Analysis of Genes Involved in Persistent Atrial Fibrillation: Comparisons of ‘Trigger’ and ‘Substrate’ Differences

Zou, Rongjun; Yang, Minglei; Shi, Wu; Zheng, Chengxi; Zeng, Hui; Lin, Xuemei; Zhang, Dingwen; Yang, Shiming; Hua, Peng

doi:10.1159/000490225

Cited by 11 publications

(10 citation statements)

References 40 publications

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“…Weighted gene co-expression network analysis has been applied to identify the core genes in AF. For example, Zou et al (2018) reported that LEP, FOS, EDN1, NMU, CALB2, TAC1 may be related to the occurrence and maintenance of AF using WGCNA method and public dataset GSE41177. Li et al (2020) used GSE79768 to perform a WGCNA analysis to determine the key modules related to atrial fibrillation.…”

Section: Discussionmentioning

confidence: 99%

Identification of Hub mRNAs and lncRNAs in Atrial Fibrillation Using Weighted Co-expression Network Analysis With RNA-Seq Data

Yang

Cao

Jian

et al. 2021

Front. Cell Dev. Biol.

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Atrial fibrillation (AF)/paroxysmal AF (PAF) is the main cause of cardiogenic embolism. In recent years, the progression from paroxysmal AF to persistent AF has attracted more and more attention. However, the molecular mechanism of the progression of AF is unclear. In this study, we performed RNA sequencing for normal samples, paroxysmal AF and persistent AF samples to identify differentially expressed gene (DEG) and explore the roles of these DEGs in AF. Totally, 272 differently expressed mRNAs (DEmRNAs) and 286 differentially expressed lncRNAs (DElncRNAs) were identified in paroxysmal AF compared to normal samples; 324 DEmRNAs and 258 DElncRNAs were found in persistent atrial fibrillation compared with normal samples; and 520 DEmRNAs and 414 DElncRNAs were identified in persistent AF compared to paroxysmal AF samples. Interestingly, among the DEGs, approximately 50% were coding genes and around 50% were non-coding RNAs, suggesting that lncRNAs may also have a crucial role in the progression of AF. Bioinformatics analysis demonstrated that these DEGs were significantly related to regulating multiple AF associated pathways, such as the regulation of vascular endothelial growth factor production and binding to the CXCR chemokine receptor. Furthermore, weighted gene co-expression network analysis (WGCNA) was conducted to identify key modules and hub RNAs and lncRNAs to determine their potential associations with AF. Five hub modules were identified in the progression of AF, including blue, brown, gray, turquoise and yellow modules. Interestingly, blue module and turquoise module were significantly negatively and positively correlated to the progression of AF respectively, indicating that they may have a more important role in the AF. Moreover, the hub protein-protein interaction (PPI) networks and lncRNA–mRNA regulatory network were constructed. Bioinformatics analysis on the hub PPI network in turquoise was involved in regulating immune response related signaling, such as leukocyte chemotaxis, macrophage activation, and positive regulation of α-β T cell activation. Our findings could clarify the underlying molecular changes associated fibrillation, and provide a useful resource for identifying AF marker.

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Section: Discussionmentioning

confidence: 99%

Identification of Hub mRNAs and lncRNAs in Atrial Fibrillation Using Weighted Co-expression Network Analysis With RNA-Seq Data

Yang

Cao

Jian

et al. 2021

Front. Cell Dev. Biol.

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“…On the other hand, when we directly compared WT and TNF-KO swim atria, the majority of genes were increased in exercised atria from TNF-KO relative to WT, with the only gene that was increased in a TNF-dependent manner after 2 weeks of exercise in WT atria was Comp, which is a biomarker for cardiac fibrosis and hypertrophic remodeling (Huang et al, 2013;Zhao et al, 2018). Comp is involved in noncollagen ECM-receptor interaction (Rosenberg et al, 1998) and appears from multiple studies to contribute to the pathogenesis of AF (Zou et al, 2018;Thomas et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…It is also worth stating that many specific ECM/mechanosensing-related genes whose expression was downregulated in TNF-dependent manner with exercise have been linked previously to AF and ECM remodeling, including Comp (Zou et al, 2018;Thomas et al, 2019), Thbs2 (Yang et al, 2000), Ltbp1 and Fbn1 (Zhang et al, 2020; Figure 3 and Table 1). On the other hand, most genes linked to collagen production (i.e., Col1a1, Col1a2, Col3a1) were TNF-independent.…”

Section: Transcriptional Responses In Atria After 2 Weeks Of Exercisementioning

confidence: 91%

Transcriptomic Bioinformatic Analyses of Atria Uncover Involvement of Pathways Related to Strain and Post-translational Modification of Collagen in Increased Atrial Fibrillation Vulnerability in Intensely Exercised Mice

Yang

Liu

et al. 2020

Front. Physiol.

