Atrial fibrillation (AF) is a common disease and is effectively managed through catheter ablation (CA). However, post-ablation AF recurrence can compromise patient outcomes, making the identification of associated risk factors crucially important. Factors influencing poor clinical outcomes include age, female sex, body mass index (BMI), non-paroxysmal AF, and comorbidities including diabetes mellitus (DM) and obstructive sleep apnea (OSA). Furthermore, the selected ablation strategy and employed technology are pivotal to long-term success in maintaining sinus rhythm control. The mechanisms of AF recurrence are complex and multifactorial; no single predictor is definitive. Thus, a personalized assessment of each patient should be tailored to the individual situation. A high risk of relapse does not preclude the option of ablation therapy, but rather underscores the necessity to address and manage underlying conditions contributing to AF pathogenesis, aiming to mitigate the risk of recurrence.

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.

Atrial fibrosis is an important component of the arrhythmic substrate in AF. Evidence suggests that atrial fibrosis also plays a role in increasing the risk of stroke in patients with the arrhythmia. Patients with embolic stroke of undetermined source (ESUS), who are suspected to have AF but are rarely shown to have it, frequently demonstrate evidence of atrial fibrosis; measured using late-gadolinium enhancement MRI, this manifests as atrial remodelling encompassing structural, functional and electrical properties. In this review, the authors discuss the available evidence linking atrial disease, including fibrosis, with the risk of ischaemic stroke in AF, as well as in the ESUS population, in whom it has been linked to recurrent stroke and new-onset AF. They also discuss the implications of this association on future research that may elucidate the mechanism of stroke and stroke prevention strategies in the AF and ESUS populations.

The involvement of fibrosis as an underlying pathology in heart diseases is becoming increasingly clear. In recent years, fibrosis has been granted a causative role in heart diseases and is now emerging as a major contributor to Atrial Fibrillation (AF) pathogenesis. AF is the most common arrhythmia encountered in the clinic, but the substrate for AF is still being debated. Consensus in the field is a combination of cardiac tissue remodeling, inflammation and genetic predisposition. The extracellular matrix (ECM) is subject of growing investigation, since measuring circulatory biomarkers of ECM formation and degradation provides both diagnostic and prognostic information. However, fibrosis is not just fibrosis. Each specific collagen biomarker holds information on regulatory mechanisms, as well as information about which section of the ECM is being remodeled, providing a detailed description of cardiac tissue homeostasis. This review entails an overview of the implication of fibrosis in AF, the different collagens and their significance, and the potential of using biomarkers of ECM remodeling as tools for understanding AF pathogenesis and identifying patients at risk for further disease progression.

The cellular and molecular mechanism involved in the pathogenesis of atrial fibrosis are highly complex. We have reviewed the literature that covers the effectors, signal transduction and physiopathogenesis concerning extracellular matrix (ECM) dysregulation and atrial fibrosis in atrial fibrillation (AF). At the molecular level: angiotensin II, transforming growth factor-β1, inflammation, and oxidative stress are particularly important for ECM dysregulation and atrial fibrotic remodelling in AF. We conclude that the Ang-II-MAPK and TGF-β1-Smad signalling pathways play a major, central role in regulating atrial fibrotic remodelling in AF. The above signalling pathways induce the expression of genes encoding profibrotic molecules (MMP, CTGF, TGF-β1). An important mechanism is also the generation of reactive oxygen species. This pathway induced by the interaction of Ang II with the ATR receptor and the activation of NADPH oxidase. Additionally, the interplay between cardiac MMPs and their endogenous tissue inhibitors of MMPs, is thought to be critical in atrial ECM metabolism and fibrosis. We also review recent evidence about the role of changes in the miRNAs expression in AF pathophysiology and their potential as therapeutic targets. Furthermore, keeping the balance between miRNA molecules exerting anti-/profibrotic effects is of key importance for the control of atrial fibrosis in AF.

