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Project description:Background: Genomic and experimental studies suggest a role for PITX2 in atrial fibrillation (AF). To assess whether this association is relevant for recurrent AF in patients, we tested whether left atrial PITX2 affects recurrent AF after AF ablation. Methods: mRNA concentrations of PITX2 and its cardiac isoform, PITX2c, were quantified in left atrial appendages (LAA) from patients undergoing thoracoscopic AF ablation, either in whole LAA tissue (n=83) or in LAA cardiomyocytes (n=52), and combined with clinical parameters to predict AF recurrence. Literature suggests bone morphogenetic protein 10 (BMP10) as a PITX2-repressed, atrial-specific, secreted protein. BMP10 plasma concentrations were combined with eleven cardiovascular biomarkers and clinical parameters to predict recurrent AF after catheter ablation in 359 patients. Results: Reduced cardiomyocyte PITX2 concentrations, but not whole LAA tissue PITX2, were associated with AF recurrence after thoracoscopic AF ablation (16% decreased recurrence per 2-(ΔΔCt) increase in PITX2). RNA sequencing, qPCR and Western blotting confirmed BMP10 as one of most PITX2-repressed atrial genes. Left atrial size (hazard ratio per mm increase, HR [95%CI] 1.055 [1.028, 1.082], non-paroxysmal AF (HR 1.672 [1.206, 2.318]) and elevated BMP10 (HR 1.339 [CI 1.159, 1.546] per quartile increase) were predictive of recurrent AF. BMP10 outperformed eleven other cardiovascular biomarkers in predicting recurrent AF. Conclusions: Reduced left atrial cardiomyocyte PITX2 and elevated plasma concentrations of the PITX2-repressed, secreted, atrial protein BMP10 identify patients at risk of recurrent AF after ablation.
2020-06-19 | GSE152181 | GEO
Project description:A single TTN point mutation- a missense variant ( TTN-T32756I) can impair sarcomere integrity and lead to atrial electrical remodeling, increasing AF- A link that needs investigation
2025-12-08 | GSE312917 | GEO
Project description:Background Atrial fibrosis plays a critical role in the development of atrial fibrillation (AF). Exosome is a promising cell-free therapeutic approach for the treatment of AF. The purpose of this study was to explore the mechanisms underlying exosomes derived from atrial myocytes regulated atrial remodeling and ask whether their manipulation allows for therapeutic modulation of fibrosis potential abnormalities during AF. Methods We isolated exosomes from atrial myocytes and patients serum, microRNA (miRNA) sequencing analyzed the exosomal miRNAs in atrial myocytes-exosomes and patients serum-exosomes. mRNA sequencing and bioinformatics analysis corroborate the key gene as direct targets of miR-210-3p. Results The miRNAs sequencing analysis identified that miR-210-3p expression significantly increased in exosomes of tachypacing atrial myocytes and serum of AF patients. In vitro, the analysis showed that miR-210-3p inhibitor reversed tachypacing-induced proliferation and collagen synthesis in atrial fibroblasts. Accordingly, KO miR-210-3p could reduce the incidence of AF and ameliorate atrial fibrosis induced by Ang Ⅱ. The mRNA sequencing analysis and Dual-Luciferase reporter assay proved that glycerol-3-phosphate dehydrogenase 1-like (GPD1L) is the potential target gene of miR-210-3p. The functional analysis suggests that GPD1L regulated atrial fibrosis via PI3K/AKT signaling pathway. Besides, silencing GPD1L in atrial fibroblasts induced cells proliferation and these effects could be reversed by PI3K inhibitor (LY294002). Conclusion We demonstrate that atrial myocytes-derived exosomal miR-210-3p promoted the proliferation and collagen synthesis via inhibiting GPD1L in atrial fibroblasts. Preventing pathological crosstalk between atrial myocytes and fibroblasts may be as a novel target to improve atrial fibrosis in AF.
