for AF management.

Proteome-Wide Mendelian Randomization Analysis Identified Potential Drug Targets for Atrial Fibrillation.

Background Finding effective and safe therapeutic drugs for atrial fibrillation (AF) is an important concern for clinicians. Proteome-wide Mendelian randomization analysis provides new ideas for finding potential drug targets. Methods and Results Using a proteome-wide Mendelian randomization approach, we assessed the genetic predictive causality between thousands of proteins and AF risk and found that genetically predicted plasma levels of phosphomevalonate kinase, tumor necrosis factor ligand superfamily member 12, sulfhydryl oxidase 2, interleukin-6 receptor subunit alpha, and low-affinity immunoglobulin gamma Fc region receptor II-b might decrease AF risk, while genetically predicted plasma levels of beta-mannosidase, collagen alpha-1(XV) chain, ANXA4 (annexin A4), COF2 (cofilin-2), and RAB1A (Ras-related protein Rab-1A) might increase AF risk (P<3.4×10-5). By using different Mendelian randomization methods and instrumental variable selection thresholds, we performed sensitivity analyses in 30 scenarios to test the robustness of positive findings. Replication analyses were also performed in independent samples to further avoid false-positive findings. Drugs targeting tumor necrosis factor ligand superfamily member 12, interleukin-6 receptor subunit alpha, low-affinity immunoglobulin gamma Fc region receptor II-b, and annexin A4 are approved or in development. The results of the phenome-wide Mendelian randomization analysis showed that changing the plasma levels of phosphomevalonate kinase, cofilin-2, annexin A4, Ras-related protein Rab-1A, sulfhydryl oxidase 2, and collagen alpha-1(XV) chain did not increase the risk of other diseases while decreasing the risk of AF. Conclusions We found a significant causal association between genetically predicted levels of 10 plasma proteins and AF risk. Four of these proteins have drugs targeting them that are approved or in development, and our results suggest the potential for these drugs to treat AF or cause AF. Sulfhydryl oxidase 2, low-affinity immunoglobulin gamma Fc region receptor II-b, and beta-mannosidase have not been suggested by previous laboratory or epidemiological studies to be associated with AF and may reveal new pathophysiological pathways as well as therapeutic targets for AF.

Recruited macrophages are a potential therapeutic target in atrial fibrillation

Recruited macrophages are a potential therapeutic target in atrial fibrillation

Resting heart rate and cardiovascular outcomes in patients with non-paroxysmal atrial fibrillation: CODE-AF registry

BackgroundThe prognostic significance of resting heart rate and its therapeutic target in atrial fibrillation (AF) is uncertain. We sought to investigate the relationship between resting heart rate and cardiovascular outcomes in patients with non-paroxysmal AF (non-PAF).MethodsIn this propensity score-weighted, multi-center prospective cohort study, 3217 patients with non-PAF were analyzed. Patients were categorized according to the baseline resting heart rate and cardiovascular outcomes were accessed for a median follow-up of 30 months. The primary outcome was a composite of cardiovascular death, heart failure hospitalization, and myocardial infarction/critical limb ischemia.ResultsFreedom from primary outcome was longest among patients with resting heart rate 80–99 beats per minute (bpm) whereas shortest among those with ≤ 59 bpm (weighted log rank, p = 0.008). Compared with heart rate ≥ 100 bpm, resting heart rate 80–99 and 60–79 bpm was associated with reduced risk of primary outcome (weighted hazard ratio [WHR] 0.52, 95% confidence interval [CI] 0.32–0.84, p = 0.008 and WHR 0.58, 95% CI 0.37–0.92, p = 0.021 for heart rate 80–99 and 60–79 bpm, respectively). Using weighted restricted cubic spline curves, there was a U-shaped association between the resting heart rate and primary outcome with reduced risk of primary outcome in heart rate range of 68–99 bpm. This association was maintained regardless of atrioventricular node (AVN) blocker use or persistent/permanent AF (p for interaction 0.767 for AVN blocker use and 0.720 for AF type).ConclusionResting heart rate was associated with cardiovascular outcomes in patients with non-PAF and those with resting heart rate between 68 and 99 bpm had lower risk of adverse cardiovascular events regardless of AVN blocker use or persistent/permanent AF.