The understanding of atrial fibrillation (AF) evolved from a sole rhythm disturbance towards the complex concept of a cardiomyopathy based on arrhythmia substrates. There is evidence that atrial fibrosis can be visualized using late gadolinium enhancement cardiac magnetic resonance imaging and that it is a powerful predictor for the outcome of AF interventions. However, a strategy of an individual and fibrosis guided management of AF looks promising but results from prospective multicentre trials are pending. This review gives an overview about the relationship between cardiac fibrosis and AF focusing on translational aspects, clinical observations, and fibrosis imaging to emphasize the concept of personalized paths in AF management taking into account the individual amount and distribution of fibrosis.

Atrial fibrillation (AF), the most commonly diagnosed arrhythmia, affects a notable percentage of the population and constitutes a major risk factor for thromboembolic events and other heart-related conditions. Fibrosis plays an important role in the onset and perpetuation of AF through structural and electrical remodelling processes. Multiple molecular pathways are involved in atrial substrate modification and the subsequent maintenance of AF. In this review, we aim to recapitulate underlying molecular pathways leading to atrial fibrosis and to indicate existing gaps in the complex interplay of atrial fibrosis and AF.

Atrial fibrillation (AF), the commonest arrhythmia, shows associations with various disease conditions. Mounting evidence indicates that atrial fibrosis is an important part of the arrhythmogenic substrate, with an essential function in the generation of conduction abnormalities that underlie the transition from paroxysmal to persistent AF, which in turn contributes to AF perpetuation. Left atrial (LA) fibrosis is considered a possible major factor and predictor in AF treatment. The present review provides insights into LA fibrosis' association with AF. The information is focused on clinical aspects and mechanisms, clinical evaluating methods that evaluate fibrosis changes and examining possible options for the prevention of atrial fibrosis.

Rhythm control of atrial fibrillation (AF) remains challenging, with modest long-term success rates. Atrial fibrosis has been associated with AF, but the clinical utility of assessment of this fibrosis has yet to be fully elucidated. In this paper we review the current state of understanding of the pathophysiology of atrial fibrosis in AF, and its impact upon the instigation and propagation of the arrhythmia. Fibrosis causes an increase in volume of dysfunctional extracellular matrix, and is associated with cellular alterations such as hypertrophy, apoptosis and membrane dysfunction within the atrial myocardium. In turn, these cause pathological alterations to atrial conduction, such as increased anisotropy, conduction block and re-entry, which can lead to AF. We review current methods of assessing atrial fibrosis and their impact upon the prediction of success of interventional rhythm control strategies such as ablation and cardioversion. We focus particularly on circulating biomarkers of fibrosis and scar formation; their role in the fibrotic process, and their value in the prediction of rhythm control success. We also review imaging and invasive electrocardiographic mapping techniques that may identify fibrosis, and again assess their potential predictive value. In this area there exist many unanswered questions, but further work will help to refine techniques to reliably identify and treat those patients who are most likely to benefit from rhythm control treatment strategies.

INTRODUCTION:Atrial Fibrillation (AF) is associated with remodeling of the atrial tissue, which leads to fibrosis that can contribute to the initiation and maintenance of AF. Delayed- Enhanced Cardiac Magnetic Resonance (DE-CMR) imaging for atrial wall fibrosis detection was used in several studies to guide AF ablation. The aim of present study was to systematically review the literature on the role of atrial fibrosis detected by DE-CMR imaging on AF ablation outcome. METHODS:Eight bibliographic electronic databases were searched to identify all published relevant studies until 21st of March, 2016. Search of the scientific literature was performed for studies describing DE-CMR imaging on atrial fibrosis in AF patients underwent Pulmonary Vein Isolation (PVI). RESULTS:Of the 763 citations reviewed for eligibility, 5 articles (enrolling a total of 1040 patients) were included into the final analysis. The overall recurrence of AF ranged from 24.4 - 40.9% with median follow-up of 324 to 540 days after PVI. With less than 5-10% fibrosis in the atrial wall there was a maximum of 10% recurrence of AF after ablation. With more than 35% fibrosis in the atrial wall there was 86% recurrence of AF after ablation. CONCLUSION:Our analysis suggests that more extensive left atrial wall fibrosis prior ablation predicts the higher arrhythmia recurrence rate after PVI. The DE-CMR imaging modality seems to be a useful method for identifying the ideal candidate for catheter ablation. Our findings encourage wider usage of DE-CMR in distinct AF patients in a pre-ablation setting.

