Pathogenesis Of Atrial Fibrillation Research Articles

Effects of Phenylacetylglutamine on the Susceptibility of Atrial Fibrillation in Overpressure-Induced HF Mice.

Phenylacetylglutamine (PAGln), a gut metabolite is substantially elevated in heart failure (HF). The increase of PAGln in plasma is associated with atrial fibrillation (AF), and contributes to AF pathogenesis. However, the role of PAGln in AF with HF remains uncertain. Therefore, this study aimed to determine the effect of PAGln on AF after HF. Thoracic aortic coarctation (TAC) created overpressure-induced HF mice for 4 weeks. Histopathology, biochemical, echocardiographic for assessment of cardiac function, and electrophysiological examination of several electrophysiological indexes (ERP, SNRT, and the occurrence rate of AF) were performed at the end of the HF mice model. We found that plasma PAGln levels were significantly elevated in PAGln-treated HF mice and that PAGln aggravated maladaptive structural remodeling and electrical remodeling, which aggravated the vulnerability of AF, shortened the ERP duration, prolonged the SNRT, increased the occurrence rate of AF in HF mice. Mechanistically, PAGln exacerbated ROS accumulation and increased the levels of phosphorylated PLB and CAMK II. Overall, PAGln played a vital role in promoting the occurrence of AF in HF mice by activating the CAMK II signaling pathway.

Differential Expression Profiles and Bioinformatics Analysis of tRNA-derived Small RNAs in Epicardial fat of Patients with Atrial Fibrillation

The exact processes underlying atrial fibrillation (AF) are still unclear. It has been suggested that epicardial adipose tissue (EAT) may contribute to arrhythmias and can release various bioactive molecules, including exosomes containing tRNA-derived small RNAs (tsRNAs). Numerous studies have indicated that these tsRNAs can significantly affect key cellular functions. However, there is currently no research investigating the relationship between tsRNAs from EAT and AF. In order to explore the regulatory mechanisms of tsRNAs from EAT associated with AF, we conducted RNA-sequencing analysis on EAT samples collected from 6 AF patients and 6 control subjects with sinus rhythm. Our analysis revealed an upregulation of 146 tsRNAs and a downregulation of 126 tsRNAs in AF. Furthermore, we randomly selected four tsRNAs (tRF-SeC-TCA-001, tiRNA-Gly-CCC-003, tRF-Gly-GCC-002, and tRF-Tyr-GTA-007) for validation using quantitative reverse transcription-polymerase chain reaction. Following this, bioinformatic analyses revealed that the target genes of these tsRNAs were prominently involved in the regulation of cell adhesion and various cellular processes mediated by plasma membrane adhesion molecules. Additionally, based on KEGG analysis, it was suggested that the majority of these target genes might contribute to the pathogenesis of AF through processes such as glycosaminoglycan biosynthesis, AMP-activated protein kinase activity, and the insulin signaling pathway. Our results elucidate changes in the expression profiles of tsRNAs within EAT samples obtained from AF patients, and they forecast potential target genes and interactions between tsRNAs and mRNA within EAT that could contribute to the pathogenesis of AF.

Inhibitory effects of propylene glycol alginate sodium sulfate derivatives on atrial fibrosis in atrial fibrillation

Atrial fibrosis is the hallmark of structural remodeling in the pathogenesis of atrial fibrillation (AF). Meanwhile, AF causes a hypercoagulable state, and then provokes pro-fibrotic response. To discover a potential effective AF treatment targeting both coagulation and atrial fibrosis, this study investigated the structure–activity relationship of propylene glycol alginate sodium sulfate (PSS) derivatives with heparin-like activity on TGF-β1-induced atrial fibrosis. We found that PSS derivatives had significantly inhibitory effects on proliferation, migration, phenotypic transformation, and secretion/deposition of extracellular matrix of atrial fibroblasts. Among them, PGGS showed the optimal anti-atrial fibrotic activity by suppressing TGF-β1-induced activation of Smad2/3 signaling pathway. Furthermore, the study in vivo indicated that PGGS treatment displayed a reduced atrial fibrosis and AF inducibility, and attenuated the hypercoagulable state by decreasing D-dimer level and thrombin (FIIa) activity in MHC-TGF-β1 cys33ser transgenic mice, which had increased fibrosis in atrium but not in the ventricles. Our results demonstrated that PSS derivatives, especially PGGS, were potential anti-atrial fibrosis and anti-coagulant agents for AF prevention. Our study is beneficial in extending the current understandings of the function of PSS on atrial fibrosis and vulnerability to AF.

