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Atrial fibrosis is a hallmark of atrial cardiomyopathy and plays a pivotal role in the pathogenesis of atrial fibrillation (AF), contributing to its onset and progression. The mechanisms underlying atrial fibrosis are multifaceted, involving stretch-induced fibroblast activation, oxidative stress, inflammation, and coagulation pathways. Variations in fibrosis types—reactive and replacement fibrosis—are influenced by patient-specific factors such as age, sex, and comorbidities, complicating therapeutic approaches. The heterogeneity of fibrosis leads to distinct electrophysiological abnormalities that promote AF via reentrant activity and enhanced automaticity mechanisms. Despite advancements in imaging, such as late gadolinium enhancement CMR and electroanatomical mapping, challenges in accurately quantifying fibrosis persist. Emerging therapeutic strategies include antifibrotic agents targeting the renin–angiotensin–aldosterone system, novel pathways like TGF-β signaling, and cardio-metabolic drugs like SGLT2 inhibitors and GLP-1 receptor agonists. Innovative interventions, including microRNA modulation and lipid nanoparticle-based therapies, show promise but require validation. Knowledge gaps remain in correlating clinical outcomes with fibrosis patterns and optimizing diagnostic tools. Future research should focus on precise phenotyping, integrating advanced imaging with molecular biomarkers, and conducting robust trials to evaluate antifibrotic therapies’ efficacy in reducing AF burden and related complications.

Background Long non-coding RNAs (lncRNA) plasmacytoma variant translocation 1 (PVT1) has been shown to be associated with liver fibrosis. Nevertheless, the role of PVT1 in atrial fibrosis remains undefined. This study aims to elucidate the pathophysiological role of lncRNA PVT1 in the regulation of atrial fibrosis and to explore the underlying mechanism. Methods Expression of PVT1, miR-128-sp, and Sp1 were examined in human atrial muscle tissues and angiotensin-II (Ang-II)-induced human atrial fibroblasts. Furthermore, the role of PVT1 in regulating atrial fibrosis in Ang-II-treated human atrial fibroblasts and Ang-II-induced atrial fibrosis in mice was investigated. Moreover, the interaction among PVT1, miR-128-3p, and Sp1 were examined using bioinformatics, expression correlation analysis, gain- or loss-of-function assays, RIP assays, and luciferase reporter assays. The involvement of transforming growth factor beta 1 (TGF-β1)/Smad pathway in this process was also explored. Results PVT1 was increased in atrial muscle tissues from AF patients and positively with collagen I and collagen III. In vitro assay revealed that PVT1 overexpression facilitated the Ang-II-induced atrial fibroblasts proliferation, collagen production, and TGF-β1/Smad signaling activation, whereas PVT1 knockdown caused the opposite effect. In vivo assay further confirmed that PVT1 knockdown attenuated the Ang-II-induced mouse atrial fibrosis. Mechanically, PVT1 acted as a sponge for miR-128-3p to facilitate Sp1 expression, thereby activating the TGF-β1/Smad signaling pathway. Conclusion LncRNA PVT1 promotes atrial fibrosis via miR-128-3p-SP1-TGF-β1-Smad axis in atrial fibrillation.

Low atrial endocardial bipolar voltage, measured during catheter ablation for atrial fibrillation (AF), is a commonly used surrogate marker for the presence of atrial fibrosis. Low voltage shows many useful associations with clinical outcomes, comorbidities and has links to trigger sites for AF. Several contemporary trials have shown promise in targeting low voltage areas as the substrate for AF ablation; however, the results have been mixed. In order to understand these results, a thorough understanding of voltage mapping techniques, the relationship between low voltage and the pathophysiology of AF, as well as the inherent limitations in voltage measurement are needed. Two key questions must be answered in order to optimally apply voltage mapping as the road map for ablation. First, are the inherent limitations of voltage mapping small enough as to be ignored when targeting specific tissue based on voltage? Second, can conventional criteria, using a binary threshold for voltage amplitude, truly define the extent of the atrial fibrotic substrate? Here, we review the latest clinical evidence with regard to voltage-based ablation procedures before analysing the utility and limitations of voltage mapping. Finally, we discuss omnipole mapping and dynamic voltage attenuation as two possible approaches to resolving these issues.