Importance:Ablation of persistent atrial fibrillation (AF) remains a challenge. Left atrial fibrosis plays an important role in the pathophysiology of AF and has been associated with poor procedural outcomes. Objective:To investigate the efficacy and adverse events of targeting atrial fibrosis detected on magnetic resonance imaging (MRI) in reducing atrial arrhythmia recurrence in persistent AF. Design, Setting, and Participants:The Efficacy of Delayed Enhancement-MRI-Guided Fibrosis Ablation vs Conventional Catheter Ablation of Atrial Fibrillation trial was an investigator-initiated, multicenter, randomized clinical trial involving 44 academic and nonacademic centers in 10 countries. A total of 843 patients with symptomatic or asymptomatic persistent AF and undergoing AF ablation were enrolled from July 2016 to January 2020, with follow-up through February 19, 2021. Interventions:Patients with persistent AF were randomly assigned to pulmonary vein isolation (PVI) plus MRI-guided atrial fibrosis ablation (421 patients) or PVI alone (422 patients). Delayed-enhancement MRI was performed in both groups before the ablation procedure to assess baseline atrial fibrosis and at 3 months postablation to assess for ablation scar. Main Outcomes and Measures:The primary end point was time to first atrial arrhythmia recurrence after a 90-day blanking period postablation. The primary safety composite outcome was defined by the occurrence of 1 or more of the following events within 30 days postablation: stroke, PV stenosis, bleeding, heart failure, or death. Results:Among 843 patients who were randomized (mean age 62.7 years; 178 [21.1%] women), 815 (96.9%) completed the 90-day blanking period and contributed to the efficacy analyses. There was no significant difference in atrial arrhythmia recurrence between groups (fibrosis-guided ablation plus PVI patients, 175 [43.0%] vs PVI-only patients, 188 [46.1%]; hazard ratio [HR], 0.95 [95% CI, 0.77-1.17]; P = .63). Patients in the fibrosis-guided ablation plus PVI group experienced a higher rate of safety outcomes (9 [2.2%] vs 0 in PVI group; P = .001). Six patients (1.5%) in the fibrosis-guided ablation plus PVI group had an ischemic stroke compared with none in PVI-only group. Two deaths occurred in the fibrosis-guided ablation plus PVI group, and the first one was possibly related to the procedure. Conclusions and Relevance:Among patients with persistent AF, MRI-guided fibrosis ablation plus PVI, compared with PVI catheter ablation only, resulted in no significant difference in atrial arrhythmia recurrence. Findings do not support the use of MRI-guided fibrosis ablation for the treatment of persistent AF. Trial Registration:ClinicalTrials.gov Identifier: NCT02529319.

Atrial fibrillation (AF) is commonly associated with congestive heart failure (CHF), and CHF has been shown to be associated with atrial structural remodeling resulting in fibrosis. Atrial interstitial fibrosis has been seen in patients with CHF and in animal models of pacing-induced heart failure. With atrial fibrosis, conduction abnormalities result in increased AF vulnerability. The mechanism of AF associated with CHF is under debate, as both focal and reentrant mechanisms have been observed in animal models of CHF. However, recent studies using frequency-domain analysis have shown that the AF within this model is characterized by discrete, stable, high-frequency areas. The precise signaling processes involved in the development of atrial fibrosis are unknown. Angiotensin appears to play a role, as inhibition of angiotensin-converting enzyme (or angiotensin-receptor blocker) blunts atrial fibrosis in animal models of heart failure and decreases the incidence of AF in patients with heart failure. Transforming growth factor-beta (TGF-beta) also appears to play an important role. Mouse models that overexpress TGF-beta1 have profound atrial fibrosis and AF (with normal ventricles). Heart failure in canine models also produces increases in atrial TGF-beta1 expression, and inhibition of this expression prevents atrial fibrosis and the development of a substrate for AF. Atrial fibrosis appears to play a role in the development of a vulnerable substrate for AF, especially in the setting of CHF.