Naringin activates semaphorin 3A to ameliorate TGF-β-induced endothelial-to-mesenchymal transition related to atrial fibrillation.

The loss of semaphorin 3A (Sema3A), which is related to endothelial-to-mesenchymal transition (EndMT) in atrial fibrosis, is implicated in the pathogenesis of atrial fibrillation (AF). To explore the mechanisms by which EndMT affects atrial fibrosis and assess the potential of a Sema3A activator (naringin) to prevent atrial fibrosis by targeting transforming growth factor-beta (TGF-β)-induced EndMT, we used human atria, isolated human atrial endocardial endothelial cells (AEECs), and used transgenic mice expressing TGF-β specifically in cardiac tissues (TGF-β transgenic mice). We evaluated an EndMT marker (Twist), a proliferation marker (proliferating cell nuclear antigen; PCNA), and an endothelial cell (EC) marker (CD31) through triple immunohistochemistry and confirmed that both EndMT and EC proliferation contribute to atrial endocardial fibrosis during AF in TGF-β transgenic mice and AF patient tissue sections. Additionally, we investigated the impact of naringin on EndMT and EC proliferation in AEECs and atrial fibroblasts. Naringin exhibited an antiproliferative effect, to which AEECs were more responsive. Subsequently, we downregulated Sema3A in AEECs using small interfering RNA to clarify a correlation between the reduction in Sema3A and the elevation of EndMT markers. Naringin treatment induced the expression of Sema3A and a concurrent decrease in EndMT markers. Furthermore, naringin administration ameliorated AF and endocardial fibrosis in TGF-β transgenic mice by stimulating Sema3A expression, inhibiting EndMT markers, reducing atrial fibrosis, and lowering AF vulnerability. This suggests therapeutic potential for naringin in AF treatment.

Upregulated Genes in Atrial Fibrillation Blood and the Left Atrium.

Atrial fibrillation (AF) is a common arrhythmia associated with aging. Many known risk factors are associated with AF, but many senior individuals do not develop AF despite having multiple risk factors. This finding suggests that other factors may be involved in AF onset. This study aimed to identify upregulated genes in the peripheral blood and left atrium of patients with AF. These genes may serve as potential biomarkers to predict AF onset risk and its complications. Gene expression data was analyzed from blood (n = 3) and left atrial samples (n = 15) of patients with AF and sinus rhythm. We evaluated the significant genes identified using p-value analysis of weighted average difference to confirm their rankings. We created figures for the genes using GeneMANIA and performed a functional analysis using Cytoscape3.10.1. Hub and bottleneck genes were identified based on degree and betweenness centrality. We used RefEx to confirm the organs in which the extracted genes were expressed. Heatmaps and Gene ontology term evaluation were performed to further elucidate the biological functions of the genes. We identified 12 upregulated genes (CAST, ASAH1, MAFB, VCAN, DDIT4, FTL, HEXB, PROS1, BNIP3L, PABPC1, YBX3, and S100A6) in both the blood and left atrium of patients with AF. We analyzed the gene functions using GeneMANIA and Cytoscape. The identified genes were involved in a variety of pathways, including lysosomal function and lipid and sphingolipid catabolism. Next, we investigated whether the 12 identified genes identified were systemically expressed or had high organ specificity. Finally, Reference expression (RefEx) was used to analyze the gene expression levels in various tissues. Four genes; FTL, ASAH1, S100A6, and PABPC1, were highly expressed in the normal heart tissue. Finally, we evaluated the expression levels of the 12 genes in the blood of patients with AF using a heatmap. Our findings suggest that the 12 genes identified in this study, especially the lysosome-related genes (FTL and ASAH1), may be involved in AF pathogenesis. Lysosome-related genes may be important to understand the AF pathophysiology and to develop AF-related future studies.

