Atrial fibrillation in the presence and absence of heart failure enhances expression of genes involved in cardiomyocyte structure, conduction properties, fibrosis, inflammation, and endothelial dysfunction

Zeemering, Stef; Isaacs, Aaron; Winters, Joris; Maesen, Bart; Bidar, Elham; Dimopoulou, Christina; Guasch, Eduard; Batlle, Montserrat; Haase, Doreen; Hatem, Stéphane; Kara, Mansour; Kääb, Stefan; Mont, Lluı́s; Sinner, Moritz F.; Wakili, Reza; Crijns, Harry J.G.M.; Fabritz, Larissa; Kirchhof, Paulus; Stoll, Monika; Schotten, Ulrich

doi:10.1016/j.hrthm.2022.08.019

Cited by 13 publications

(17 citation statements)

References 32 publications

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“…Figure 2A, indicates that 24% (54/221) of the differentially expressed genes found in the Zeemering et al study, are also found in the Van den Berg et al study [9,10]. When further overlaying the human studies with the two large animal studies, there is only a single shared gene: CKAP4.…”

Section: Figurementioning

confidence: 84%

“…Differentially expressed genes that did not have a (human ortholog) gene symbol assigned were omitted from the overlap analysis. Additionally, a gene list for total differentially expressed gene overlap is included in Supplementary Table S1 [9,10]. When further overlaying the human studies with the two large animal studies, there is only a single shared gene: CKAP4.…”

Section: Figurementioning

confidence: 99%

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Dissecting the Molecular Mechanisms Driving Electropathology in Atrial Fibrillation: Deployment of RNA Sequencing and Transcriptomic Analyses

Huiskes,

Creemers,

Brundel

2023

Cells

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Despite many efforts to treat atrial fibrillation (AF), the most common progressive and age-related cardiac tachyarrhythmia in the Western world, the efficacy is still suboptimal. A plausible reason for this is that current treatments are not directed at underlying molecular root causes that drive electrical conduction disorders and AF (i.e., electropathology). Insights into AF-induced transcriptomic alterations may aid in a deeper understanding of electropathology. Specifically, RNA sequencing (RNA-seq) facilitates transcriptomic analyses and discovery of differences in gene expression profiles between patient groups. In the last decade, various RNA-seq studies have been conducted in atrial tissue samples of patients with AF versus controls in sinus rhythm. Identified differentially expressed molecular pathways so far include pathways related to mechanotransduction, ECM remodeling, ion channel signaling, and structural tissue organization through developmental and inflammatory signaling pathways. In this review, we provide an overview of the available human AF RNA-seq studies and highlight the molecular pathways identified. Additionally, a comparison is made between human RNA-seq findings with findings from experimental AF model systems and we discuss contrasting findings. Finally, we elaborate on new exciting RNA-seq approaches, including single-nucleotide variants, spatial transcriptomics and profiling of different populations of total RNA, small RNA and long non-coding RNA.

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Section: Figurementioning

confidence: 84%

Section: Figurementioning

confidence: 99%

Dissecting the Molecular Mechanisms Driving Electropathology in Atrial Fibrillation: Deployment of RNA Sequencing and Transcriptomic Analyses

Huiskes,

Creemers,

Brundel

2023

Cells

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“…Human left and/or right atrial appendage samples were collected from the CATCH-ME (www.catch-me.info) atrial tissue biobank of 227 patients undergoing coronary artery bypass grafting (CABG), valvular surgery or heart transplant surgery (HTX). An RNA sequencing data set of this study population was recently published (33). A total of 170 tissue samples (n=95 LA, n=76 RA, 20 of which were paired) were of sufficient quality and included in the analyses.…”

Section: Patient Selection and Tissue Samplingmentioning

confidence: 99%

Heart failure, female sex and atrial fibrillation are the main drivers of human atrial cardiomyopathy: results from the CATCH ME consortium