Background Atrial fibrillation (AF) is associated with profound structural and functional changes in the atria. In the present study, we investigated the association between left atrial (LA) phasic function and the extent of LA fibrosis using advanced cardiovascular magnetic resonance (CMR) imaging techniques, including 3-dimensional (3D) late gadolinium enhancement (LGE) and feature tracking. Methods Patients with paroxysmal and persistent AF ( n  = 105) underwent CMR in sinus rhythm. LA global reservoir strain, conduit strain and contractile strain were derived from cine CMR images using CMR feature tracking. The extent of LA fibrosis was assessed from 3D LGE images. Healthy subjects underwent CMR and served as controls ( n  = 19). Results Significantly lower LA reservoir strain, conduit strain and contractile strain were found in AF patients, as compared to healthy controls (− 15.9 ± 3.8% vs. − 21.1 ± 3.6% P  < 0.001, − 8.7 ± 2.7% vs. − 12.6 ± 2.5% P  < 0.001 and − 7.2 ± 2.3% vs. − 8.6 ± 2.2% P  = 0.02, respectively). Patients with a high degree of LA fibrosis (dichotomized by the median value) had lower reservoir strain and conduit strain compared to patients with a low degree of LA fibrosis (− 15.0 ± 3.9% vs. − 16.9 ± 3.3%, P  = 0.02 and − 7.9 ± 2.7% vs. − 9.5 ± 2.6%, P  = 0.01, respectively) . In contrast, no difference was found for LA contractile strain (− 7.1 ± 2.4% vs. − 7.4 ± 2.3%, P  = 0.55). Conclusions Impaired LA reservoir and conduit strain are present in AF patients with extensive atrial fibrosis. Future studies are needed to examine the biologic nature of this association and possible therapeutic implications.

This study focused on miR-486-5p in atrial fibrillation (AF) evaluating its clinical significance and revealing its regulatory mechanism in cardiac fibroblasts, aiming to explore a novel biomarker for AF. The study enrolled 131 AF patients and 77 non-AF individuals. With the help of polymerase chain reaction (PCR), the expression of miR-486-5p was evaluated. The significance of miR-486-5p in the diagnosis of AF and the occurrence of left atrial fibrosis (LAF) was assessed by receiver operating curve (ROC) and logistic analyses. The regulatory effect and mechanism of miR-486-5p on cardiac fibrosis were investigated in human cardiac fibroblasts treated with angiotensin II. miR-486-5p was significantly upregulated in AF patients and discriminated AF patients from non-AF individuals. Increasing miR-486-5p showed a significant association with decreasing left ventricular ejection fraction (LVEF), increasing left atrial diameter (LAD) and left ventricular end-diastolic diameter (LVEDd), and the high incidence of LAF in AF patients. Moreover, miR-486-5p was identified as a risk factor for LAF and could distinguish AF patients with LAF and without LAF. In cardiac fibroblasts, angiotensin II induced the upregulation of miR-486-5p and promoted cell proliferation, migration, and collagen synthesis. miR-486-5p negatively regulated forkhead box O1 (FOXO1) and its knockdown could reverse the promoted effect of angiotensin II. FOXO1 alleviated the effect of miR-486-5p, and the miR-486-5p/FOXO1 could activate PI3K/Akt signaling. The activation of PI3K/Akt signaling alleviated the enhanced proliferation, migration, and collagen synthesis of cardiac fibroblasts induced by angiotensin II, and its inhibition showed opposite effects. Increased miR-486-5p served as a biomarker for the diagnosis and development prediction of AF. miR-486-5p regulated cardiac fibroblast viability and collagen synthesis via modulating the PI3K/Akt signaling through targeting FOXO1.

Atrial fibrillation (AF) is one of the most common tachyarrhythmias observed in the clinic and is characterized by structural and electrical remodelling. Atrial fibrosis, an emblem of atrial structural remodelling, is a complex multifactorial and patient-specific process involved in the occurrence and maintenance of AF. Whilst there is already considerable knowledge regarding the association between AF and fibrosis, this process is extremely complex, involving intricate neurohumoral and cellular and molecular interactions, and it is not limited to the atrium. Current technological advances have made the non-invasive evaluation of fibrosis in the atria and ventricles possible, facilitating the selection of patient-specific ablation strategies and upstream treatment regimens. An improved understanding of the mechanisms and roles of fibrosis in the context of AF is of great clinical significance for the development of treatment strategies targeting the fibrous region. In the present review, a focus was placed on the atrial fibrosis underlying AF, outlining its role in the occurrence and perpetuation of AF, by reviewing recent evaluations and potential treatment strategies targeting areas of fibrosis, with the aim of providing a novel perspective on the management and prevention of AF.

Atrial fibrillation (AF) is associated with atrial fibrosis. Inhibition of atrial fibrosis might be a plausible approach for AF prevention and therapy. This study is designed to evaluate the potential role of CD44, a membrane receptor known to regulate fibrosis, and its related signaling in the pathogenesis of atrial fibrosis and AF. Treatment of cultured rat atrial fibroblasts with transforming growth factor-β (TGF-β, a key mediator of atrial fibrosis) led to a higher expression of hyaluronan (HA), CD44, STAT3, and collagen (a principal marker of fibrosis) than that of ventricular fibroblasts. In vivo, TGF-β transgenic mice and AF patients exhibited a greater expression of HA, CD44, STAT3, and collagen in their atria than wild-type mice and sinus rhythm subjects, respectively. Treating TGF-β transgenic mice with an anti-CD44 blocking antibody resulted in a lower expression of STAT3 and collagen in their atria than those with control IgG antibody. Programmed stimulation triggered less AF episodes in TGF-β transgenic mice treated with anti-CD44 blocking antibody than in those with control IgG. Blocking CD44 signaling with anti-CD44 antibody and mutated CD44 plasmids attenuated TGF-β-induced STAT3 activation and collagen expression in cultured atrial fibroblasts. Deletion and mutational analysis of the collagen promoter along with chromatin immunoprecipitation demonstrated that STAT3 served as a vital transcription factor in collagen expression. TGF-β-mediated HA/CD44/STAT3 pathway plays a crucial role in the development of atrial fibrosis and AF. Blocking CD44-dependent signaling may be a feasible way for AF management.