Therapeutic advances in atrial fibrillation based on animal models.

Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia among humans, with its incidence increasing significantly with age. Despite the high frequency of AF in clinical practice, its etiology and management remain elusive. To develop effective treatment strategies, it is imperative to comprehend the underlying mechanisms of AF; therefore, the establishment of animal models of AF is vital to explore its pathogenesis. While spontaneous AF is rare in most animal species, several large animal models, particularly those of pigs, dogs, and horses, have proven as invaluable in recent years in advancing our knowledge of AF pathogenesis and developing novel therapeutic options. This review aims to provide a comprehensive discussion of various animal models of AF, with an emphasis on the unique features of each model and its utility in AF research and treatment. The data summarized in this review provide valuable insights into the mechanisms of AF and can be used to evaluate the efficacy and safety of novel therapeutic interventions.

The Association between Coagulation and Atrial Fibrillation.

The existing literature highlights the presence of numerous coagulation factors and markers. Elevated levels of coagulation factors are associated with both existing and newly diagnosed cases of atrial fibrillation (AF). However, this article summarizes the role of coagulation in the pathogenesis of AF, which includes fibrinogen and fibrin, prothrombin, thrombomodulin, soluble urokinase plasminogen activator receptor, von Willebrand factor, P-selectin, D-dimer, plasminogen activator inhibitor-1, and platelet activation. Coagulation irregularities play a significant role in the pathogenesis of AF.

Oxidative Stress, Inflammation, and Mitochondrial Dysfunction: A Link between Obesity and Atrial Fibrillation.

The adipose tissue has long been thought to represent a passive source of triglycerides and fatty acids. However, extensive data have demonstrated that the adipose tissue is also a major endocrine organ that directly or indirectly affects the physiological functions of almost all cell types. Obesity is recognized as a risk factor for multiple systemic conditions, including metabolic syndrome, type 2 diabetes mellitus, sleep apnea, cardiovascular disorders, and many others. Obesity-related changes in the adipose tissue induce functional and structural changes in cardiac myocytes, promoting a wide range of cardiovascular disorders, including atrial fibrillation (AF). Due to the wealth of epidemiologic data linking AF to obesity, the mechanisms underlying AF occurrence in obese patients are an area of rich ongoing investigation. However, progress has been somewhat slowed by the complex phenotypes of both obesity and AF. The triad inflammation, oxidative stress, and mitochondrial dysfunction are critical for AF pathogenesis in the setting of obesity via multiple structural and functional proarrhythmic changes at the level of the atria. The aim of this paper is to provide a comprehensive view of the close relationship between obesity-induced oxidative stress, inflammation, and mitochondrial dysfunction and the pathogenesis of AF. The clinical implications of these mechanistic insights are also discussed.

The role of laboratory markers in predicting the effectiveness of catheter treatment for atrial fibrillation: a literature review

Atrial fibrillation (AF) is the most common cardiac arrhythmia among the adult population. There are many possible causes of AF: structural heart disease, inflammatory and autoimmune diseases, obesity, alcohol abuse, diabetes mellitus, obstructive sleep apnea and old age. The ectopic activity of pulmonary vein couplings lies in the pathogenesis of paroxysmal and persistent forms of AF. The role of AF itself in triggering the inflammatory process in the atrium myocardium has also been proven. Despite the large amount of existing data, the search for the causes of AF continues. Previously, AF was considered the outcome of prolonged hemodynamic stress, arterial hypertension and valvular heart disease. Recently, views on the pathogenesis of AF have changed, since patients with metabolic diseases, without hypertrophy and dilatation of the left ventricle, but with disturbances in the structure and function of the atria, most often the left atrium, are increasingly encountered. There is an active search for laboratory markers to identify groups of patients most susceptible to developing AF. Determining the cause of atrial fibrillation and pathogenesis in each patient is important for selecting therapy and determining treatment tactics. Currently, a search is underway for laboratory markers that may be associated with the manifestation of atrial fibrillation, with atriopathy, and the effectiveness/ineffectiveness of catheter treatment for atrial fibrillation. An analysis of clinical studies was carried out based on articles indexed in the Scopus, VAK, Russian Science Citation Index, PubMed, and Web of Science databases.