High fibroblast growth factor 23 (FGF23) concentrations are a strong predictor of atrial fibrillation (AF), but researchers have not clearly determined the mechanism by which FGF23 causes atrial fibrosis in patients with AF. This study aims to elucidate the mechanism by which FGF23 induces atrial fibrosis in patients with AF. Immunohistochemistry was used to study the expression of FGF23, FGFR4, and fibrotic factors in patients with a normal sinus rhythm (SR) and patients with AF. Cardiac fibroblasts (CFs) were cocultured with different concentrations of the recombinant FGF23 protein. Compared with the SR group, the levels of FGF23, FGFR4, α-smooth muscle actin (α-SMA), and collagen-1 were significantly increased in the AF group. Exposure to high concentrations of the recombinant FGF23 protein increased the accumulation of reactive oxygen species (ROS) and activated α-SMA, collagen-1, signal transducer and activator of transcription 3 (STAT3) and SMAD3 signaling in cultured CFs. The levels of fibrotic proteins in CFs stimulated with high concentrations of the recombinant FGF23 protein were reversed by N-acetylcysteine (NAC, a ROS inhibitor), ship information system 3 (a SMAD3 inhibitor), and Stattic (a STAT3 inhibitor). Furthermore, compared to untreated CFs, CFs treated with the recombinant FGF23 protein were characterized by an increased interaction between STAT3 and SMAD3. Based on these results, FGF23 induces atrial fibrosis in patients with AF by increasing ROS production and subsequently activating STAT3 and SMAD3 signaling.

OBJECTIVES:The aim of this study was to define the population-based familial clustering of atrial fibrillation (AF) that is associated with fibrosis and describe evidence for a heritable predisposition. BACKGROUND:Although a heritable contribution to AF is well-established and the association of fibrosis with AF is well-recognized, no studies have analyzed the genetic contribution to AF co-occurring with fibrosis. METHODS:AF patients with magnetic resonance imaging-confirmed fibrosis were identified in a population-based health sciences center database linked to a Utah genealogy. Familial clustering of AF/fibrosis was defined by analysis of pairwise case relatedness, estimation of relative risk of AF/fibrosis in relatives, and identification of high-risk AF/fibrosis pedigrees. RESULTS:The 694 individuals identified with AF/fibrosis who had at least 3 generations of genealogy data were found to have significantly elevated pairwise relatedness (p < 0.001), even when first- and second-degree relationships were ignored (p < 0.001). Significantly elevated risks for AF/fibrosis among first- (relative risk [RR]: 4.65), second- (RR: 3.14), and third-degree (RR: 2.70) relatives of individuals with AF/fibrosis were observed. We identified 157 extended Utah pedigrees with a significant excess of AF/fibrosis among descendants. CONCLUSIONS:There is a strong heritable contribution to predisposition to AF co-occurring with fibrosis. We suggest that this study provides a unique foundation for a search for predisposition genes, specifically for AF co-occurring with fibrosis.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice. The pathogenesis of AF is linked to inflammatory reaction and oxidative stress, which leads to fibrosis of the atria and progression of the disease. The purpose of this study was to define the role of several biomarkers of inflammation, fibrosis, and oxidative stress (OxS). We included 75 patients with paroxysmal/persistent AF, who were admitted for electrical cardioversion or pulmonary vein isolation (PVI). High-sensitivity C-reactive protein (hsCRP), galectin-3 (Gal-3), myeloperoxidase (MPO), oxidized low-density lipoprotein (oxLDL), and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured before the procedures. We compared the results with those of 75 healthy age-, sex-, and blood pressure-matched individuals. The patients were followed up for 1 year after the intervention to establish the recurrence of AF and its association with the measured markers. Patients with AF had higher MPO (52.6 vs. 36.2 ng/ml, < 0.001) and NT-proBNP (209.0 vs. 28.0 pg/ml, < 0.001) compared to healthy subjects. Also, they showed significantly higher levels of hsCRP (1.5 vs. 1.1 mg/l, = 0.001) and Gal-3 (11.4 vs. 9.7 mg/l, = 0.003), while there was no difference found in oxLDL (71.5 vs. 71.7 U/l, = 0.449). MPO (OR = 1.012, = 0.014), hsCRP (OR = 1.265, = 0.026), and weight (OR = 1.029, = 0.013) were independently associated with AF in a multivariable logistic regression analysis. Patients with successful maintenance of sinus rhythm (SR) for one year had lower baseline MPO (40.5 vs. 84.3 ng/ml, = 0.005) and NT-proBNP (127.5 vs. 694.0 pg/ml, < 0.001) compared to patients with recurrent AF episodes, but there was no difference in hsCRP, Gal-3, or oxLDL between them. MPO (OR = 0.985, = 0.010) was independently associated with AF recurrence during the follow-up period when adjusted for cofounders. Patients with AF had increased markers of inflammation and fibrosis, while there was no increase detected in the OxS marker oxLDL. MPO was independently associated with AF in a multivariate model. Inflammatory and fibrotic mechanisms are important factors in electrical and structural remodelling progress in the atria of patients with AF.

