The role of stromal and immune cells in atrial disease [III]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE225671 | GEO | 2023/07/13
REPOSITORIES: GEO
Similar Datasets
Project description:In atrial fibrillation, disturbed electrical conduction disrupts the coordinated contraction of the heart’s antechambers, increasing the risk of stroke and heart failure. The rising prevalence of this disease approaches 9% in patients >65 years. Studying freshly isolated human atrial tissue and a new mouse model, we here decipher how immune and stromal cells contribute to the structural tissue remodeling that underlies atrial fibrillation. Single-cell transcriptomes from control and diseased human atria documented macrophage doubling at the expense of endothelial and mural cells. An inflammatory monocyte and a pro-fibrotic SPP1+ macrophage cluster expanded in patients with atrial fibrillation. To experimentally perturb pathways observed in patients, we matched their risk factors Hypertension, Obesity and Mitral valvE Regurgitation (HOMER) in mice. Atrial single-cell transcriptomes obtained in HOMER mice, which developed enlarged, fibrillation-prone atria, recapitulated human cell composition and transcriptome variations. Recruitment drove the expansion of atrial macrophages; accordingly, inhibition of monocyte migration reduced arrhythmia in Ccr2-/- HOMER mice. Deleting Spp1 established macrophage-derived osteopontin as a pleiotropic signal that promotes atrial fibrillation through pro-fibrotic, inflammatory crosstalk with an arsenal of local immune and stromal cells. Taken together, we identify SPP1+ macrophages as targets for immunomodulatory therapy in atrial fibrillation.
2023-07-13 | GSE197518 | GEO
Project description:In atrial fibrillation, disturbed electrical conduction disrupts the coordinated contraction of the heart’s antechambers, increasing the risk of stroke and heart failure. The rising prevalence of this disease approaches 9% in patients >65 years. Studying freshly isolated human atrial tissue and a new mouse model, we here decipher how immune and stromal cells contribute to the structural tissue remodeling that underlies atrial fibrillation. Single-cell transcriptomes from control and diseased human atria documented macrophage doubling at the expense of endothelial and mural cells. An inflammatory monocyte and a pro-fibrotic SPP1+ macrophage cluster expanded in patients with atrial fibrillation. To experimentally perturb pathways observed in patients, we matched their risk factors Hypertension, Obesity and Mitral valvE Regurgitation (HOMER) in mice. Atrial single-cell transcriptomes obtained in HOMER mice, which developed enlarged, fibrillation-prone atria, recapitulated human cell composition and transcriptome variations. Recruitment drove the expansion of atrial macrophages; accordingly, inhibition of monocyte migration reduced arrhythmia in Ccr2-/- HOMER mice. Deleting Spp1 established macrophage-derived osteopontin as a pleiotropic signal that promotes atrial fibrillation through pro-fibrotic, inflammatory crosstalk with an arsenal of local immune and stromal cells. Taken together, we identify SPP1+ macrophages as targets for immunomodulatory therapy in atrial fibrillation.
2023-07-13 | GSE224947 | GEO
Project description:Note this data set has identical data files: Files GSM40994.txt and GSM40995.txt. GSE2240 contains two different experimental subsets:; 1) Comparison of atrial and ventricular gene expression (atrial tissue of patients with sinus rhythm vs. human left ventricular non-failing myocardium); The purpose of our investigation was to identify the transcriptional basis for ultrastructural and functional specialization of human atria and ventricles. Using exploratory microarray analysis (Affymetrix U133A+B), we detected 11,740 transcripts expressed in human heart, representing the most comprehensive report of the human myocardial transcriptome to date. Variation in gene expression between atria and ventricles accounted for the largest differences in this data set, as 3.300 and 2.974 transcripts showed higher expression in atria and ventricles, respectively. Functional classification based on Gene Ontology identified chamber-specific patterns of gene expression and provided molecular insights into the regional specialization of cardiomyocytes, correlating important functional pathways to transcriptional activity: Ventricular myocytes preferentially express genes satisfying contractile and energetic requirements, while atrial myocytes exhibit specific transcriptional activities related to neurohumoral function. In addition, several pro-fibrotic and apoptotic pathways were concentrated in atrial myocardium, substantiating the higher susceptibility of atria to programmed cell death and extracellular matrix remodelling observed in human and experimental animal models of heart failure. Differences in transcriptional profiles of atrial and ventricular myocardium thus provide molecular insights into myocardial cell diversity and distinct region-specific adaptations to physiological and pathophysiological conditions (Barth AS et al., Eur J Physiol, 2005). 