A High-Protein Diet Promotes Atrial Arrhythmogenesis via Absent-in-Melanoma 2 Inflammasome.

High-protein diets (HPDs) offer health benefits, such as weight management and improved metabolic profiles. The effects of HPD on cardiac arrhythmogenesis remain unclear. Atrial fibrillation (AF), the most common arrhythmia, is associated with inflammasome activation. The role of the Absent-in-Melanoma 2 (AIM2) inflammasome in AF pathogenesis remains unexplored. In this study, we discovered that HPD increased susceptibility to AF. To demonstrate the involvement of AIM2 signaling in the pathogenesis of HPD-induced AF, wildtype (WT) and Aim2-/- mice were fed normal-chow (NC) and HPD, respectively. Four weeks later, inflammasome activity was upregulated in the atria of WT-HPD mice, but not in the Aim2-/--HPD mice. The increased AF vulnerability in WT-HPD mice was associated with abnormal sarcoplasmic reticulum (SR) Ca2+-release events in atrial myocytes. HPD increased the cytoplasmic double-strand (ds) DNA level, causing AIM2 activation. Genetic inhibition of AIM2 in Aim2-/- mice reduced susceptibility to AF, cytoplasmic dsDNA level, mitochondrial ROS production, and abnormal SR Ca2+-release in atrial myocytes. These data suggest that HPD creates a substrate conducive to AF development by activating the AIM2-inflammasome, which is associated with mitochondrial oxidative stress along with proarrhythmic SR Ca2+-release. Our data imply that targeting the AIM2 inflammasome might constitute a novel anti-AF strategy in certain patient subpopulations.

Impact of Obesity on Atrial Fibrillation Pathogenesis and Treatment Options.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. AF increases the risk of stroke, heart failure, dementia, and hospitalization. Obesity significantly increases AF risk, both directly and indirectly, through related conditions, like hypertension, diabetes, and heart failure. Obesity-driven structural and electrical remodeling contribute to AF via several reported mechanisms, including adiposity, inflammation, fibrosis, oxidative stress, ion channel alterations, and autonomic dysfunction. In particular, expanding epicardial adipose tissue during obesity has been suggested as a key driver of AF via paracrine signaling and direct infiltration. Weight loss has been shown to reverse these changes and reduce AF risk and recurrence after ablation. However, studies on how obesity affects pharmacologic or interventional AF treatments are limited. In this review, we discuss mechanisms by which obesity mediates AF and treatment outcomes, aiming to provide insight into obesity-drug interactions and guide personalized treatment for this patient subgroup.

The ratio of cytochrome c oxidase subunit 4 isoform 4I1 and 4I2 mRNA is changed in permanent atrial fibrillation.

The conditions of hypoxia are suggested to induce permanent atrial fibrillation (AF). The regulation of COX4I2 and COX4I1 depends on oxygen availability in tissues. A role of COX4I2 in the myocardium of AF patients is supposed for pathogenesis of AF and subsequent alterations in the electron transfer chain (ETC) under hypoxia. In vitro, influence of hypoxia on HeLa 53 cells was studied and elevated parts of COX 4I2 were confirmed. Myocardial biopsies were taken ex vivo from the patients' Right Atria with SR (n=31) and AF (n=11), respectively. RT- PCR for mRNA expresson, mitochondrial respiration by polarography and the protein content of cytochrome c oxidase (CytOx) subunit 4I1 and CytOx subunit 4I2 by ELISA were studied. Clinical data were correlated to the findings of gene expressions in parallel. Patients with permanent AF had a change in isoform 4I2/4I1 expression along with a decrease of isoform COX 4I1 expression. The 4I2/4I1 ratio of mRNA expression was increased from 0.630 to 1.058 in comparison. However, the protein content of CytOx subunit 4 was much lower in the AF group, whereas the respiration/units enzyme activity in both groups remained the same. This study describes a possible molecular correlate for the development of AF. Due to the known functional significance of COX 4I2, mitochondrial dysfunction can be assumed as a part of the pathogenesis of AF.