Excessive atrial fibrosis is involved in the pathogenesis of atrial fibrillation (AF), but little is known of left ventricular (LV) fibrotic status in patients with AF. In the present study, we investigated the presence of abnormal LV fibrosis in AF, its effect on cardiac function, a possible association with arterial stiffness (i.e., systemic cardiovascular fibrosis), and the parameters of endothelial activation, dysfunction, and damage. We also studied whether LV fibrosis could be linked to the future risk of AF onset. In a cross-sectional study, the severity of LV fibrosis was assessed by echocardiographic acoustic densitometry in patients with permanent AF (n = 49), patients with paroxysmal AF (n = 44), AF-free "disease controls" (n = 42) and "healthy controls" (n = 48). Arterial stiffness (pulse wave velocity), plasma markers of endothelial activation (E-selectin), endothelial damage/dysfunction (von Willebrand factors), and microvascular endothelial function (laser Doppler flowmetry) were quantified. In a longitudinal study, 93 patients with pacemakers (22 with AF) were followed up for ≥1 year to assess the predictive value of LV fibrosis for the development of new-onset AF. More severe LV fibrosis was present in both paroxysmal and permanent AF than in the AF-free controls (p <0.001), with more LV fibrosis in permanent than in paroxysmal AF (p = 0.002). The severity of LV fibrosis in AF wais independently associated with diastolic dysfunction (p = 0.03), but not with LV contractility, arterial stiffness, or endothelial damage/dysfunction. In conclusion, LV fibrosis might contribute to LV diastolic dysfunction and the high prevalence of heart failure with preserved ejection fraction in subjects with AF.

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.

Healthy aging results in cardiac structural and electrical remodeling that increase susceptibility to cardiovascular diseases. Relaxin has shown broad cardioprotective effects including anti-fibrotic, anti-arrhythmic and anti-inflammatory outcomes in multiple models. This paper focuses on the cardioprotective effects of Relaxin in a rat model of aging. Sustained atrial or ventricular fibrillation are readily induced in the hearts of aged but not young control animals. Treatment with Relaxin suppressed this arrhythmogenic response by increasing conduction velocity, decreasing fibrosis and promoting substantial cardiac remodeling. Relaxin treatment resulted in a significant increase in the levels of: Nav1.5, Cx43, βcatenin and Wnt1 in rat hearts. In isolated cardiomyocytes, Relaxin increased Nav1.5 expression. These effects were mimicked by CHIR 99021, a pharmacological activator of canonical Wnt signaling, but blocked by the canonical Wnt inhibitor Dickkopf1. Relaxin prevented TGF-β-dependent differentiation of cardiac fibroblasts into myofibroblasts while increasing the expression of Wnt1; the effects of Relaxin on cardiac fibroblast differentiation were blocked by Dickkopf1. RNASeq studies demonstrated reduced expression of pro-inflammatory cytokines and an increase in the expression of α- and β-globin in Relaxin-treated aged males. Relaxin reduces arrhythmogenicity in the hearts of aged rats by reduction of fibrosis and increased conduction velocity. These changes are accompanied by substantial remodeling of the cardiac tissue and appear to be mediated by increased canonical Wnt signaling. Relaxin also exerts significant anti-inflammatory and anti-oxidant effects in the hearts of aged rodents. The mechanisms by which Relaxin increases the expression of Wnt ligands, promotes Wnt signaling and reprograms gene expression remain to be determined.

