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![Gene Network Analysis. Result of the functional network analysis of the list of genes with differential expression in poAF by the GeneMANIA algorithm [19]. Connections were assessed using the list of differentially expressed genes (black, black stripes) in the context of a left atrial co-expression network (gray connections) and the default GeneMANIA networks on genetic interactions (green) or shared protein domains (yellow). Two gene function categories were overrepresented in the output, the Wnt Signaling pathway (red) and the cGMP metabolic process (blue)](publication/316639149/figure/fig3/AS:962847718789121@1606572193117/Gene-Network-Analysis-Result-of-the-functional-network-analysis-of-the-list-of-genes.gif)
Gene Network Analysis. Result of the functional network analysis of the list of genes with differential expression in poAF by the GeneMANIA algorithm [19]. Connections were assessed using the list of differentially expressed genes (black, black stripes) in the context of a left atrial co-expression network (gray connections) and the default GeneMANIA networks on genetic interactions (green) or shared protein domains (yellow). Two gene function categories were overrepresented in the output, the Wnt Signaling pathway (red) and the cGMP metabolic process (blue)
Source publication
Background
Both ambulatory atrial fibrillation (AF) and post-operative AF (poAF) are associated with substantial morbidity and mortality. Analyzing the tissue-specific gene expression in the left atrium (LA) can identify novel genes associated with AF and further the understanding of the mechanism by which previously identified genetic variants ass...
Citations
... Other RNA-seq studies found a broad spectrum of AF-related pathways by comparing expression profiles between SR patients and PeAF patients. Enrichment of downregulated genes was found in pathways related to calcium signaling, MAPK signaling and Wnt signaling [11,[13][14][15][16]22,25]. Calcium signaling and MAPK signaling have previously been connected with clinical AF in electrical and structural remodeling [26][27][28][29][30]. Upregulated genes were enriched in focal adhesion, MAPK signaling, RAP1 signaling, PI3KT signaling and cardiac muscle contraction pathways. ...
... Hsu and Sigurdsson studied the role of genetic variation on gene expression changes in AF [24,25]. Hsu performed RNA-seq on LAA tissue from a large group of 265 subjects and combined the expression profiles with SNP data [24]. ...
... The authors associated genetic variation in loci 10q22.2 and 5q31.2 to calcineurin signaling, sarcomere association and Wnt RhoGAP signaling in AF. Sigurdsson specified differential gene expression in a study on mechanisms involved in developing post-operative AF (PoAF) [25]. Differential expression of 23 genes was found in comparison between patients who did or did not develop PoAF. ...
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.
... Several clinical factors have been found to increase the risk of POAF such as older age, co-morbid diseases including hypertension, chronic obstructive pulmonary disease, and atrial fibrillation, withdrawal of beta-blocker medications in patients using them chronically, and the type of procedure performed [3]. In addition, genome-wide association studies have identified several genetic variants that are associated with POAF and could play a role in its etiology [4,5]. ...
Purpose
Prophylactic beta-blockers are recommended to prevent postoperative atrial fibrillation (POAF) after coronary artery bypass grafting (CABG). Polymorphisms in the beta-1 adrenergic receptor (ADRB1) and G protein-coupled receptor kinase 5 (GRK5) genes are associated with variable responses to beta-blockers. The aim of this study was to determine the clinical and genetic factors that influence the response to beta-blockers for POAF prophylaxis after CABG.
Methods
Patients undergoing isolated CABG and receiving prophylactic beta-blockers (n = 249) were prospectively recruited and followed up for 6 postoperative days. Genotyping of ADRB1 rs1801253, and 3 GRK5 SNPs (rs3740563, rs10787959, and rs17098707) was performed.
Results
Of the 249 patients, 52 patients (20.8%) experienced POAF. Age, hypertension, vasopressor use, calculated POAF risk score, GRK5 rs2230345 T-allele, and GRK5 rs3740563 A-allele were associated with POAF despite beta-blocker prophylaxis. The multivariate analysis revealed that age [odds ratio (OR) 1.06, 95% CI 1.02–1.11, p = 0.003] and GRK5 rs2230345 T-allele [OR 2.81, 95% CI 1.39–5.67, p = 0.004] were independent predictors of POAF after CABG despite beta-blocker prophylaxis.
Conclusion
GRK5 rs2230345 T-allele carriers were less responsive than AA genotype carriers to prophylactic beta-blockers for the prevention of POAF after CABG.