Mendelian randomization provides evidence for a causal effect of serum insulin-like growth factor family concentration on risk of atrial fibrillation.

Atrial fibrillation (AF) is one of the most common persistent arrhythmias among adult cardiovascular diseases. It is important to identify potential risk factors for AF. Members of the insulin-like growth factor (IGF) family exert a variety of effects on various cell types in the context of the pathogenesis of cardiovascular diseases, and previous population-based studies indicate associations between IGF family members and AF. However, the causal effects of IGF family members in AF have not been evaluated. In the current study two-sample Mendelian Randomization (MR) was used to assess genetic relationships between IGF family members and AF. MR was performed based on genome-wide association study (GWAS) datasets, and concentration levels of 14 IGF family members were retrieved. An initial MR analysis was conducted to identify single nucleotide polymorphisms potentially associated with IGF serum concentrations. A GWAS meta-analysis including 60620 AF cases and 970216 control participants of European ancestry was then conducted to identify AF causal effects. Two-sample MR packages were used to perform MR analysis in R. MR-Egger, weighted median (WM), and inverse variance weighted (IVW) methods were used. In two-sample MR assessments there were lower levels of circulating IGF binding protein 3 in both WM [odds ratio (OR) 0.964, 95% confidence interval (CI) 0.940-0.960, P = 0.006] and IVW (OR 0.968, 95%CI: 0.947-0.987, P = 0.001) analyses. Higher serum levels of IGF2 receptor were associated with AF (OR 1.045, 95%CI: 1.016-1.076, P = 0.039). In reverse MR analysis conducted to investigate casual effects, elevated levels of circulating CYR61 were associated with AF (OR 1.060, 95%CI: 1.005-1.119, P = 0.031). The results of the present study provide novel insights into the pathogenesis of AF, and the implications of serum IGF family member concentrations when assessing the risk of AF. The study generated evidence on the potential roles of developmental pathological effects in the pathogenesis of AF. Further observational and experimental studies are critically needed.

Opposite causal effects of birthweight on myocardial infarction and atrial fibrillation and the distinct mediating pathways: a Mendelian randomization study

BackgroundPrevious observational studies have documented an inverse association of birthweight with myocardial infarction (MI) but a positive association with atrial fibrillation (AF). However, the causality of these associations and the underlying mediating pathways remain unclear. We aimed to investigate the causal effects of birthweight, incorporating both fetal and maternal genetic effects, on MI and AF, and identify potential mediators in their respective pathways.MethodsWe performed Mendelian randomization (MR) analyses using genome-wide association study summary statistics for birthweight (N = 297,356 for own birthweight and 210,248 for offspring birthweight), MI (Ncase=61,000, Ncontrol=577,000), AF (Ncase=60,620, Ncontrol=970,216), and 52 candidate mediators (N = 13,848-1,295,946). Two-step MR was employed to identify and assess the mediation proportion of potential mediators in the associations of birthweight with MI and AF, respectively. As a complement, we replicated analyses for fetal-specific birthweight and maternal-specific birthweight.ResultsGenetically determined each 1-SD lower birthweight was associated with a 40% (95% CI: 1.22–1.60) higher risk of MI, whereas each 1-SD higher birthweight was causally associated with a 29% (95% CI: 1.16–1.44) higher risk of AF. Cardiometabolic factors, including lipids and lipoproteins, glucose and insulin, blood pressure, and fatty acids, each mediated 4.09-23.71% of the total effect of birthweight on MI, followed by body composition and strength traits (i.e., appendicular lean mass, height, and grip strength) and socioeconomic indicators (i.e., education and household income), with the mediation proportion for each factor ranging from 8.08 to 16.80%. By contrast, appendicular lean mass, height, waist circumference, childhood obesity, and body mass index each mediated 15.03-45.12% of the total effect of birthweight on AF. Both fetal-specific birthweight and maternal-specific birthweight were inversely associated with MI, while only fetal-specific birthweight was positively associated with AF. Psychological well-being and lifestyle factors conferred no mediating effect in either association.ConclusionsCardiometabolic factors mainly mediated the association between lower birthweight and MI, while body composition and strength traits mediated the association between higher birthweight and AF. These findings provide novel evidence for the distinct pathogenesis of MI and AF and advocate adopting a life-course approach to improving fetal development and subsequent causal mediators to mitigate the prevalence and burden of cardiovascular diseases.

