NAD+ Deficiency Drives Metabolic Dysfunction-Associated Atrial Fibrillation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE334551 | GEO | 2026/06/24
REPOSITORIES: GEO
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Project description:Obesity is linked to an increased risk of atrial fibrillation (AF) via increased oxidative stress. While NADPH oxidase II (NOX2), a major source of oxidative stress and reactive oxygen species (ROS) in the heart predisposes to AF, the underlying mechanisms remain unclear. Here, we studied NOX2-mediated ROS production in obesity-mediated AF using Nox2-knock-out (KO) mice and mature human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). Diet-induced obesity (DIO) mice and hiPSC-aCMs treated with palmitic acid (PA) were infused with a NOX blocker (apocynin) and a NOX2-specific inhibitor, respectively. We showed that NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling with reduced AF burden. Unbiased transcriptomics analysis revealed that NOX2 mediates atrial remodeling in obesity-mediated AF in DIO mice, PA-treated hiPSC-aCMs, and human atrial tissue from obese individuals by upregulation of paired-like homeodomain transcription factor 2 (PITX2). Furthermore, hiPSC-aCMs treated with hydrogen peroxide, a NOX2 surrogate, displayed increased PITX2 expression, establishing a mechanistic link between increased NOX2-mediated ROS production and modulation of PITX2. Our findings offer insights into possible mechanisms through which obesity triggers AF and support NOX2 inhibition as a potential novel prophylactic or adjunctive therapy for patients with obesity-mediated AF.
2024-10-09 | GSE271748 | GEO
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.
2025-05-09 | GSE218250 | GEO
Project description:Atrial fibrillation (AF), the most common cardiac rhythm disorder, is a major cause of cardiovascular morbidity and mortality. AF is characterized by the rapid and irregular activation of the atrium with diverse abnormalities, including electrical, structural, metabolic, neurohormonal, or molecular alterations.3 Although the pathophysiology of AF is complex, it has traditionally been treated with antiarrhythmic drugs that control the rhythm by altering cardiac electrical properties, principally by modulating ion channel function. However, treatments of AF with antiarrhythmic drugs have mostly failed to control the heart rhythm, because the electrical characteristics of atrial cardiomyocytes are eventually altered or remodeled during the course of AF. The aims of this study were to characterize the global changes in miRNA expression in human atrial appendages and to identify the target ion channel(s) responsible for electrical remodeling in AF. In this study, we performed a comprehensive analysis of miRNA microarrays, using a strict selection for human samples.
2017-04-25 | GSE68475 | GEO
Project description:Background: Horses and humans are among the few mammals prone to developing spontaneous atrial fibrillation (AF), both suffering from high recurrence rates after treatment. Treatment resistance is often attributed to functional, structural, and metabolic remodeling of the atria. The aim of this explorative study was to evaluate the molecular pathways associated with early stages of AF in horses and to compare the AF proteomes between horses and humans. Methods: We performed data-independent acquisition mass spectrometry on myocardial biopsies collected from the right atrium (RA), left atrium (LA), and left ventricular chamber (LV) in horses with early stages of naturally occurring persistent AF and controls (n=8 in each group). Results: We identified a total of 3400 quantifiable proteins, several of which were differentially regulated between AF horses and controls (268 in RA, 324 in LA, and 284 in LV, p<0.05). Pathway enrichment analyses identified changes in metabolic, contractile, and extracellular matrix (ECM) proteins. Atrial hypocontractility and ECM remodeling were confirmed by echocardiography and histology, respectively. Key proteomic changes in horses with AF overlapped with human AF public datasets, underscoring the translational relevance of the equine AF model. Particularly, contractile proteins, such as cardiac troponins (TNNT2), myosin (MYH6) and tropomyosin (TPM2), along with metabolic regulators as heat shock protein family A (HSPA4) and Proteasome 26S Subunit, Non-ATPase 13 (PSMD13) were shared between horses and humans with AF. Moreover, a significant increase in several ECM glycoproteins was detected in both species, highlighting the importance of early ECM remodeling that extends beyond the fibrotic changes often associated with AF. Conclusion: The horse and human cardiac proteome share similar AF-related changes. Metabolic, functional, and structural protein changes identified in early-stage AF may provide clues to pharmacological targets for preventing AF-associated atrial remodeling and improving treatment success across species.