Atrial fibrillation (AF) is the most commonly encountered cardiac arrhythmia in clinical practice. However, current therapeutic interventions for atrial fibrillation have limited clinical efficacy as a consequence of major knowledge gaps in the mechanisms sustaining atrial fibrillation. From a mechanistic perspective, there is increasing evidence that atrial fibrosis plays a central role in the maintenance and perpetuation of atrial fibrillation. Electrophysiologically, atrial fibrosis results in alterations in conduction velocity, cellular refractoriness, and produces conduction block promoting meandering, unstable wavelets and micro-reentrant circuits. Clinically, atrial fibrosis has also linked to poor clinical outcomes including AF-related thromboembolic complications and arrhythmia recurrences post catheter ablation. In this article, we review the pathophysiology behind the formation of fibrosis as AF progresses, the role of fibrosis in arrhythmogenesis, surrogate markers for detection of fibrosis using cardiac magnetic resonance imaging, echocardiography and electroanatomic mapping, along with their respective limitations. We then proceed to review the current evidence behind therapeutic interventions targeting atrial fibrosis, including drugs and substrate-based catheter ablation therapies followed by the potential future use of electro phenotyping for AF characterization to overcome the limitations of contemporary substrate-based methodologies.

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.

IMPORTANCE:Left atrial fibrosis is prominent in patients with atrial fibrillation (AF). Extensive atrial tissue fibrosis identified by delayed enhancement magnetic resonance imaging (MRI) has been associated with poor outcomes of AF catheter ablation. OBJECTIVE:To characterize the feasibility of atrial tissue fibrosis estimation by delayed enhancement MRI and its association with subsequent AF ablation outcome. DESIGN, SETTING, AND PARTICIPANTS:Multicenter, prospective, observational cohort study of patients diagnosed with paroxysmal and persistent AF (undergoing their first catheter ablation) conducted between August 2010 and August 2011 at 15 centers in the United States, Europe, and Australia. Delayed enhancement MRI images were obtained up to 30 days before ablation. MAIN OUTCOMES AND MEASURES:Fibrosis quantification was performed at a core laboratory blinded to the participating center, ablation approach, and procedure outcome. Fibrosis blinded to the treating physicians was categorized as stage 1 (<10% of the atrial wall), 2 (≥10%-<20%), 3 (≥20%-<30%), and 4 (≥30%). Patients were followed up for recurrent arrhythmia per current guidelines using electrocardiography or ambulatory monitor recording and results were analyzed at a core laboratory. Cumulative incidence of recurrence was estimated by stage at days 325 and 475 after a 90-day blanking period (standard time allowed for arrhythmias related to ablation-induced inflammation to subside) and the risk of recurrence was estimated (adjusting for 10 demographic and clinical covariates). RESULTS:Atrial tissue fibrosis estimation by delayed enhancement MRI was successfully quantified in 272 of 329 enrolled patients (57 patients [17%] were excluded due to poor MRI quality). There were 260 patients who were followed up after the blanking period (mean [SD] age of 59.1 [10.7] years, 31.5% female, 64.6% with paroxysmal AF). For recurrent arrhythmia, the unadjusted overall hazard ratio per 1% increase in left atrial fibrosis was 1.06 (95% CI, 1.03-1.08; P < .001). Estimated unadjusted cumulative incidence of recurrent arrhythmia by day 325 for stage 1 fibrosis was 15.3% (95% CI, 7.6%-29.6%); stage 2, 32.6% (95% CI, 24.3%-42.9%); stage 3, 45.9% (95% CI, 35.5%-57.5%); and stage 4, 51.1% (95% CI, 32.8%-72.2%) and by day 475 was 15.3% (95% CI, 7.6%-29.6%), 35.8% (95% CI, 26.2%-47.6%), 45.9% (95% CI, 35.6%-57.5%), and 69.4% (95% CI, 48.6%-87.7%), respectively. Similar results were obtained after covariate adjustment. The addition of fibrosis to a recurrence prediction model that includes traditional clinical covariates resulted in an improved predictive accuracy with the C statistic increasing from 0.65 to 0.69 (risk difference of 0.05; 95% CI, 0.01-0.09). CONCLUSIONS AND RELEVANCE:Among patients with AF undergoing catheter ablation, atrial tissue fibrosis estimated by delayed enhancement MRI was independently associated with likelihood of recurrent arrhythmia. The clinical implications of this association warrant further investigation.