Sphingolipids (SLs) are vital constituents of the plasma membrane of animal cells and concurrently regulate numerous cellular processes. An escalating number of research have evinced that SLs assume a crucial part in the progression of tissue fibrosis, a condition for which no efficacious cure exists as of now. Cardiac fibrosis, and in particular, atrial fibrosis, is a key factor in the emergence of atrial fibrillation (AF). AF has become one of the most widespread cardiac arrhythmias globally, with its incidence continuing to mount, thereby propelling it to the status of a major public health concern. This review expounds on the structure and biosynthesis pathways of several pivotal SLs, the pathophysiological mechanisms of AF, and the function of SLs in cardiac fibrosis. Delving into the influence of sphingolipid levels in the alleviation of cardiac fibrosis offers innovative therapeutic strategies to address cardiac fibrosis and AF.

Atrial remodelling is the principal pathological mechanism for atrial fibrillation (AF) development and progression. Long noncoding RNAs (LncRNAs) exhibit important effects on cardiovascular diseases. However, the role of LncRNAs in AF development requires further investigation. This study aimed to explore the function and mechanism of LncRNAs in AF. The differentially expressed LncRNAs of atrial tissue in a mouse AF model, which was established via continuous infusion of Ang II for 3 weeks, were screened with RNA sequencing. Experiments included an electrophysiological study; Masson, H&E and TUNEL staining; flow cytometry; and RNA pull‐down; FISH and RNA immunoprecipitation assays were performed to define the function and underlying mechanisms of LncRNAs in AF susceptibility and atrial remodelling. The Kaplan–Meier method was used to plot the curve of freedom from atrial tachyarrhythmia. LncRNA Dleu2 expression was increased in atrial tissue and peripheral blood and was positively associated with left atrial fibrosis in persistent AF. Furthermore, elevated expression of LncRNA Dleu2 was correlated with a higher AF recurrence rate after ablation at the 24‐month follow‐up (65.0% vs. 85.0%, p = 0.03). Accordingly, upregulation and downregulation of LncRNA Dleu2 expression could regulate atrial remodelling and AF susceptibility, and we also demonstrated that LncRNA Dleu2 directly bound to Nr4a1. Subsequently, inhibition of Nr4a1 expression could also regulate AF susceptibility and atrial remodelling and reverse the effects of LncRNA Dleu2 on AF occurrence. This study demonstrated that LncRNA Dleu2 was independently associated with atrial fibrosis and AF recurrence after ablation, and contributed to AF susceptibility by directly targeting Nr4a1.

Background Atrial Fibrillation (AF), a prevalent arrhythmic condition, is intricately associated with atrial fibrosis, a major pathological contributor. Central to the development of atrial fibrosis is myocardial inflammation. This study focuses on Atrial Natriuretic Peptide (ANP) and its role in mitigating atrial fibrosis, aiming to elucidate the specific mechanisms by which ANP exerts its effects, with an emphasis on fibroblast dynamics. Methods and results The study involved forty Sprague-Dawley rats, divided into four groups: control, Angiotensin II (Ang II), Ang II + ANP, and ANP only. The administration of 1 µg/kg/min Ang II was given to Ang II and Ang II + ANP groups, while both Ang II + ANP and ANP groups received 0.1 µg/kg/min ANP intravenously for a duration of 14 days. Cardiac fibroblasts were used for in vitro validation of the proposed mechanisms. The study observed that rats in the Ang II and Ang II + ANP groups showed an increase in blood pressure and a decrease in body weight, more pronounced in the Ang II group. Diastolic dysfunction, a characteristic of the Ang II group, was alleviated by ANP. Additionally, ANP significantly reduced Ang II-induced atrial fibrosis, myofibroblast proliferation, collagen overexpression, macrophage infiltration, and the elevated expression of Interleukin 6 (IL-6) and Tenascin-C (TN-C). Transcriptomic sequencing indicated enhanced PI3K/Akt signaling in the Ang II group. Furthermore, in vitro studies showed that ANP, along with the PI3K inhibitor LY294002, effectively reduced PI3K/Akt pathway activation and the expression of TN-C, collagen-I, and collagen-III, which were induced by Ang II. Conclusions The study demonstrates ANP’s potential in inhibiting myocardial inflammation and reducing atrial fibrosis. Notably, ANP’s effect in countering atrial fibrosis seems to be mediated through the suppression of the Ang II-induced PI3K/Akt-Tenascin-C signaling pathway. These insights enhance our understanding of AF pathogenesis and position ANP as a potential therapeutic agent for treating atrial fibrosis.