The Nine RNA Methylation Regulatory Gene Signature Is Associated with the Pathogenesis of Atrial Fibrillation by Modulating the Immune Microenvironment in the Atrial Tissues

Background. Atrial fibrillation (AF) is the most common type of cardiac arrhythmias and a major cause of cardiovascular disease (CVD)-related deaths globally. RNA methylation is the most frequent posttranscriptional modification in the eukaryotic RNAs. Previous studies have demonstrated close associations between the status of RNA methylation and CVD. Methods. We comprehensively evaluated the relationship between RNA methylation and AF. Least absolute shrinkage and selection operator (LASSO) logistic regression analysis was used to establish a risk score model in AF. Biological functional analysis was used to explore the relationship between RNA methylation related signatures and immune microenvironment characteristics. Machine learning was used to recognize the outstanding RNA methylation regulators in AF. Results. There was a significant variant of the mRNA expression of RNA methylation regulators in AF. RNA methylation related risk score could predict the onset of AF and closely associated with immune microenvironment features. XG-Boost algorithm and SHAP recognized that NSUN3 and DCPS might play a key role in the development of AF. Meanwhile, NSUN3 and DCPS had potential diagnostic value in AF. Conclusion. RNA methylation regulatory genes are associated with the onset of AF by modulating the immune microenvironment. The nine AF risk-related RNA methylation regulatory gene signature is a potential diagnostic biomarker and therapeutic target for AF.

Sex-specific contribution of small-conductance Ca2+-activated K+ current to atrial electrophysiology and arrhythmogenesis.

Small-conductance Ca2+-activated K+ (SK) channels are predominantly expressed in the atria, thus offering a unique therapeutic target for atrial fibrillation (AF) independent of ventricular function. Several studies have reported remodeling of SK channels in AF, whereby SK current is increased during AF-induced remodeling in several animal models. Nevertheless, data on SK current (ISK) in atrial myocytes from patients remain scarce, and the AF-associated changes are controversial. Both upregulation and downregulation have been reported in chronic AF vs. normal sinus rhythm, accompanied by increased or decreased action potential duration (APD) lengthening by SK-channel inhibition. A potential confounding factor is the observation that sex-specific differences exist in ISK function in the ventricles, which could also be present in the atria, though this remains unknown.

Sarcomere remodeling of left atrial myocytes in non-failing atrial fibrillation patients.

Atrial fibrillation (AF) significantly contributes to adverse cardiac events like stroke. To identify novel pathways to target therapeutically, we performed mass spectrometry on left atrial (LA) tissue from patients in Sinus Rhythm (SR, n = 3) or with AF (n = 3), with no other cardiovascular disease that could confound interpretation. Pathway analysis identified inflammatory, metabolic, and extracellular matrix pathways as highly altered in AF, all of which are currently active areas of AF research. However, contractile proteins were also significantly altered, and the role of the sarcomere in AF remains mostly unstudied. To understand the functional impact of AF on the sarcomere, we measured force-calcium relationships in single cardiomyocytes from LA and left ventricular (LV) tissue from SR (n = 6) and AF (n = 3) patients. Surprisingly, maximal calcium-activated force (Fmax) was almost doubled in AF compared to SR patients. This result contradicts previous work which observed depressed contractile function in AF patients; however, these patients had heart failure and valve disease. Ventricular cells from these patients showed no change in Fmax (expected in non-failing patients), but a slight calcium sensitization in AF due to decreased troponin I (TnI) phosphorylation, possibly in compensation for elevated heart rate. Mass spec analysis showed that AF atria had decreased myosin-binding protein H-like, slow skeletal TnI, and increased alpha tropomyosin and beta-MHC (confirmed by gel electrophoresis). These changes suggest that AF drives a more “ventricular-like” or mature sarcomere in atrial myocytes, resulting in increased force production that is also similar to ventricular myocytes. Together, these data provide insight into the development and outcomes of atrial fibrillation in absence of other cardiovascular conditions in humans and suggests that the sarcomere may be a feasible therapeutic target in atrial fibrillation.