Atrial fibrillation in coronary artery disease patients: gut microbiota composition and echocardiography indexes

The aim: to find connections between gut microbiota composition and transthoracic echocardiography (TTE) indexes in patients with coronary artery disease (CAD) and atrial fibrillation (AF).
 Materials and methods: 300 patients were divided into 3 groups: first (CAD) – 149 patients with CAD but without arrhythmias; second (CAD+AF) – 124 patients with CAD and AF paroxysm; and the control group – 27 patients without CAD and arrhythmias. 16-S rRNA sequencing checked gut microbiota composition. TTE was done by ALOKA SSD-5000.
 Results: The II group patients were characterized by the increase of LAD (10.03 %), LAV (15.40 %) and LAVI (11.48 %) in comparison with the I group, P<0.05. The II group patients were characterized by a rise of Pseudomonadota in comparison with the I group, P<0.05. Also, II group patients were characterized by rise of Actinobacter Spp. and decrease of Blautia Spp., Bacteroides Thetaiotaomicron in comparison with the I group, P<0.05. Firmicutes were correlated with AO (r=0.308), LADI (r=-0.363), RV (r=-0.470), IVS (r=-0.381), LVPW (r=-0.345), LVM (r=-0.476) and EF (r=0,312), P<0.05. Akkermansia Muciniphila was correlated with LAD (r=-0.343), LADI (r=-0.308), LAV (r=-0.494), LAVI (r=-0.488), RAV (r=-0.316), RAVI (r=-0.397), RV (r=-0.383), EF (r=0.332), P<0.05. Bifidobacterium Spp. were correlated with LAV (r=-0.487), LAVI (r=-0.327), RV (r=-0.341), IVS (r=-0.306), RWT (r=-0.389), LVM (r=-0.369), LVMI (r=-0.312), EF (r=0.317), P<0.05. Streptococcus Spp. were correlated with AO (r=0,329), LVOT (r=0,390), RV (r=0,393), IVS (r=0,648), LVPW (r=0,579), RWT (r=0,356), LVM (r=0,336), LVMI (r=0,376), P<0.05. Ruminococcus Spp. were correlated with AO (r=0,412), LVOT (r=0,351), LADI (r=-0.343), IVS (r=-0.316), LVPW (r=-0.367), LVM (r=-0.302), LVMI (r=-0.379), P<0.05.
 Conclusion: Gut microbiota composition and TTE indexes play a significant role in CAD and AF pathogenesis. Firmicutes, Bifidobacterium spp., and Verrucomicrobiota (Akkermansia muciniphila) were significantly correlated with left atrium size and volume, as well as their ultrasound indexes. Bifidobacterium spp., Bacteroides Spp., Streptococcus Spp. and Ruminococcus Spp. were significantly correlated with left ventricular sizes and its hypertrophy indexes

Retracted: The Nine RNA Methylation Regulatory Gene Signature Is Associated with the Pathogenesis of Atrial Fibrillation by Modulating the Immune Microenvironment in the Atrial Tissues

Retracted: The Nine RNA Methylation Regulatory Gene Signature Is Associated with the Pathogenesis of Atrial Fibrillation by Modulating the Immune Microenvironment in the Atrial Tissues

USP38 exacerbates atrial inflammation, fibrosis, and susceptibility to atrial fibrillation after myocardial infarction in mice