2) Comparison of atrial gene expression in patients with permanent atrial fibrillation and sinus rhythm. Atrial fibrillation is associated with increased expression of ventricular myosin isoforms in atrial myocardium, regarded as part of a dedifferentiation process. Whether re-expression of ventricular isoforms in atrial fibrillation is restricted to transcripts encoding for contractile proteins is unknown. Therefore, this study compares atrial mRNA expression in patients with permanent atrial fibrillation to atrial mRNA expression of patients with sinus rhythm as well as to ventricular gene expression using Affymetrix U133 arrays. In atrial myocardium, we identified 1.434 genes deregulated in atrial fibrillation, the majority of which, including key elements of calcium-dependent signaling pathways, displayed down-regulation. Functional classification based on Gene Ontology provided the specific gene sets of the interdependent processes of structural, contractile and electrophysiological remodeling. In addition, we demonstrate for the first time a prominent up-regulation of transcripts involved in metabolic activities, suggesting an adaptive response to an increased metabolic demand in fibrillating atrial myocardium. Ventricular-predominant genes were five times more likely to be up-regulated in atrial fibrillation (174 genes up-regulated, 35 genes down-regulated), while atrial-specific transcripts were predominantly down-regulated (56 genes up-regulated, 564 genes down-regulated). Overall, in atrial myocardium, functional classes of genes characteristic of ventricular myocardium were found to be up-regulated (e.g. metabolic processes) while functional classes predominantly expressed in atrial myocardium were down-regulated in atrial fibrillation (e.g. signal transduction and cell communication). Therefore, dedifferentiation with adoption of a ventricular-like signature is a general feature of the fibrillating atrium, uncovering the transcriptional response pattern in pmAF (Barth AS et al., Circ Res, 2005).
2007-10-27 | E-GEOD-2240 | biostudies-arrayexpress
Project description:GSE2240 contains two different experimental subsets: 1) Comparison of atrial and ventricular gene expression (atrial tissue of patients with sinus rhythm vs. human left ventricular non-failing myocardium) The purpose of our investigation was to identify the transcriptional basis for ultrastructural and functional specialization of human atria and ventricles. Using exploratory microarray analysis (Affymetrix U133A+B), we detected 11,740 transcripts expressed in human heart, representing the most comprehensive report of the human myocardial transcriptome to date. Variation in gene expression between atria and ventricles accounted for the largest differences in this data set, as 3.300 and 2.974 transcripts showed higher expression in atria and ventricles, respectively. Functional classification based on Gene Ontology identified chamber-specific patterns of gene expression and provided molecular insights into the regional specialization of cardiomyocytes, correlating important functional pathways to transcriptional activity: Ventricular myocytes preferentially express genes satisfying contractile and energetic requirements, while atrial myocytes exhibit specific transcriptional activities related to neurohumoral function. In addition, several pro-fibrotic and apoptotic pathways were concentrated in atrial myocardium, substantiating the higher susceptibility of atria to programmed cell death and extracellular matrix remodelling observed in human and experimental animal models of heart failure. Differences in transcriptional profiles of atrial and ventricular myocardium thus provide molecular insights into myocardial cell diversity and distinct region-specific adaptations to physiological and pathophysiological conditions (Barth AS et al., Eur J Physiol, 2005). 2) Comparison of atrial gene expression in patients with permanent atrial fibrillation and sinus rhythm. Atrial fibrillation is associated with increased expression of ventricular myosin isoforms in atrial myocardium, regarded as part of a dedifferentiation process. Whether re-expression of ventricular isoforms in atrial fibrillation is restricted to transcripts encoding for contractile proteins is unknown. Therefore, this study compares atrial mRNA expression in patients with permanent atrial fibrillation to atrial mRNA expression of patients with sinus rhythm as well as to ventricular gene expression using Affymetrix U133 arrays. In atrial myocardium, we identified 1.434 genes deregulated in atrial fibrillation, the majority of which, including key elements of calcium-dependent signaling pathways, displayed down-regulation. Functional classification based on Gene Ontology provided the specific gene sets of the interdependent processes of structural, contractile and electrophysiological remodeling. In addition, we demonstrate for the first time a prominent up-regulation of transcripts involved in metabolic activities, suggesting an adaptive response to an increased metabolic demand in fibrillating atrial myocardium. Ventricular-predominant genes were five times more likely to be up-regulated in atrial fibrillation (174 genes up-regulated, 35 genes down-regulated), while atrial-specific transcripts were predominantly down-regulated (56 genes up-regulated, 564 genes down-regulated). Overall, in atrial myocardium, functional classes of genes characteristic of ventricular myocardium were found to be up-regulated (e.g. metabolic processes) while functional classes predominantly expressed in atrial myocardium were down-regulated in atrial fibrillation (e.g. signal transduction and cell communication). Therefore, dedifferentiation with adoption of a ventricular-like signature is a general feature of the fibrillating atrium, uncovering the transcriptional response pattern in pmAF (Barth AS et al., Circ Res, 2005). Keywords = human myocardium Keywords = atrial fibrillation Keywords = sinus rhythm Keywords = left ventricular gene expression Keywords: other
2005-05-13 | GSE2240 | GEO
Project description:Next Generation RNA Sequencing was carried out on human paired left and right atrial appendages from patients with and without Atrial Fibrillation. EdgeR software was used to show a total of 247 genes were found to have significant differential expression between left and right atria.