Winters

Isaacs

Zeemering

et al. 2023

Preprint

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Background: Atrial cardiomyopathy (AtCM) is emerging as an independent prognostic factor in cardiovascular disease. Fibrotic remodeling, cardiomyocyte hypertrophy, and capillary density are histological hallmarks of atCM. The contribution of etiological factors and atrial fibrillation (AF) to the development of differential atCM phenotypes has not been robustly quantified. We aimed to evaluate the association between histological features of atCM and the clinical phenotype. Methods: We examined left (LA,n=95) and right (RA,n=76) atrial appendages from a European cohort of patients undergoing cardiac surgery. Quantification of histological atCM features was performed using the JavaCyte algorithm, following staining with agglutinin (WGA), CD31 and vimentin. The contributions of AF, heart failure (HF), sex and age to histological characteristics were determined in multivariate models. K-means clustering of histological features was performed to identify different types of atCM. Results: In both atria, persistent AF was associated with increased endomysial fibrosis (LA:+1.07±0.41μ m,p=0.01; RA:+0.89±0.43μm,p=0.032), whereas total extracellular matrix (ECM) content was unchanged in AF. Men had larger cardiomyocytes (LA:+1.87±0.72μm,p=0.012), while women had a higher degree of endomysial fibrosis (LA:+0.99±0.51μm,p=0.048). Heart failure patients showed more endomysial fibrosis (LA:+1.79±0.41μ m,p<0.001) and ECM content (LA:+2.93±1.15%, p=0.014), and a higher capillary density (LA:+0.14±0.06,p=0.032) and size (LA:+0.48±0.23μ m,p=0.041; RA:+0.31±0.16μm,p=0.047). Clustering of samples based on structural features identified 2 distinct atCM phenotypes; one characterized by enhanced endomysial fibrosis (LA:+3.35μ m,p<0.001; RA:+1.88μm,p<0.001), ECM content (LA:+5.68%,p<0.001; RA:+7.78%,p<0.001), and a higher fibroblast density (LA:+4.79%,p<0,001) and one characterized by cardiomyocyte hypertrophy (LA:+1.20μ m,p=0.009; RA:+2.95μm ,p<0.001). Patients with fibrotic atCM were more often female (LA:OR=1.31,p=0.003; RA:OR=1.55,p=0.003), had more often persistent AF (LA:OR=1.23,p=0.031) or heart failure (LA:OR=1.62,p<0.001) whereas hypertrophic features were more common in men (LA:OR=1.31,p=0.031; RA:OR= 1.55,p=0.003). Conclusions: AtCM phenotypes vary with patient characteristics. Fibrotic atCM is associated with female sex, persistent AF and heart failure, while hypertrophic features are more common in men.

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Section: History Of Genetic Analysis Of Afmentioning

confidence: 99%

“…Zeemering et al, who performed RNA sequencing in the right and left atrial appendage tissue of AF patients, detected genes associated with persistent but could not find a gene associated with heart failure. 50 Ahlberg et al reported that CILP , which encodes cartilage intermediate layer protein 1, was a genetic marker for atrial and ventricular fibrosis and can promote heart failure. 51 Our group reported that the HCN4 SNV rs7164883, which encodes the cardiac hyperpolarization‐activated cyclic nucleotide‐gated I f channel, was a genetic marker of tachycardia‐induced cardiomyopathy in patients with AF.…”

Section: History Of Genetic Analysis Of Afmentioning

confidence: 99%

Genome and atrial fibrillation

Nakano

2023

Journal of Arrhythmia

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Atrial fibrillation (AF), the most common type of arrhythmia, can cause several adverse effects, such as stroke, heart failure, and cognitive dysfunction, also in addition to reducing quality of life and increasing mortality. Evidence suggests that AF is caused by a combination of genetic and clinical predispositions. In line with this, genetic studies on AF have progressed significantly through linkage studies, genome-wide association studies, use of polygenic risk scores, and studies on rare coding variations, gradually elucidating the relationship between genes and the pathogenesis and prognosis of AF. This article will review current trends in genetic analysis concerning AF.

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Atrial fibrillation in the presence and absence of heart failure enhances expression of genes involved in cardiomyocyte structure, conduction properties, fibrosis, inflammation, and endothelial dysfunction

Cited by 13 publications

References 32 publications

Dissecting the Molecular Mechanisms Driving Electropathology in Atrial Fibrillation: Deployment of RNA Sequencing and Transcriptomic Analyses

Dissecting the Molecular Mechanisms Driving Electropathology in Atrial Fibrillation: Deployment of RNA Sequencing and Transcriptomic Analyses

Heart failure, female sex and atrial fibrillation are the main drivers of human atrial cardiomyopathy: results from the CATCH ME consortium

Genome and atrial fibrillation

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