The study was registered on http://clinicaltrials.gov in March 2019, with trial registration number (TRN): NCT03871647.
... 74 Typically, MYOZ1 is involved in cardiac muscle calcineurin signaling to stabilize the sarcomere. 75 Overall, the 10q22 locus modulates sarcomere function that, when disrupted, causes higher incidence of AF. ...
Atrial fibrillation (AF) is the most common arrhythmic disorder and its prevalence in the United States is projected to increase to more than twelve million cases in 2030. AF increases the risk of other forms of cardiovascular disease, including stroke. As the incidence of atrial fibrillation increases dramatically with age, it is paramount to elucidate risk factors underlying AF pathogenesis. Here, we review tissue and cellular pathways underlying AF, as well as critical components that impact AF susceptibility including genetic and environmental risk factors. Finally, we provide the latest information on potential links between SARS-CoV-2 and human AF. Improved understanding of mechanistic pathways holds promise in preventative care and early diagnostics, and also introduces novel targeted forms of therapy that might attenuate AF progression and maintenance.
... Гены MYOZ1 и SYNPO2L активно экспрессируются в тканях сердца. Белок миозенин-1, кодируемый геном MYOZ1, по-видимому, участвует в пути передачи сигналов кальциневрина и взаимодействует с белками Z-диска саркомера, включая α-актинин и γ-филамин, обеспечивая стабильность структур саркомеров мышечных клеток [17]. ...
Atrial fibrillation (AF) is one of the most common tachyarrhythmias, contributing to both environmental and genetic factors, a clear understanding of which can be extremely important for determining management tactics and predicting the disease course. The article provides a brief overview of studies on genetic predictors of AF, in particular, SNP markers found on chromosome 10. Establishing a relationship between the identified SNPs on chromosome 10 and functional genes, changes in the structure or regulation of which can affect the development of AF, opens the veil of understanding how these SNPs affect the pathogenesis of AF.
... Nevertheless, these studies using human atrial tissue have provided important insight into the molecular mechanisms underlying AF. Most of the published work points towards similar pathways through which atrial remodeling occurs: ion channel alteration [125][126][127][128][129], contractile dysfunction [130], increased oxidative stress [131], development of cardiac fibrosis [132][133][134][135], increased risk of thromboembolic events [128,132,136] and inflammation [137]. However, when examining the degree of overlap of differentially expressed genes identified in the various studies, it is unexpectedly small (Fig. 3, Table 1). ...
... However, when examining the degree of overlap of differentially expressed genes identified in the various studies, it is unexpectedly small (Fig. 3, Table 1). We examined publications using left [128,129,134,[138][139][140][141][142] and right atria [129,131,[142][143][144], finding little overlap between genes identified as differentially expressed (Fig. 3A). Most probably, the disparities Table 1. between experimental design, sample number, microarray platforms and use of different technologies (RNA-seq) explains in part the small coincidence observed. ...
Atrial fibrillation is a progressive cardiac arrhythmia that increases the risk of hospitalization and adverse cardiovascular events. Despite years of study, we still do not have a full comprehension of the molecular mechanism responsible for the disease. The recent implementation of large-scale approaches in both patient samples, population studies and animal models has helped us to broaden our knowledge on the molecular drivers responsible for AF and on the mechanisms behind disease progression. Understanding genomic and epigenomic changes that take place during chronification of AF will prove essential to design novel treatments leading to improved patient care.
... Wnt signaling has been proposed to play a role in cardiac fibrosis and in the pathogenesis of AF (Naito et al. 2010). Interestingly, this pathway was found to be affected in atrial remodeling in two studies: Sigurdsson et al. (2017) identified Wnt-signaling-related remodeling of left atrial tissue from patients who developed poAF. Zou et al. (2018) compared tissue from the pulmonary vein/left atria junction (LA-PV) to LAA tissue in AF patients. ...
Atrial fibrillation is the most common sustained cardiac arrhythmia in humans, and its prevalence continues to increase because of the aging of the world population. Much still needs to be learned about the molecular pathways involved in the development and the persistence of the disease. Analysis of the transcriptome of cardiac tissue has provided valuable insight into diverse aspects of atrial remodeling, in particular concerning electrical remodeling—related to ion channels—and structural remodeling identified by dysregulation of processes linked to inflammation, fibrosis, oxidative stress, and thrombogenesis. The huge amount of data produced by these studies now represents a valuable source for the identification of novel potential therapeutic targets. In addition, the shift from cardiac tissue to peripheral blood as a substrate for transcriptome analysis revealed this strategy as a promising tool for improved diagnosis and therefore better patient care.