2025-05-28 | PXD052818 | Pride
Project description:Objectives: We studied the signal transduction of atrial structural remodelling that contributes to the pathogenesis of atrial fibrillation (AF). Backround: Fibrosis is a hallmark of arrhythmogenic structural remodelling but the underlying molecular mechanisms are incompletely understood. Methods: We performed transcriptional profiling of left atrial myocardium (LA) from patients with AF and sinus rhythm (SR) and applied cultured primary cardiac cells and transgenic mice with overexpression of constitutively active V12Rac1 (RacET) who develop AF at old age to characterize mediators of the signal transduction of atrial remodeling. Results: LA from patients with AF showed a marked upregulation of connective tissue growth factor (CTGF) expression compared SR patients. This was associated with increased fibrosis, NADPH-oxidase-, Rac1- and RhoA activity, upregulation of N-cadherin and connexin 43 (Cx43) expression and increased angiotensin II tissue concentration. In neonatal rat cardiac myocytes and -fibroblasts, a specific small molecule inhibitor of Rac1 or simvastatin completely prevented the angiotensin II induced upregulation of CTGF, Cx43 and N-cadherin expression. Transfection with small-inhibiting CTGF RNA blocked Cx43 and N-cadherin expression. RacET mice showed upregulation of CTGF, Cx43 and N-cadherin protein expression. Inhibition of Rac1 by oral statin treatment prevented these effects, identifying Rac1 as a key regulator of CTGF in vivo. Conclusion: The data identify CTGF as an important mediator of atrial structural remodelling during AF. Angiotensin II activates CTGF via activation of Rac1 and NADPH oxidase, leading to upregulation of Cx43, N-cadherin and interstitial fibrosis and therefore contributing to the signal transduction of atrial structural remodelling. Array design study consists of 5 Atrial Fibrillation patients and matched 5 samples of patients in sinus rhythm (controls).
2010-02-21 | E-GEOD-14975 | biostudies-arrayexpress
Project description:Background: Horses are one of the few animals that spontaneously develop atrial fibrillation (AF), making them a powerful model for studying AF mechanisms and treatment effects. Despite the initial effectiveness of treatment in both horses and humans, AF-induced atrial remodelling compromises long-term success. Observational studies have suggested that metformin reduces the risk of AF, but its effects on progressive AF-induced atrial remodelling have not yet been evaluated in a high-fidelity large animal model. Methods: Here, we employed a longitudinal horse model of tachypacing-induced self-sustained AF to characterize the electrical, molecular, and metabolic atrial changes over four months of disease, with and without metformin treatment. Electrophysiological and multi-omic approaches were combined with histology, echocardiography, biochemical and mitochondrial analyses to evaluate disease progression and treatment response. Results: The horse model replicated critical aspects of AF-induced atrial remodelling observed in humans, including electrical and structural changes. Despite upregulation of metabolic genes and proteins in AF, no significant ultrastructural mitochondrial changes were detected. Metformin-treated horses were less susceptible to AF and sustained a less complex AF substrate in the right atrium after four months of disease. These effects were associated with increased activity of the metabolic regulator, AMP-activated kinase (AMPK) , changes in metabolic pathways and modulation of ion-channel gene expression. Metformin did not appear to alter left atrial substrate remodelling. Conclusion: Metformin treatment conferred electrical protection in both the early and later stages of AF in a translationally relevant preclinical model. These findings support metformin as a lead molecul ar for AF-prevention, warranting further mechanistic and clinical studies.
2025-12-03 | PXD059963 | Pride
Project description:Atrial fibrillation (AF) remains challenging to prevent and treat. It is associated with increased rates of heart failure, stroke and neurological decline. A key feature of AF is atrial enlargement. However, not all atrial enlargement progresses to pathology and AF.
In the current study, we characterized mouse atria from a 1) pathological model (cardiac-specific transgenic (Tg) that develops dilated cardiomyopathy [DCM] and AF due to reduced protective signalling [PI3K]; DCM-dnPI3K), and a 2) physiological model (cardiac-specific Tg with an enlarged heart due to increased insulin-like growth factor 1 receptor; IGF1R). Atrial enlargement in the DCM-dnPI3K Tg, but not IGF1R Tg, was associated with atrial dysfunction, fibrosis and a heart failure gene expression pattern. Proteomics analysis identified proteins and pathways that were differentially regulated in pathological and physiological atrial enlargement, and provides a resource to study potential drug targets for AF.