2022-08-17 | GSE210894 | GEO
Project description:Atrial fibrillation (AF) is a progressive arrhythmia for which current therapy is inadequate. During AF, rapid stimulation causes atrial remodeling that promotes further AF. The cellular signals that trigger this process remain poorly understood, however, and elucidation of these factors would likely identify new therapeutic targets. We have previously shown that immortalized mouse atrial (HL-1) myocytes subjected to 24 hr of rapid stimulation in culture undergo remodeling similar to that seen in animal models of atrial tachycardia (AT) and human AF. This preparation is devoid of confounding in vivo variables that can modulate gene expression (e.g., hemodynamics). Therefore, we investigated the transcriptional profile associated with early atrial cell remodeling. RNA was harvested from HL-1 cells cultured for 24 hr in the absence and presence of rapid stimulation and subjected to microarray analysis. Data were normalized using Robust Multichip Analysis (RMA), and genes exhibiting significant differential expression were identified using the Significance Analysis of Microarrays (SAM) method. Using this approach, 919 genes were identified that were significantly altered with rapid stimulation (763 up-regulated and 156 down-regulated). For many individual transcripts, changes typical of AF/AT were observed, with marked up-regulation of genes encoding BNP and ANP precursors, heat shock proteins, and MAP kinases, while novel signaling pathways and molecules were also identified. Both stress and survival response were evident, as well as up-regulation of multiple transcription factors. Genes were also functionally classified based on cellular component, biologic process, and molecular function using the Gene Ontology database to permit direct comparison of our data with other gene sets regulated in human AF and experimental AT. For broad categories of genes grouped by functional classification, there was striking conservation between rapidly stimulated HL-1 cells and AF/AT. Results were confirmed using real-time quantitative RT-PCR on 13 genes selected by physiological relevance in AF/AT and regulation in the microarray analysis (up, down, and nonregulated). Rapidly-stimulated atrial myocytes provide a complementary experimental paradigm to explore the initial cellular signals in AT remodeling to identify novel targets in the treatment of AF. Experiment Overall Design: HL-1 cell expression profile in vitro with and without rapid electric stimulation
2008-10-26 | E-GEOD-10598 | biostudies-arrayexpress
Project description:Most of the mechanistic insights into atrial fibrillation (AF) pathophysiology have been reported on cardiomyocytes, and it is commonly assumed that such apply in the same manner to the atria as a whole. This study shows that atrial remodeling during persistent AF (PsAF) underlies differential adaptative changes in non-myocyte populations, which depend on the functional relevance of individual-specific atrial regions to drive the overall arrhythmia. Radiofrequency delivery at driver regions can terminate the arrhythmia in pigs and achieve long-term arrhythmia AF-free survival in patients. Importantly, driver regions show overt compositional shifts in fibroblasts and myeloid populations that are highly consistent across pig models and patients. More specifically, driver regions underlie a phenotypic shift towards cardiac resident macrophages with an associated transcriptomic and proteomic profile favoring cardiomyocyte homeostasis and cell survival within a substrate prone to reentry. In fibroblasts, PTX3 represented a transcriptional hallmark exclusively present in driver regions, which supports their role on modulating the immune response of the surrounding tissue.
2025-11-06 | E-MTAB-14275 | biostudies-arrayexpress
Project description:Background. A recent study identified a rare variant in the MRC2 gene in individuals with familial reentrant supraventricular tachycardia, a Wolff-Parkinson-White (WPW) ECG pattern, and structurally normal hearts. WPW syndrome is associated with atrial fibrillation (AF), and MRC2 was recently proposed as a protective gene for AF. Objective. We aimed to determine whether the E990G-heterozygous (het) loss-of-function variant in MRC2 increases AF susceptibility and aberrant atrial cardiofibroblast (ACF) function in mice. Methods. Programmed electrical stimulation (PES) was performed to determine AF susceptibility in E990G-het mice and wild-type (WT) controls. ACFs were isolated from these mice and cultured, and their migration, and collagen deposition were quantified. Finally, transcriptomic profiling by RNA sequencing and secretomic/proteomic profiling by mass spectrometry were performed on ACFs and whole atrial tissue. Results. E990G-het mice exhibited increased susceptibility to pacing-induced AF and had decreased atrioventricular effective refractory periods compared to WT controls. ACFs isolated from E990G-het mice deposited greater amounts of acid-soluble collagen in 2D cultures as quantified by Sirius red staining compared with WT controls. Transcriptomic, secretomic, and proteomic profiling of cultured ACFs and whole-atrial tissue suggest that some fibrotic regulators are differentially expressed or secreted, including decreased ACF expression of matrix metalloproteinase 13 (MMP-13), which degrades collagen types I, II, and III; decreased ACF expression, ACF secretion, and atrial tissue levels of matrix metalloproteinase 12 (MMP-12), which degrades collagen types I, III, IV, elastin, and fibronectin; and increased tissue levels of cellular communication network factor 2/connective tissue growth factor (CCN2/CTGF), a profibrotic regulator. Conclusions. MRC2 E990G-het mice exhibit increased AF susceptibility, altered collagen deposition by ACFs, and differentially regulated fibrotic genes and proteins. Together, these findings suggest that excessive collagen deposition and reduced MMP-mediated collagen removal generate a substrate for the development of AF in the presence of a loss-of-function variant in MRC2.
2025-06-01 | GSE281559 | GEO
Project description:Atrial fibrillation (AF) is a common arrhythmia with a complex genetic basis, yet the molecular mechanisms linking rare and common variants remain unclear. Using induced pluripotent stem cell-derived atrial cardiomyocytes, we uncover a novel mechanism by which a rare pathogenic LMNA variant encoding Lamin A/C disrupts chromatin accessibility and gene regulation at AF-associated loci. Specifically, reduced accessibility at an SCN5A enhancer harboring an AF-associated variant leads to reduced sodium current, conduction abnormalities, and re-entrant AF. These electrophysiological defects are rescued by CRISPR-mediated activation of the SCN5A promoter and enhancer providing the first molecular evidence of epistatic gene-gene interactions driving arrhythmia risk and mechanistically linking atrial myopathy and AF. At the population level, we demonstrate carriers of LMNA proteinaltering variants with a high polygenic risk score are at two-fold increased risk of earlyonset AF, highlighting the need to integrate rare and common variants for more accurate AF risk assessment.