Inflammation and fibrosis have been implicated in the pathophysiology of atrial fibrillation. Atrial fibrosis causes conduction disturbances and is a central component of atrial remodeling in atrial fibrillation. Cardiac fibroblasts, the cells responsible for fibrosis formation, are activated by inflammatory mediators and growth factors associated with systemic inflammatory conditions. Thus, inflammation contributes to atrial fibrosis; the complex interplay of these maladaptive components creates a vicious cycle of atrial remodeling progression, maintaining atrial fibrillation and increasing thrombogenicity. This review provides up-to-date knowledge regarding inflammation and fibrosis in atrial fibrillation pathophysiology and their potential as therapeutic targets.

The current paradigm of stroke risk assessment and mitigation in patients with atrial fibrillation (AF) is centred around clinical risk factors which, in the presence of AF, lead to thrombus formation. The mechanisms by which these clinical risk factors lead to thromboembolism, including any role played by atrial fibrosis, are not understood. In patients who had embolic stroke of undetermined source (ESUS), the problem is compounded by the absence of AF in a majority of patients despite long-term monitoring. Atrial fibrosis has emerged as a unifying mechanism that independently provides a substrate for arrhythmia and thrombus formation. Fibrosis-based computational models of AF initiation and maintenance promise to identify therapeutic targets in catheter ablation. In ESUS, fibrosis is also increasingly recognised as a major risk factor, but the underlying mechanism of this correlation is unclear. Simulations have uncovered potential vulnerability to arrhythmia induction in patients who had ESUS. Likewise, computational models of fluid dynamics representing blood flow in the left atrium and left atrium appendage have improved our understanding of thrombus formation, in particular left atrium appendage shapes and blood flow changes influenced by atrial remodelling. Multiscale modelling of blood flow dynamics based on structural fibrotic and morphological changes with associated cellular and tissue electrical remodelling leading to electromechanical abnormalities holds tremendous promise in providing a mechanistic understanding of the clinical problem of thromboembolisation. We present a review of clinical knowledge alongside computational modelling frameworks and conclude with a vision of a future paradigm integrating simulations in formulating personalised treatment plans for each patient.

Atrial fibrillation (AF) is the most common cardiac arrhythmia despite substantial efforts to understand the pathophysiology of the condition and develop improved treatments. Identifying the underlying causative mechanisms of AF in individual patients is difficult and the efficacy of current therapies is suboptimal. Consequently, the incidence of AF is steadily rising and there is a pressing need for novel therapies. Research has revealed that defects in specific molecular pathways underlie AF pathogenesis, resulting in electrical conduction disorders that drive AF. The severity of this so-called electropathology correlates with the stage of AF disease progression and determines the response to AF treatment. Therefore, unravelling the molecular mechanisms underlying electropathology is expected to fuel the development of innovative personalized diagnostic tools and mechanism-based therapies. Moreover, the co-creation of AF studies with patients to implement novel diagnostic tools and therapies is a prerequisite for successful personalized AF management. Currently, various treatment modalities targeting AF-related electropathology, including lifestyle changes, pharmaceutical and nutraceutical therapy, substrate-based ablative therapy, and neuromodulation, are available to maintain sinus rhythm and might offer a novel holistic strategy to treat AF.

Atrial fibrillation (AF) is the most frequent arrhythmia managed in clinical practice, and it is linked to an increased risk of death, stroke, and peripheral embolism. The Global Burden of Disease shows that the estimated prevalence of AF is up to 33.5 million patients. So far, successful therapeutic techniques have been implemented, with a high health-care cost burden. As a result, identifying modifiable risk factors for AF and suitable preventive measures may play a significant role in enhancing community health and lowering health-care system expenditures. Several mechanisms, including electrical and structural remodeling of atrial tissue, have been proposed to contribute to the development of AF. This review article discusses the predisposing factors in AF including the different pathogenic mechanisms, sedentary lifestyle, and dietary habits, as well as the potential genetic burden.