Vaspin Attenuates Atrial Abnormalities by Promoting ULK1/FUNDC1-Mediated Mitophagy.

The worldwide incidence and prevalence of atrial fibrillation (AF) are increasing, making it a life-threatening condition due to the higher numbers of people suffering from obesity. Vaspin, an adipokine derived from epicardial adipose tissue, has been reported to reduce inflammation, inhibit apoptosis, and induce autophagy; however, its role in the pathogenesis of AF is not known. In this study, we investigated the role of vaspin in patients with AF and explored the molecular mechanisms using atrial myocytes in vitro. Our data showed that vaspin levels were significantly reduced in the plasma of patients with AF. Lower plasma levels of vaspin were also associated with a higher risk of AF in patients with obesity. Vaspin treatment in vitro alleviated cardiomyocyte injury, atrial fibrosis, atrial myocyte apoptosis, and mitochondrial injury in atrial myocytes following Ang-II stress. Moreover, our results demonstrated that vaspin protected against Ang-II-induced atrial myocyte dysfunction by inducing mitophagy. We also observed that vaspin treatment enhanced the phosphorylation of Fun14 domain-containing protein 1 (FUNDC1) at Ser17 by unc-51 like autophagy activating kinase 1 (ULK1), resulting in the induction of mitophagy. These positive effects of vaspin were reversed by ULK1 silencing in Ang-II-stimulated HL-1 cells. Our study is the first to propose that vaspin plays a vital role in AF pathogenesis via ULK1/FUNDC1-regulated mitophagy and could be a novel therapeutic target for AF.

Inhibition of late sodium current via PI3K/Akt signaling prevents cellular remodeling in tachypacing-induced HL-1 atrial myocytes

An aberrant late sodium current (INa,Late) caused by a mutation in the cardiac sodium channel (Nav1.5) has emerged as a contributor to electrical remodeling that causes susceptibility to atrial fibrillation (AF). Although downregulation of phosphoinositide 3-kinase (PI3K)/Akt signaling is associated with AF, the molecular mechanisms underlying the negative regulation of INa,Late in AF remain unclear, and potential therapeutic approaches are needed. In this work, we constructed a tachypacing-induced cellular model of AF by exposing HL-1 myocytes to rapid electrical stimulation (1.5 V/cm, 4 ms, 10 Hz) for 6 h. Then, we gathered data using confocal Ca2+ imaging, immunofluorescence, patch-clamp recordings, and immunoblots. The tachypacing cells displayed irregular Ca2+ release, delayed afterdepolarization, prolonged action potential duration, and reduced PI3K/Akt signaling compared with controls. Those detrimental effects were related to increased INa,Late and were significantly mediated by treatment with the INa,Late blocker ranolazine. Furthermore, decreased PI3K/Akt signaling via PI3K inhibition increased INa,Late and subsequent aberrant myocyte excitability, which were abolished by INa,Late inhibition, suggesting that PI3K/Akt signaling is responsible for regulating pathogenic INa,Late. These results indicate that PI3K/Akt signaling is critical for regulating INa,Late and electrical remodeling, supporting the use of PI3K/Akt-mediated INa,Late as a therapeutic target for AF.