2026-04-10 | GSE294948 | GEO
Project description:Objectives: We studied the signal transduction of atrial structural remodelling that contributes to the pathogenesis of atrial fibrillation (AF). Backround: Fibrosis is a hallmark of arrhythmogenic structural remodelling but the underlying molecular mechanisms are incompletely understood. Methods: We performed transcriptional profiling of left atrial myocardium (LA) from patients with AF and sinus rhythm (SR) and applied cultured primary cardiac cells and transgenic mice with overexpression of constitutively active V12Rac1 (RacET) who develop AF at old age to characterize mediators of the signal transduction of atrial remodeling. Results: LA from patients with AF showed a marked upregulation of connective tissue growth factor (CTGF) expression compared SR patients. This was associated with increased fibrosis, NADPH-oxidase-, Rac1- and RhoA activity, upregulation of N-cadherin and connexin 43 (Cx43) expression and increased angiotensin II tissue concentration. In neonatal rat cardiac myocytes and -fibroblasts, a specific small molecule inhibitor of Rac1 or simvastatin completely prevented the angiotensin II induced upregulation of CTGF, Cx43 and N-cadherin expression. Transfection with small-inhibiting CTGF RNA blocked Cx43 and N-cadherin expression. RacET mice showed upregulation of CTGF, Cx43 and N-cadherin protein expression. Inhibition of Rac1 by oral statin treatment prevented these effects, identifying Rac1 as a key regulator of CTGF in vivo. Conclusion: The data identify CTGF as an important mediator of atrial structural remodelling during AF. Angiotensin II activates CTGF via activation of Rac1 and NADPH oxidase, leading to upregulation of Cx43, N-cadherin and interstitial fibrosis and therefore contributing to the signal transduction of atrial structural remodelling. Array design study consists of 5 Atrial Fibrillation patients and matched 5 samples of patients in sinus rhythm (controls).
2010-02-21 | E-GEOD-14975 | biostudies-arrayexpress
Project description:Background. A recent study identified a rare variant in the MRC2 gene in individuals with familial reentrant supraventricular tachycardia, a Wolff-Parkinson-White (WPW) ECG pattern, and structurally normal hearts. WPW syndrome is associated with atrial fibrillation (AF), and MRC2 was recently proposed as a protective gene for AF. Objective. We aimed to determine whether the E990G-heterozygous (het) loss-of-function variant in MRC2 increases AF susceptibility and aberrant atrial cardiofibroblast (ACF) function in mice. Methods. Programmed electrical stimulation (PES) was performed to determine AF susceptibility in E990G-het mice and wild-type (WT) controls. ACFs were isolated from these mice and cultured, and their migration, and collagen deposition were quantified. Finally, transcriptomic profiling by RNA sequencing and secretomic/proteomic profiling by mass spectrometry were performed on ACFs and whole atrial tissue. Results. E990G-het mice exhibited increased susceptibility to pacing-induced AF and had decreased atrioventricular effective refractory periods compared to WT controls. ACFs isolated from E990G-het mice deposited greater amounts of acid-soluble collagen in 2D cultures as quantified by Sirius red staining compared with WT controls. Transcriptomic, secretomic, and proteomic profiling of cultured ACFs and whole-atrial tissue suggest that some fibrotic regulators are differentially expressed or secreted, including decreased ACF expression of matrix metalloproteinase 13 (MMP-13), which degrades collagen types I, II, and III; decreased ACF expression, ACF secretion, and atrial tissue levels of matrix metalloproteinase 12 (MMP-12), which degrades collagen types I, III, IV, elastin, and fibronectin; and increased tissue levels of cellular communication network factor 2/connective tissue growth factor (CCN2/CTGF), a profibrotic regulator. Conclusions. MRC2 E990G-het mice exhibit increased AF susceptibility, altered collagen deposition by ACFs, and differentially regulated fibrotic genes and proteins. Together, these findings suggest that excessive collagen deposition and reduced MMP-mediated collagen removal generate a substrate for the development of AF in the presence of a loss-of-function variant in MRC2.
2026-06-01 | GSE285911 | GEO
Project description:Atrial fibrillation (AF) is the most common sustained arrhythmia with increased risk of stroke and congestive heart failure. AF is a highly genetic heterogeneous disease, but a large proportion of AF cannot be explained by genetic variants only. Some risk factors of AF, tendentious heritable phenomenon, potentially reversible conditions and some subtypes without DNA sequence variation all indicate the participation of DNA methylation in the pathogenesis of AF. Bisulphite converted DNA from the 11 left atrium samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip GPL13534
2014-10-28 | E-GEOD-62727 | biostudies-arrayexpress