Importance:In the US, approximately 10.55 million adults have atrial fibrillation (AF). AF is associated with significantly increased risk of stroke, heart failure, myocardial infarction, dementia, chronic kidney disease, and mortality. Observations:Symptoms of AF include palpitations, dyspnea, chest pain, presyncope, exertional intolerance, and fatigue, although approximately 10% to 40% of people with AF are asymptomatic. AF can be detected incidentally during clinical encounters, with wearable devices, or through interrogation of cardiac implanted electronic devices. In patients presenting with ischemic stroke without diagnosed AF, an implantable loop recorder (ie, subcutaneous telemetry device) can evaluate patients for intermittent AF. The 2023 American College of Cardiology (ACC)/American Heart Association (AHA)/American College of Clinical Pharmacy (ACCP)/Heart Rhythm Society (HRS) Guideline writing group proposed 4 stages of AF evolution: stage 1, at risk, defined as patients with AF-associated risk factors (eg, obesity, hypertension); stage 2, pre-AF, signs of atrial pathology on electrocardiogram or imaging without AF; stage 3, the presence of paroxysmal (recurrent AF episodes lasting ≤7 days) or persistent (continuous AF episode lasting >7 days) AF subtypes; and stage 4, permanent AF. Lifestyle and risk factor modification, including weight loss and exercise, to prevent AF onset, recurrence, and complications are recommended for all stages. In patients with estimated risk of stroke and thromboembolic events of 2% or greater per year, anticoagulation with a vitamin K antagonist or direct oral anticoagulant reduces stroke risk by 60% to 80% compared with placebo. In most patients, a direct oral anticoagulant, such as apixaban, rivaroxaban, or edoxaban, is recommended over warfarin because of lower bleeding risks. Compared with anticoagulation, aspirin is associated with poorer efficacy and is not recommended for stroke prevention. Early rhythm control with antiarrhythmic drugs or catheter ablation to restore and maintain sinus rhythm is recommended by the 2023 ACC/AHA/ACCP/HRS Guideline for some patients with AF. Catheter ablation is first-line therapy in patients with symptomatic paroxysmal AF to improve symptoms and slow progression to persistent AF. Catheter ablation is also recommended for patients with AF who have heart failure with reduced ejection fraction (HFrEF) to improve quality of life, left ventricular systolic function, and cardiovascular outcomes, such as rates of mortality and heart failure hospitalization. Conclusions and Relevance:AF is associated with increased rates of stroke, heart failure, and mortality. Lifestyle and risk factor modification are recommended to prevent AF onset, recurrence, and complications, and oral anticoagulants are recommended for those with an estimated risk of stroke or thromboembolic events of 2% or greater per year. Early rhythm control using antiarrhythmic drugs or catheter ablation is recommended in select patients with AF experiencing symptomatic paroxysmal AF or HFrEF.

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. Atrial fibrosis has emerged as an important pathophysiological contributor and has been linked to AF recurrences, resistance to therapy and complications. Here, the author reviews the molecular and cellular mechanisms that control atrial fibrosis. It is important to note that not all tissue fibrosis is identical. For example, reactive (interstitial) fibrosis increases the amount of collagen between cardiac muscle bundles without fundamentally altering muscle bundle architecture. Replacement (reparative) fibrosis replaces dead cardiomyocytes with extracellular matrix tissue and fibroblasts, preserving tissue integrity at the expense of muscle bundle continuity. Replacement fibrosis may be much more disruptive to electric conduction and more difficult to reverse than reactive fibrosis. The author reviews the complex signaling systems that cause fibrosis, including those connected to connective tissue growth factor, angiotensin-II, platelet-derived growth factor, and transforming growth factor-β. The author then considers the molecular constitution of fibrous tissue, including the production and maturation of collagen and the roles of important extracellular matrix proteins such as fibronectin, tenascin-C, and thrombospodin-1. The author then discusses the evolving evidence for an important role of Ca entry in the profibrotic activation of fibroblasts, along with evidence that dysregulation of Ca-transporting transient potential receptor channels and inward rectifier K channels in AF fibroblasts is profibrotic. Finally, the author reviews the evidence for micro-ribonucleic acid involvement in atrial fibrotic signaling and AF promotion. It is hoped that an improved understanding of the mechanisms controlling atrial fibrosis will open up new opportunities for AF prevention and management.