Resting heart rate and cardiovascular outcomes in patients with atrial fibrillation: CODE-AF registry

Abstract Funding Acknowledgements Type of funding sources: None. Background The prognostic significance of resting heart rate and its therapeutic target in atrial fibrillation (AF) is uncertain. Purpose The aim of this study was to investigate the relationships between resting heart rate and cardiovascular outcomes in patients with AF. Methods A total of 8,886 patients with AF was included from the COmparison study of Drugs for symptom control and complication prEvention of AF (CODE-AF) registry. Patients were categorized according to baseline heart rate, and cardiovascular outcomes were accessed during a median follow-up of 30 months. The primary outcome was a composite of cardiovascular death, hospitalization due to heart failure, and myocardial infarction/critical limb ischemia. Results Compared to heart rate ≥100 beats per minute (bpm), heart rate 80-99 bpm was associated with the lowest risk of primary outcome (adjusted hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.40-0.79, p=0.001). In subgroup of patients with heart failure with preserved ejection fraction (HFpEF), heart rate between 80-99 bpm was associated with reduced risk of primary outcome compared to heart rate ≥100 bpm (HR 0.40, 95% CI 0.16-0.98, p=0.045). However, in patients with heart failure with reduced ejection fraction (HFrEF), there was no association between resting heart rate and cardiovascular outcomes (P for interaction 0.001). Conclusion Resting heart rate was associated with cardiovascular outcomes in patients with AF, and those with a resting heart rate between 80-99 bpm had the lowest risk of adverse events. The impact of resting heart rate on adverse events persisted in patients with concomitant HFpEF but was not apparent in those with concomitant HFrEF.

Research Progress of LncRNAs in Atrial Fibrillation.

Atrial fibrillation (AF) is one of the most common arrhythmias in adults, with high morbidity and increased mortality risk. In recent years, the clinical diagnosis, treatment, and mechanistic research of AF have increased exponentially, and regulation based on the potential molecular mechanism of AF is a research hotspot. Long noncoding RNAs (LncRNAs), usually refer to noncoding RNA transcripts greater than 200 nucleotides in length, have been shown to play a role in cardiovascular diseases such as coronary artery disease, heart failure, and myocardial fibrosis through various regulatory methods. An increasing number of researchers have begun to pay attention to the identification and function of LncRNAs in AF. This article reviews changes in the expression of related LncRNAs detected in AF and describes the LncRNAs that play a regulatory role in AF-related processes, to explore the potential of LncRNAs as new biomarkers and therapeutic targets in AF.

Abstract 14447: Increased Autophagy Flux May Underline Cardiomyocyte Remodeling in Atrial Fibrillation

Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural remodeling that impairs electrical activation of the atria. Studies have shown that mitochondrial dysfunction underlies cardiomyocyte remodeling. Here, we report a 50% reduction in total mitochondrial DNA in the atria tissue of RAP dogs as compared to control dogs, as assessed by qPCR the levels of mitochondrial DNA including mt-NT-1, mt-NT-4, mt-NT 5, mt-NT 6. This reduction in mitochondrial DNA suggests reduced mitochondria number in RAP dogs. Autophagic flux (LC3 II protein levels) was markedly increased in the atria tissue of the AF dog model (vs control dog).Furthermore, we examined autophagy flux in isolated cardiomyocytes. Results showed that LC3II was remarkably activated when subject to electrical stimulation for 6 hours under 3 Hertz condition, suggesting the direct effect of electrical stimulation on increasing autophagy. There was no change in the mRNA levels of autophagosome genes including Belin 1, ATG8, LC3, Lamp1 in the RAP dog tissue as compared to control, however, ATG7 increased by 2 fold and GNG2 increased by 5 fold. In conclusion, our study suggests that electrical stimulation-induced autophagy, and reduced mitochondria number and function, may underlie cardiomyocyte remodeling in AF. Targeting the autophagy pathway may present new therapeutic targets for AF. Ongoing AAV-mediated knockdown experiments in isolated cardiomyocytes will further elucidate the mechanism of electrical stimulation-induced autophagy.

Identification and Validation of Autophagy-Related Genes as Potential Biomarkers and Therapeutic Targets in Atrial Fibrillation.