2019-03-13 | GSE128188 | GEO
Project description:Obscurins are giant, modular, cytoskeletal proteins that regulate striated muscle structure and function. Immunoglobulin domains 58/59 (Ig58/59) of obscurin interact with diverse proteins including titin variants and phospholamban. Mutations within Ig58/59 that alter these binding interactions have been linked to the development of myopathy in humans, underscoring the pathophysiological significance of this module. We previously generated a constitutive deletion mouse model, Obscn-ΔIg58/59, that expresses obscurin lacking Ig58/59 and comprehensively characterized the effects of this deletion on cardiac morphology and function through aging. Our findings demonstrated that Obscn-ΔIg58/59 male animals develop severe arrhythmia characterized by spontaneous atrial fibrillation/junctional escape by 6-months of age, with atrial enlargement and ventricular remodeling manifesting by 12-months. Herein, we aim to mechanistically evaluate the impact of the Ig58/59 deletion in atria at the cellular level and determine the molecular basis for atrial enlargement and arrhythmia due to the physiological process of aging. Ultrastructural evaluation of sedentary aging male Obscn-ΔIg58/59 atria revealed prominent Z-disk streaming and misalignment. More importantly, Obscn-ΔIg58/59 atrial cardiomyocytes exhibited increased Ca2+ spark frequency and age-specific alterations in Ca2+ cycling kinetics and sarcoplasmic reticulum Ca2+ content that preceded those observed in Obscn-ΔIg58/59 ventricular cardiomyocytes. Proteomic and phospho-proteomic analyses revealed extensive and novel alterations in the expression and phosphorylation profile of major cytoskeletal proteins, Ca2+ regulators, and Z-disk associated protein complexes in Obscn-ΔIg58/59 atria through aging that likely underlie the observed atrial pathologies. These studies are the first to evaluate the role of obscurin in atria and to reveal chamber-specific molecular alterations due to Ig58/59 deletion. Moreover, our findings provide new molecular insights into a genetic model of spontaneous atrial fibrillation and remodeling where atrial dysfunction precedes ventricular maladaptation.
2023-04-11 | PXD028904 | Pride
Project description:We report the application of a pericentriolar material 1 (PCM-1) based cardiomyocyte-specific nuclear isolation protocol on human cardiac tissue to specifically ask what transcriptional changes occur in cardiomyocytes of humans with atrial fibrillation. We performed RNA-sequencing on the cardiomyocyte-specific nuclear RNA and found that there are more differentially dysregulated (1343) than similarly regulated transcripts (99) in the right versus left atria. This study is the first of its kind aimed at understanding the transcriptional changes that occur specifically in the left and right atrial cardiomyocytes of humans with atrial fibrillation.
2020-09-11 | GSE138252 | GEO
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
Project description:We report the mRNA sequencing of right and left atria from an adult inducible, cardiomyocyte-specific Notch gain-of-function mouse model (iNICD). Using the tetracycline-on system, we activated Notch by feeding doxycycline chow for 3 weeks to mice that were at least 8 weeks old. We asked what transcriptional changes occur in right versus left atrial cardiomyocytes in response to the same stimulus (Notch signaling). mRNA sequencing on separated right and left atria revealed that there are more differentially dysregulated transcripts (1,011) than similarly regulated transcripts (447) in the right and left atria, which is a simiar paradigm as what occurs in human atrial cardiomyocytes of patients with atrial fibrillation.
2020-07-01 | GSE138253 | GEO
Project description:This study will report the incidence of atrial fibrillation after elective colorectal cancer resection in the over 65 age group. This will be used to validate a risk model for the development of post-operative atrial fibrillation.
Eligible patients will undergo electrocardiogram based screening for atrial fibrillation, as well as brain natriuretic peptide tests prior to surgery. They will undergo 24 hour holter monitor prior to surgery, and at 30 and 90 days following surgery.
The primary outcome will be occurrence of atrial fibrillation within 90 days of surgery. Secondary outcomes include quality of life change, use of hospital services for atrial fibrillation, and complications of atrial fibrillation. This will be used to validate the pre-existing model for prediction of atrial fibrillation.
| 2312263 | ecrin-mdr-crc