Fibroblast-restricted inflammasome activation promotes atrial fibrillation and heart failure with diastolic dysfunction
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA902802 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22325470_1.fastq.gz | Fastqsanger.gz | |||
| SRR22325470_2.fastq.gz | Fastqsanger.gz | |||
| SRR22325471_1.fastq.gz | Fastqsanger.gz | |||
| SRR22325471_2.fastq.gz | Fastqsanger.gz |
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Project description:Background: Atrial fibrillation (AF) is commonly associated with diastolic dysfunction. Both conditions involve overactivation of inflammatory signaling and cardiac fibroblasts (FBs). While the activation of the NLRP3-inflammasome in cardiomyocytes is known to cause atrial electrical remodeling and arrhythmogenicity, the role of FB NLRP3-inflammasome in heart disease is unknown. Objectives: We aimed to elucidate the contribution of FB-specific NLRP3-inflammasome activation to cardiac function and arrhythmogenesis. Methods: Human atrial FBs were isolated from atrial biopsies of AF and sinus rhythm patients. We established an FB-specific knockin (FB-KI) mouse model with FB-restricted expression of constitutively active NLRP3. Cardiac function and AF susceptibility were assessed through echocardiography, tissue Doppler, programmed electrical stimulation, and optical mapping. Results: NLRP3 and IL1B were upregulated in atrial FBs of patients with persistent AF. FB-KI mice exhibited enlarged left atria, enhanced AF-susceptibility, and heart failure with diastolic dysfunction. FBs from FB-KI mice were more transdifferentiated, migratory, and proliferative than those from control. FB-KI mice showed increased fibrous content in both atria and ventricles, atrial gap junction remodeling, and reduced atrial conduction velocity. Single-nuclei RNA-seq analysis revealed prominent transcript remodeling of metabolic pathways across multiple cell types, enhanced extracellular matrix signaling, and altered intercellular communications. Knockdown of Nlrp3 in FBs via adeno-associated virus type-dj/8 mediated transfer of shRNA reduced AF-susceptibility and prevented cardiomyopathy in FB-KI mice. Conclusions: FB-restricted activation of the NLRP3-inflammasome promotes cardiac fibrosis and AF-susceptibility. This study identifies the FB NLRP3-inflammasome activation as a key mechanism governing the concomitant AF and heart failure with diastolic dysfunction.
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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.
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Project description:Analysis for early diagnosis of atrial fibrillation by finding changes in miRNA in the urine of patients with atrial fibrillation
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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
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Project description:Regional differential expression of atrial fibrillation risk genes in the left atrium and pulmonary veins is not well studied, but may yield insights into atrial fibrillation pathogenesis. We tested the hypothesis that there is significant regional differential expression in left atrium structures. RNAseq was performed in 25 regions within the pulmonary veins (n=12), left atrial body (n=10), and left atrial appendage (n=3) from a 75 year old male with hypertension and atrial fibrillation who died of a stroke. These data show that genes involved in atrial fibrillation pathogenesis have substantial regional expression heterogeneity, particularly when comparing the left atrial body, pulmonary veins and left atrial appendage.
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Project description:Atrial fibrillation (AF) is the most common heart arrhythmia disease. The greatest risk of atrial fibrillation is stroke, and stroke caused by valvular heart disease with atrial fibrillation (AF-VHD) is more serious. the development mechanism from VHD to AF-VHD is not yet clear. The research on expression profiles of lncRNA and mRNA is helpful to explore molecular mechanism in patients with valvular heart disease who develop atrial fibrillation.
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Project description:Purpose: The aim of this study was to evaluate the difference of plasma circRNA between patients with atrial fibrillation and normal subjects by high-throughput sequencing results. Methods: Total RNA was extracted using a miRNeasy Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions.Then, 200 ng RNA was sequenced with high throughput, and then pathway and go analysis were used for comprehensive analysis.Finally, RT-PCR method was used to validate in large sample population Results: High throughput sequencing results showed that there were significant differences in plasma circRNA expression between patients with atrial fibrillation and non-atrial fibrillation, and 2 optional circRNA in 12 randomly selected circRNA differences were found to be significant in the population Conclusions:It is the first time that we have used high-throughput sequencing to study the difference of plasma circrna between patients with atrial fibrillation and normal people. The results of sequencing show that the expression of circrna is quite different between the two groups of people. Therefore, we believe that circRNA may play an important role in the occurrence and development of atrial fibrillation.
2023-06-17 | GSE133420 | GEO
Project description:Electrical and structural remodeling processes are contributors to the self-perpetuating nature of atrial fibrillation (AF). However, their correlation has not been clarified. In this study, human atrial tissues from the patients with rheumatic mitral valve disease in either sinus rhythm or persistent AF were analyzed using a combined transcriptomic and proteomic approach. An up-regulation in chloride intracellular channel (CLIC) 1, 4, 5 and a rise in type IV collagen were revealed. Combined with the results from immunohistochemistry and electron microscope analysis, the distribution of type IV collagen and effects of fibrosis on myocyte membrane indicated the possible interaction between CLIC and type IV collagen, confirmed by protein structure prediction and co-immunoprecipitation. These results indicate that CLICs play an important role in the development of atrial fibrillation and that CLICs and structural type IV collagen may interact on each other to promote the development of AF in rheumatic mitral valve disease.
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