BackgroundAutophagy is an evolutionary conserved important process for the turnover of intracellular substances in eukaryotes and is closely related to the development of atrial fibrillation (AF). The aim of this study is to identify and validate potential autophagy-related genes (ARGs) of AF through bioinformatics analysis and experimental validation.MethodsWe downloaded two data sets from the Gene Expression Omnibus (GEO) database, GSE14975 and GSE31821. After merging the data of the two microarrays, adjusting the batch effect, and integrating the differentially expressed genes (DEGs) with ARGs to obtain differentially expressed autophagy-related genes (DEARGs). Functional and pathway enrichment analyses were carried out based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Use the STRING database to construct a protein–protein interaction (PPI) network. Finally, mRNA expression levels of DEARGs were validated in right atrial tissue samples from AF patients and non-AF controls by qRT-PCR.ResultsThrough bioinformatics analysis, we finally identified 11 DEARGs (CDKN1A, CXCR4, DIRAS3, HSP90AB1, ITGA3, PRKCD, TP53INP2, DAPK2, IFNG, PTK6, and TNFSF10) in AF using [log2 (fold change)] > 0.5 and P < 0.05. In the pathway enrichment analysis, the most significantly enriched pathway was the autophagy pathway. The results of validation showed that the expression levels of CXCR4, DAPK2, and TNFSF10 corroborating with our computational findings, and the results were statistically significant (P<0.05).ConclusionOur study demonstrates that these 11 potential crucial ARGs, especially CXCR4, DAPK2, and TNFSF10, may be potential biomarkers and therapeutic targets in AF, which will help the personalized treatment of AF patients.

Identification of high priority focal activations in persistent atrial fibrillation using a novel mapping strategy.

Focal activation is believed to be an atrial fibrillation (AF) driver; however, little is known about whether all focal activations are necessary for AF persistence. The purpose of this study was to assess the electrical nature of focal activation and identify high-priority focal activations using a novel mapping system (CARTOFINDER). Thirty-five patients with persistent AF who underwent catheter ablation were assessed. Cycle length (CL) and CL standard deviation (CLSD) on unipolar recordings and voltage amplitude and electrogram morphologies on bipolar recordings were evaluated at all points of interest. The most frequent CL at each mapping site was defined as the dominant CL. We identified dominant focal activations (DFAs) that had a shorter dominant CL on the integrated CARTOFINDER map. The effect of elimination of DFAs on AF maintenance was assessed by the composite endpoint (termination to sinus rhythm, organization of the rhythm to atrial tachycardia, and AF CL slowing). In all, 450 focal activations were identified among 10,868 points, and 50.4% of focal activations were DFAs. Focal activations showed relatively long CL and regularity with short CLSD. Most focal activations showed an isoelectric baseline and were located outside of the fractionated electrogram area. Both DFAs and non-DFAs were typically observed in the normal voltage range. Elimination of DFAs was achieved in 19 (54.3%) patients, with a remarkable impact on AF maintenance (68.4% vs. 25.0%, p = 0.018). In conclusion, DFAs may play an important role in AF maintenance and could be an attractive therapeutic target for AF.

The Changes of Gene Expression and Protein Level of Stretch-Activated Chloride Channel in Atrial Myocardium of Dogs with Atrial Fibrillation.

ICl,stretch have been reported to be involved in the development of atrial fibrillation, so we observed the changes of transcription and translation levels of ICl,stretch in isolated atrial myocardium of heart failure canine models. In the control group (N = 10), five dogs were untreated and the other five received sham operation, while dogs in the heart failure group (N = 10) were implanted with cardiac pacemakers and underwent right ventricular pacing to induce heart failure. Cardiac structure and function were evaluated. The gene expression and protein level of ICl,stretch in the left atrial appendage were detected. The left atrial diameter, right atrial dimension, left ventricular diastolic dimension, and right ventricular diastolic dimension were significantly larger in the heart failure group (P < 0.05). In contrast, the ejection fraction and the left ventricular shorten fraction were higher in the control group (P < 0.05). Both the mRNA and protein expression levels of ICl,stretch in atrial myocardium of the heart failure group were significantly higher compared with the control group. ICl,stretch might play an important role in the vulnerability to atrial fibrillation in dilated atria with heart failure and could be a potential therapeutic target for atrial fibrillation.