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Atrial Fibrillation (AF) is the most common supraventricular tachyarrhythmia that is typically associated with cardiovascular disease (CVD) and poor cardiovascular health. Paradoxically, endurance athletes are also at risk for AF. While it is well-established that persistent AF is associated with atrial fibrosis, hypertrophy and inflammation, intensely exercised mice showed similar adverse atrial changes and increased AF vulnerability, which required tumor necrosis factor (TNF) signaling, even though ventricular structure and function improved. To identify some of the molecular factors underlying the chamber-specific and TNF-dependent atrial changes induced by exercise, we performed transcriptome analyses of hearts from wild-type and TNF-knockout mice following exercise for 2 days, 2 or 6 weeks of exercise. Consistent with the central role of atrial stretch arising from elevated venous pressure in AF promotion, all 3 time points were associated with differential regulation of genes in atria linked to mechanosensing (focal adhesion kinase, integrins and cell-cell communications), extracellular matrix (ECM) and TNF pathways, with TNF appearing to play a permissive, rather than causal, role in gene changes. Importantly, mechanosensing/ECM genes were only enriched, along with tubulin- and hypertrophy-related genes after 2 days of exercise while being downregulated at 2 and 6 weeks, suggesting that early reactive strain-dependent remodeling with exercise yields to compensatory adjustments. Moreover, at the later time points, there was also downregulation of both collagen genes and genes involved in collagen turnover, a pattern mirroring aging-related fibrosis. By comparison, twofold fewer genes were differentially regulated in ventricles vs. atria, independently of TNF. Our findings reveal that exercise promotes TNF-dependent atrial transcriptome remodeling of ECM/mechanosensing pathways, consistent with increased preload and atrial stretch seen with exercise. We propose that similar preload-dependent mechanisms are responsible for atrial changes and AF in both CVD patients and athletes.

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“…A study including patients with persistent AF, who underwent LA tissue characterization with MRI scans and concomitant high-density mapping of the LA, demonstrated increased AF rotor activity in areas of relatively low and patchy late-gadolinium enhancement (LGE) [ 42 ]. Bioinformatics’ analysis has recently revealed that LA–PV junction demonstrates distinct gene expression differences in AF patients as compared to sinus rhythm (SR) controls, favoring extracellular matrix (ECM) synthesis and chemokine up-regulation [ 43 ].…”

Section: Atrial Fibrillation Pathogenesismentioning

confidence: 99%

Molecular Insights in Atrial Fibrillation Pathogenesis and Therapeutics: A Narrative Review

et al. 2021

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The prevalence of atrial fibrillation (AF) is bound to increase globally in the following years, affecting the quality of life of millions of people, increasing mortality and morbidity, and beleaguering health care systems. Increasingly effective therapeutic options against AF are the constantly evolving electroanatomic substrate mapping systems of the left atrium (LA) and ablation catheter technologies. Yet, a prerequisite for better long-term success rates is the understanding of AF pathogenesis and maintenance. LA electrical and anatomical remodeling remains in the epicenter of current research for novel diagnostic and treatment modalities. On a molecular level, electrical remodeling lies on impaired calcium handling, enhanced inwardly rectifying potassium currents, and gap junction perturbations. In addition, a wide array of profibrotic stimuli activates fibroblast to an increased extracellular matrix turnover via various intermediaries. Concomitant dysregulation of the autonomic nervous system and the humoral function of increased epicardial adipose tissue (EAT) are established mediators in the pathophysiology of AF. Local atrial lymphomononuclear cells infiltrate and increased inflammasome activity accelerate and perpetuate arrhythmia substrate. Finally, impaired intracellular protein metabolism, excessive oxidative stress, and mitochondrial dysfunction deplete atrial cardiomyocyte ATP and promote arrhythmogenesis. These overlapping cellular and molecular alterations hinder us from distinguishing the cause from the effect in AF pathogenesis. Yet, a plethora of therapeutic modalities target these molecular perturbations and hold promise in combating the AF burden. Namely, atrial selective ion channel inhibitors, AF gene therapy, anti-fibrotic agents, AF drug repurposing, immunomodulators, and indirect cardiac neuromodulation are discussed here.

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Analysis of Genes Involved in Persistent Atrial Fibrillation: Comparisons of ‘Trigger’ and ‘Substrate’ Differences

Cited by 11 publications

References 40 publications

Identification of Hub mRNAs and lncRNAs in Atrial Fibrillation Using Weighted Co-expression Network Analysis With RNA-Seq Data

Identification of Hub mRNAs and lncRNAs in Atrial Fibrillation Using Weighted Co-expression Network Analysis With RNA-Seq Data

Transcriptomic Bioinformatic Analyses of Atria Uncover Involvement of Pathways Related to Strain and Post-translational Modification of Collagen in Increased Atrial Fibrillation Vulnerability in Intensely Exercised Mice

Molecular Insights in Atrial Fibrillation Pathogenesis and Therapeutics: A Narrative Review

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