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Single Cell Landscape of Left Atria Reveals Amphiregulin and Insulin-like Growth Factor 1 as Surrogate Markers in Patients with Atrial Fibrillation.

ABSTRACT: Atrial fibrillation (AF) is strongly associated with strokes, heart failure, and increased mortality. Inflammation plays a role in the pathophysiology of AF; however, how inflammation in AF is sustained and induces fibrosis is unclear. Therefore, this study aimed to identify the characteristic monocyte–macrophage heterogeneity and the cell–cell interactions between immune and non-immune cells at a single cell level in the left atrial (LA) tissues of patients with AF who underwent LA appendectomies. Myeloid cells were divided into five macrophage clusters, TNF+, two IL1B+, TREM2+, LYVE1+ resident macrophages, three monocyte clusters, five dendritic cell clusters, neutrophils, and mast cells. The CellChat analysis revealed that IL1B+ macrophages send epidermal growth factor (EGF) signalling to fibroblasts and resident macrophages send IGF1 singalling to cardiomyocytes. When compared to openly published control samples, Amphiregulin (AREG) was the most upregulated gene in monocytes and monocyte-derived IL1B+ macrophages in the AF group. We also found that AREG levels in serum were higher in patients with AF than controls. EGF signalling from IL1B+ macrophages could be therapeutic targets for AF, and AREG could be a functional biomarker for AF.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261170 | GEO | 2024/06/01

REPOSITORIES: GEO

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Atrial fibrillation is associated with altered left-to-right atria gene expression ratio: implications for arrhythmogenesis and thrombogenesis

Project description:Background: Atrial fibrillation (AF) causes atrial remodeling, and the left atrium (LA) is the favored substrate for maintaining AF. However, it remains unclear if AF remodels both atria differently and contributes to LA arrhythmogenesis and thrombogenesis. Results: AF was associated with differential LA-to-RA gene expression related to specific ion channels and pathways as well as upregulation of thrombogenesis-related genes in the LA appendage. Targeting the molecular mechanisms underlying the LA-to-RA difference and AF-related remodeling in the LA appendage may help provide new therapeutic options in treating AF and preventing thromboembolism in AF. Paired left atrial and right atrial specimens were obtained from 13 patients with persistent AF receiving valvular surgery. The Paired specimens were sent for microarray comparison. Selected results were validated by quantitative real time-PCR (q-PCR) and Western blotting. Ultrastructural changes in the atria were evaluated by immunohistochemistry.

2016-08-09 | E-GEOD-79768 | biostudies-arrayexpress

Atrial fibrillation is associated with altered left-to-right atria gene expression ratio: implications for arrhythmogenesis and thrombogenesis

2016-08-09 | GSE79768 | GEO

Valvular heart disease and atrial fibrillation regulate microRNA expression profiles in left and right atria differently

Project description:Background: Chronic atrial fibrillation (AF) is a complication associated with the dilated atria of patients with valvular heart disease and contributes to worsened pathology. Methods and Results: Using microarray technology, we examined microRNA (miR) expression profiles in right and left atrial appendage tissue from valvular heart disease (VHD) patients. Right atrial appendage from patients undergoing coronary artery bypass grafting (CABG) and left atrial (LA) appendage from healthy hearts not used for transplant were used as controls. VHD induced different changes in miR expression in LA compared with right atria (RA). Fifty-two (52) miRs were altered by VHD in LA, compared with 5 in RA tissue. There was no detectable effect of chronic AF on miR expression in LA tissue, but miR expression in RA was strongly influenced by AF, with 47 miRs showing differential expression. LA volume correlated with miR expression changes in both LA and RA, but the affected miRs were different for the two atrial groups. Conclusions: VHD and AF influence miR expression patterns in LA and RA, but these are affected differently by disease progression and by the development of AF. These findings provide new insights into the progression of VHD. RA tissue is not a useful surrogate for LA in studies of mitral valve disease.

2011-12-21 | GSE28954 | GEO

Valvular heart disease and atrial fibrillation regulate microRNA expression profiles in left and right atria differently

2011-12-21 | E-GEOD-28954 | biostudies-arrayexpress

Large-scale Single-nuclei Profiling Identifies Role for ATRNL1 in Atrial Fibrillation [bulk RNA-seq]

Project description:Atrial fibrillation (AF) is the most common sustained arrhythmia in humans, yet the molecular basis of AF remains incompletely understood. To determine the cell type-specific transcriptional changes underlying AF, we performed single-nucleus RNA-seq (snRNA-seq) on age- and sex-matched left atrial (LA) samples from 18 patients with AF and 16 controls without AF. From more than 175,000 nuclei we identified 15 cell types but found that only cardiomyocytes (CMs) and macrophages (MΦs) had a significant number of differentially expressed genes in patients with AF. Attractin Like 1 (ATRNL1) was strongly overexpressed in CMs among patients with AF and localized to the intercalated discs. Further, in both knockdown and overexpression experiments in atrial human embryonic stem cell-derived CMs (hESC-aCMs) we identified a potent role for ATRNL1 in cell stress response, cardiac conduction, cell junction organization and in modulation of the cardiac action potential. Finally, we prioritized genes at the known genetic loci for AF and identified an unexpected expression for a leading AF candidate gene, KCNN3. In sum, we have identified a role for ATRNL1 and other differentially regulated genes that may serve as potential therapeutic targets for this common arrhythmia.

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Large-scale Single-nuclei Profiling Identifies Role for ATRNL1 in Atrial Fibrillation [snRNA-seq]

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Rac1-Induced Connective Tissue Growth Factor regulates Connexin 43 and N-Cadherin Expression in Atrial Fibrillation

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

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Project description:Background: Inflammation is closely related to atrial fibrillation (AF), in which macrophages play an important role as immune cells. Recent studies have shown that macrophages participate in the electron conduction in the heart, indicating that they have electrophysiological characteristics. However, whether the electrophysiology of macrophages is associated with AF remained unclear. Methods: In the present study, we investigated the electrophysiological changes in macrophages using patch-clamping after tachypacing to mimic AF. RNA-seq was performed to investigate the expression change of atrial myocytes after tachypacing. Rapid atrial stimulation was performed to measure the AF incidence in macrophages-specific CX43 knockout mice. Results: We found that the APD90 and the ICa,L were reduced. Further, we found that tachypacing atrial myocytes led to the secretion of Wnt 7a, further inhibiting the expression of CACNA1C in macrophages. Moreover, the knockout of CX43 in macrophages decreased the incidence of AF in a chronic inflammation mice model. Conclusion: Altogether, these results demonstrated that the electrophysiology of macrophages was related to the development of AF and might be a potential therapeutic target for AF.

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Rac1-Induced Connective Tissue Growth Factor regulates Connexin 43 and N-Cadherin Expression in Atrial Fibrillation

2010-02-11 | GSE14975 | GEO

Decoding the PITX2 controlled genetic network in atrial fibrillation

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2022-04-28 | GSE183310 | GEO

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