... IL34 expression has recently been associated with post-operative atrial fibrillation. 54 Some genes have been directly related to cardiac conduction (CACNB1: Rank 392, voltage-gated L-type calcium channels), contractility (TPM2: Rank 191, tropomyosin 2 slow-type muscle fibre 55 ; MYL7: Rank 400, myosin light chain 7), and cardiomyopathy. 56 Overlap with previous studies of DNA methylation and heart failure There have been previous microarray studies of HF including one by Hass and colleagues 11 using the Illumina 27k Infinium array of LV tissues comprising eight controls and nine patients with DCM, which identified three differentially methylated genes LY75, ERBB3, and ADORA2A. ...
Aims
Natriuretic peptides are useful for diagnosis and prognostication of heart failure of any cause. Now, research aims to discover novel biomarkers that will more specifically define the heart failure phenotype. DNA methylation plays a critical role in the development of cardiovascular disease with the potential to predict fundamental pathogenic processes. There is a lack of data relating DNA methylation in heart failure that specifically focuses on patients with severe multi‐vessel coronary artery disease. To begin to address this, we conducted a pilot study uniquely exploring the utility of powerful whole‐genome methyl‐binding domain‐capture sequencing in a cohort of cardiac surgery patients, matched for the severity of their coronary artery disease, aiming to identify candidate peripheral blood DNA methylation markers of ischaemic cardiomyopathy and heart failure.
Methods and results
We recruited a cohort of 20 male patients presenting for coronary artery bypass graft surgery with phenotypic extremes of heart failure but who otherwise share a similar coronary ischaemic burden, age, sex, and ethnicity. Methylation profiling in patient blood samples was performed using methyl‐binding domain‐capture sequencing. Differentially methylated regions were validated using targeted bisulfite sequencing. Gene set enrichment analysis was performed to identify differences in methylation at or near gene promoters in certain known Reactome pathways. We detected 567 188 methylation peaks of which our general linear model identified 68 significantly differentially methylated regions in heart failure with a false discovery rate <0.05. Of these regions, 48 occurred within gene bodies and 25 were located near enhancer elements, some within coding genes and some in non‐coding genes. Gene set enrichment analyses identified 103 significantly enriched gene sets (false discovery rate <0.05) in heart failure. Validation analysis of regions with the strongest differential methylation data was performed for two genes: HDAC9 and the uncharacterized miRNA gene MIR3675. Genes of particular interest as novel candidate markers of the heart failure phenotype with reduced methylation were HDAC9, JARID2, and GREM1 and with increased methylation PDSS2.
Conclusions
We demonstrate the utility of methyl‐binding domain‐capture sequencing to evaluate peripheral blood DNA methylation markers in a cohort of cardiac surgical patients with severe multi‐vessel coronary artery disease and phenotypic extremes of heart failure. The differential methylation status of specific coding genes identified are candidates for larger longitudinal studies. We have further demonstrated the value and feasibility of examining DNA methylation during the perioperative period to highlight biological pathways and processes contributing to complex phenotypes.
... An intriguing finding in this arena has been 'ventricularization' or de-differentiation of atrial gene expression in PoAF [42]. It is unclear if this is an adaption versus cause for PoAF. ...
Purpose of review:
The present review examines how targeted approaches to care, based on individual variability in patient characteristics, could be applied in the perioperative setting. Such an approach would enhance individualized risk assessment and allow for targeted preventive and therapeutic decision-making in patients at increased risk for adverse perioperative events.
Recent findings:
Prior and current studies highlight valuable lessons on how future investigations attempting to link specific patient-related characteristics or treatment modalities with outcomes and adverse drug responses might be designed in the perioperative setting.
Summary:
Our review highlights the past, present, and future directions of perioperative precision medicine. Current evidence provides important lessons on how a specific patient and disease tailored approach can help perioperative physicians in delivering the most appropriate and safest perioperative care.