BackgroundInflammation plays an important role in the pathogenesis of atrial fibrillation (AF) after myocardial infarction (MI). The role of USP38, a member of the ubiquitin-specific protease family, on MI-induced atrial inflammation, fibrosis, and associated AF is unclear.MethodsIn this study, we surgically constructed a mouse MI model using USP38 cardiac conditional knockout (USP38-CKO) and cardiac-specific overexpression (USP38-TG) mice and applied biochemical, histological, electrophysiological characterization and molecular biology to investigate the effects of USP38 on atrial inflammation, fibrosis, and AF and its mechanisms.ResultsOur results revealed that USP38-CKO attenuates atrial inflammation, thereby ameliorating fibrosis, and abnormal electrophysiologic properties, and reducing susceptibility to AF on day 7 after MI. USP38-TG showed the opposite effect. Mechanistically, The TAK1/NF-κB signaling pathway in the atria was significantly activated after MI, and phosphorylated TAK1, P65, and IκBα protein expression was significantly upregulated. USP38-CKO inhibited the activation of the TAK1/NF-κB signaling pathway, whereas USP38-TG overactivated the TAK1/NF-κB signaling pathway after MI. USP38 is dependent on the TAK1/NF-κB signaling pathway and regulates atrial inflammation, fibrosis, and arrhythmias after MI to some extent.ConclusionsUSP38 plays an important role in atrial inflammation, fibrosis, and AF susceptibility after MI, providing a promising target for the treatment of AF after MI.

Assessment of multi-trait analysis of GWAS (MTAG) for discovery of novel genetic variants and mechanistic insight in common cardiovascular diseases

Abstract Background Variability in cardiovascular conditions is partly explained by common genomic variation identifiable by genome-wide association studies (GWAS). Genetic substrate may overlap in certain entities, this being quantified by genetic correlation. We aimed to leverage multi-trait analysis of GWAS (MTAG), (1) which boosts statistical power by joint analysis of genetically correlated traits, to improve genetic loci discovery in 3 common cardiovascular diseases: atrial fibrillation (AF), coronary artery disease (CAD), and heart failure (HF). Methods and Results Cardiovascular phenotypes with available GWAS summary statistics most correlated with the disease of interest were analysed jointly by MTAG (workflow depicted in Figure 1). These included body mass index and HF for AF (2); HF, LDL-cholesterol, and systolic blood pressure for CAD (3); and AF, CAD, and dilated cardiomyopathy for HF (4). MTAG increased statistical power for all 3 disease GWAS and allowed the identification of 19 new genomic loci for AF, 89 for CAD and 52 for HF (at a GWAS significance level P<5x10-8) (Figure 2). New loci were defined as not previously identified in the single trait original GWAS. Consistently, 19/19, 85/89 and 48/52 of new loci reached nominal significance (P<0.05) in the original studies; and 37%, 44% and 36% of new loci have been associated with AF, CAD and HF in GWAS and phenome wide association studies (PheWAS) in independent cohorts. MTAG summary statistics annotation and functional analysis integrated the distance to the canonical transcriptional start site, chromatin interaction experiments, quantitative molecular phenotype trait experiments and in silico functional prediction through OpenTargets Genetics. MAGMA gene-set functional analysis of the new MTAG results showed 87, 27 and 24 significant associated pathways to AF, CAD and HF respectively. Among the top associations, cardiac depolarization, repolarization, and muscle contraction in AF; macromolecular complex remodeling, triglyceride, chylomicron and LDL metabolism in CAD; and muscle structure, tissue development and RNA transcription initiation in HF. Among novel relevant genes in AF, SRR on chromosome 16 is involved in central nervous system development through regulation of NMDA receptors. This locus has been previously associated with QRS in another GWAS and SRR is related to reduction in heart rate variability and AF enhancement in rats. In CAD, RSPO3 and JAG1 genes, on chromosomes 6 and 20 respectively, have a relevant role in angiogenesis, where RSPO3 is a crucial regulator of coronary artery formation in the developing heart. Conclusions MTAG allows the discovery of new trait-specific loci involved in the pathogenesis of AF, CAD, and HF congruent with the mechanisms of each disease and consistent with independent external cohort PheWAS and GWAS. Thus, MTAG is an interesting tool to unravel relevant mechanisms and potential therapeutic targets in common cardiovascular diseases.