2023-12-07 | MSV000093605 | MassIVE
Project description:Background: Genomic and experimental studies suggest a role for PITX2 in atrial fibrillation (AF). To assess whether this association is relevant for recurrent AF in patients, we tested whether left atrial PITX2 affects recurrent AF after AF ablation. Methods: mRNA concentrations of PITX2 and its cardiac isoform, PITX2c, were quantified in left atrial appendages (LAA) from patients undergoing thoracoscopic AF ablation, either in whole LAA tissue (n=83) or in LAA cardiomyocytes (n=52), and combined with clinical parameters to predict AF recurrence. Literature suggests bone morphogenetic protein 10 (BMP10) as a PITX2-repressed, atrial-specific, secreted protein. BMP10 plasma concentrations were combined with eleven cardiovascular biomarkers and clinical parameters to predict recurrent AF after catheter ablation in 359 patients. Results: Reduced cardiomyocyte PITX2 concentrations, but not whole LAA tissue PITX2, were associated with AF recurrence after thoracoscopic AF ablation (16% decreased recurrence per 2-(ΔΔCt) increase in PITX2). RNA sequencing, qPCR and Western blotting confirmed BMP10 as one of most PITX2-repressed atrial genes. Left atrial size (hazard ratio per mm increase, HR [95%CI] 1.055 [1.028, 1.082], non-paroxysmal AF (HR 1.672 [1.206, 2.318]) and elevated BMP10 (HR 1.339 [CI 1.159, 1.546] per quartile increase) were predictive of recurrent AF. BMP10 outperformed eleven other cardiovascular biomarkers in predicting recurrent AF. Conclusions: Reduced left atrial cardiomyocyte PITX2 and elevated plasma concentrations of the PITX2-repressed, secreted, atrial protein BMP10 identify patients at risk of recurrent AF after ablation.
2020-06-19 | GSE152181 | GEO
Project description:Background: ZFHX3, a gene that encodes a large transcription factor, is the second-most significantly associated locus with AF, but its function in the heart is unknown. This study aims to identify causative genetic variation related to AF at the ZFHX3 locus and examine the impact of Zfhx3 loss on cardiac function in mice. Methods: CRISPR-Cas9 genome editing, chromatin immunoprecipitation, and luciferase assays in pluripotent stem cell-derived cardiomyocytes were used to identify causative genetic variation related to AF at the ZFHX3 locus. Cardiac function was assessed by echocardiography, MRI, electrophysiology studies, calcium imaging, and RNA sequencing in mice with heterozygous and homozygous cardiomyocyte-restricted Zfhx3 deletion (Zfhx3 Het and KO, respectively). Human cardiac single-nucleus ATAC-sequencing data was analyzed to determine which genes in atrial cardiomyocytes are directly regulated by ZFHX3. Results: We found SNP rs12931021 modulates an enhancer regulating ZFHX3 expression, and the AF risk allele is associated with decreased ZFHX3 transcription. We observed a gene-dose response in AF susceptibility withZfhx3KO mice having higher incidence, frequency, and burden of AF thanZfhx3Het and WT mice, with alterations in conduction velocity, atrial action potential duration, calcium handling and the development of atrial enlargement and thrombus, and dilated cardiomyopathy. Zfhx3 loss results in atrial-specific differential effects on genes and signaling pathways involved in cardiac pathophysiology and AF. Conclusions: Our findings implicate ZFHX3 as the causative gene at the 16q22 locus for AF, and cardiac abnormalities caused by loss of cardiac Zfhx3 are due to atrial-specific dysregulation of pathways involved in AF-susceptibility. Together, these data reveal a novel and important role for Zfhx3 in the control of cardiac genes and signaling pathways essential for normal atrial function.
2023-06-30 | GSE229525 | GEO
Project description:Atrial fibrillation (AF), a common cardiac arrhythmia, is more prevalent in patients with elevated interleukin (IL)-1β levels. Our study shows that 15-day IL-1β injections sensitize mice to AF, inducing fibrosis, β-pleated protein accumulation in the atria, and systemic inflammation resembling AF patients. Increased caspase-1 and IL-1β maturation in the left atrium and elevated Il1b and Casp1 transcription in resident macrophages—dependent on IL-1 receptor (IL-1R)—indicate a positive feedback loop. IL-1β shortened action potentials (APs), accelerating AP and Ca2+ transient restitution, and AF sensitivity required shortened APs, caspase-1, and IL-1R. Cre-Lox knockout models revealed IL-1β signaling relies on IL-1R in macrophages, not cardiomyocytes. While Ccr2-/- mice, lacking recruited macrophages, remained AF-susceptible, mice with IL-1R deletion in cardiac resident macrophages were protected. We present a novel IL-1β-driven AF etiology mediated by IL-1R in cardiac resident macrophages and caspase-1, offering insights into therapeutic targets and distinct AF etiologies.
2024-12-16 | GSE284265 | GEO