... However, the GTEx project has reported that most eQTLs are shared It is becoming increasingly evident that many genetic variants that are not associated with gene expression levels at steady state, may be found to impact dynamic programs of gene expression in specific contexts. This includes specific developmental stages (Strober et al., 2019), or specific exposure to an environmental stimulus such as endoplasmic reticulum stress (Dombroski et al., 2010), hormone treatment (Maranville et al., 2011), radiation-induced cell death (Smirnov et al., 2012), vitamin D exposure (Kariuki et al., 2016), drug-induced cardiotoxicity (Knowles et al., 2018), and response to infection (Alasoo et al., 2018;Barreiro et al., 2012;Caliskan et al., 2015;Kim-Hellmuth et al., 2017;Manry et al., 2017;Nedelec et al., 2016). The studies of context-specific dynamic eQTLs highlight the need to determine the effects of genetic variants in the relevant environment. ...
One life-threatening outcome of cardiovascular disease is myocardial infarction, where cardiomyocytes are deprived of oxygen. To study inter-individual differences in response to hypoxia, we established an in vitro model of induced pluripotent stem cell-derived cardiomyocytes from 15 individuals. We measured gene expression levels, chromatin accessibility, and methylation levels in four culturing conditions that correspond to normoxia, hypoxia and short or long-term re-oxygenation. We characterized thousands of gene regulatory changes as the cells transition between conditions. Using available genotypes, we identified 1,573 genes with a cis expression quantitative locus (eQTL) in at least one condition, as well as 367 dynamic eQTLs, which are classified as eQTLs in at least one, but not in all conditions. A subset of genes with dynamic eQTLs is associated with complex traits and disease. Our data demonstrate how dynamic genetic effects on gene expression, which are likely relevant for disease, can be uncovered under stress.
... While SCN5A sodium channels (Na V 1.5) are the predominant isoform in the heart [14], recent evidence suggested the involvement of SCN10A sodium channels (Na V 1.8) in atrial conduction [8]. Moreover, genome-wide association studies showed that variants of Na V 1.8 are associated with the development of atrial fibrillation [17,21,25]. Therefore, the aim of our study was to fundamentally investigate the molecular and functional role of Na V 1.8 in the human and murine atria. ...
... Of note, one previous study reported a generally lower Na V 1.8 mRNA expression in the atria compared to other Na V isoforms [19] and other studies described difficulties in the detection of Na V 1.8, which may be due to a high rate of alternate splicing [6,9]. Recent genetic studies demonstrated an involvement of SCN10A in atrial cellular electrophysiology and could associate SCN10A variants with AF [17,18,25]. We therefore investigated whether Na V 1.8 compared to Na V 1.5 expression might be differentially regulated in patients with SR or with AF. ...
Pharmacologic approaches for the treatment of atrial arrhythmias are limited due to side effects and low efficacy. Thus, the identification of new antiarrhythmic targets is of clinical interest. Recent genome studies suggested an involvement of SCN10A sodium channels (NaV1.8) in atrial electrophysiology. This study investigated the role and involvement of NaV1.8 (SCN10A) in arrhythmia generation in the human atria and in mice lacking NaV1.8. NaV1.8 mRNA and protein were detected in human atrial myocardium at a significant higher level compared to ventricular myocardium. Expression of NaV1.8 and NaV1.5 did not differ between myocardium from patients with atrial fibrillation and sinus rhythm. To determine the electrophysiological role of NaV1.8, we investigated isolated human atrial cardiomyocytes from patients with sinus rhythm stimulated with isoproterenol. Inhibition of NaV1.8 by A-803467 or PF-01247324 showed no effects on the human atrial action potential. However, we found that NaV1.8 significantly contributes to late Na+ current and consequently to an increased proarrhythmogenic diastolic sarcoplasmic reticulum Ca2+ leak in human atrial cardiomyocytes. Selective pharmacological inhibition of NaV1.8 potently reduced late Na+ current, proarrhythmic diastolic Ca2+ release, delayed afterdepolarizations as well as spontaneous action potentials. These findings could be confirmed in murine atrial cardiomyocytes from wild-type mice and also compared to SCN10A-/- mice (genetic ablation of NaV1.8). Pharmacological NaV1.8 inhibition showed no effects in SCN10A-/- mice. Importantly, in vivo experiments in SCN10A-/- mice showed that genetic ablation of NaV1.8 protects against atrial fibrillation induction. This study demonstrates that NaV1.8 is expressed in the murine and human atria and contributes to late Na+ current generation and cellular arrhythmogenesis. Blocking NaV1.8 selectively counteracts this pathomechanism and protects against atrial arrhythmias. Thus, our translational study reveals a new selective therapeutic target for treating atrial arrhythmias.