Effect of epigenetic regulation on left atrial function and recurrence after catheter ablation in patients with atrial fibrillation

Abstract Background Genetic variation and modifiable risk factors play a significant role in the pathogenesis of atrial fibrillation (AF). However, the influence of epigenetic modification on AF remains to be elucidated. Methods Epigenetic evaluation was performed in 115 AF patients who underwent radiofrequency catheter ablation (RFCA) in a single institution. We measured methylation at approximately 850,000 bp cytosine-phosphate-guanine (CpG) sites in the 115 samples. Results The degree of methylation was compared across seven classification criteria: type of AF, late recurrence, impaired left atrium (LA) function, late gadolinium enhancement, LA diameter, LA volume, and flow velocity of the LA appendage. The four most significantly methylated genes in our cohort were DEFB104B, C3, TANC1, and TMEM9B. The DEFB104B gene (cg20223677 in the transcription start site), which encodes β-defensin 104B, was hypomethylated in three groups: those with late recurrence, impaired LA function, and impaired LAA flow velocity. Enriched functional annotation of the differentially methylated datasets revealed that five out of the seven AF groups in this cohort were associated with genes involved in the cell movement of endothelial cell lines, sprouting angiogenesis by endothelial cell lines, or migration of endothelial cell lines. Conclusion In this study, epigenetic profiling revealed that epigenetic modification might affect crucial traits of AF, such as the degree of atrial myopathy and treatment effects after RFCA, suggesting the hypothesis that the pathogenesis of AF might be affected by not only genetic variation or modifiable factors but also by epigenetic modulation. The identified methylation-susceptible loci can be used in targeting for epigenetic-based therapeutic agents.

AF in the AFternoon: The circadian pattern of incident atrial fibrillation in a loop recorder population

Abstract Introduction Loop recorders have provided the opportunity to systematically screen individuals for arrhythmias, and in doing so provide new appreciated mechanistic insights to arrhythmia pathophysiology. Atrial fibrillation (AF) is a complex arrhythmia with a multitude of precipitants and substrates. Previous studies looking at the circadian rhythm of AF, have required patient symptoms to define onset. All studies on the circadian rhythm of AF suggest that AF does not occur randomly. It has been suggested that the circadian variation in autonomic function may provide an underlying substrate for AF initiation. This is the largest study to utilise loop recorder detected AF to explore the circadian pattern of AF. Purpose We sought to ascertain how the detection of incident AF varied throughout the day, in patients monitored with a loop recorder Methods This was a single-centre retrospective observational study. Consecutive adult patients referred for ILR implantation between March 2009 and November 2019, without prevalent AF or atrial flutter, were included. Demographic and anthropometric data was identified from the individuals medical notes. The time of incident AF episodes was identified from loop recorder reports. Results A total of 1168 AF episodes of any duration were identified by the ILR, of which onset time was available for 1118 episodes. Onset of AF episodes in our data for the entire population demonstrated a monophasic distribution (figure 1a). The OR for developing AF between 13.00-14.59 compared to 03.00-04.59 was 4.89 (95% CI 3.47-6.90). Amongst the ESUS population time of onset distribution showed multiple daytime peaks (figure 1b). The OR for developing AF between 10.00-11.59 compared to 03.00-04.59 was 4.39 (95% CI 2.68-7.20). Amongst the non- ESUS population time of onset distribution (figure 1c) shows a monophasic pattern with the peak at time blocks 12.00-14.59. The OR for developing AF between 13.00-14.59 compared to 02.00-03.59 was 6.75 (95% CI 4.17-10.93). Conclusion(s) Our study demonstrated that there is a diurnal variation for incident AF detection using a loop recorder. There is a general propensity for episodes to occur in the afternoon, with a nadir at night. This is in contrast to previous reports which have suggested that the nocturnal and morning peaks are more apparent. Moreover, different cohorts appear to show different temporal patterns, with ESUS patients having multiple time peaks, whereas the non-stroke cohort had a solitary peak period. Understanding the diurnal variation of AF may help to shed more light on the complex pathogenesis of AF, and whether different AF phenotypes are associated with stroke risk. Moreover, the finding of a day-time propensity for AF, adds weight to the utilisation of consumer facing non-invasive monitoring tools during the day for AF identification in high-risk populations.