The risk factors of Atrial Substrate Remodeling in the Patients of Paroxysmal Atrial Fibrillation following Pulmonary Vein Isolation

The risk factors of Atrial Substrate Remodeling in the Patients of Paroxysmal Atrial Fibrillation following Pulmonary Vein Isolation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The risk factors of Atrial Substrate Remodeling in the Patients of Paroxysmal Atrial Fibrillation following Pulmonary Vein Isolation Ji-Fang Ma, Juan Hu, Hai-Xia Fu, You Zhou, Mu Chen, Peng-Pai Zhang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5778159/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Sep, 2025 Read the published version in BMC Cardiovascular Disorders → Version 1 posted 11 You are reading this latest preprint version Abstract BACKGROUND Atrial substrate remodeling (ASR) was emerged as a critical determinant of very late recurrence (VLR) in paroxysmal atrial fibrillation (PaAF). However, the multifaceted risk factors driving ASR progression and their interplay with clinical outcomes remain incompletely characterized. This study aimed to identify clinical, electrophysiological, and structural risk factors associated with ASR in PaAF patients experiencing VLR after catheter ablation (CA). METHODS A total of 1786 consecutive patients with PaAF who underwent catheter ablation at Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine between May 2006 and July 2023 were screened. Patients with normal atrial substrate at baseline who subsequently experienced recurrent AF were enrolled and categorized into two cohorts: the ASR group (with ASR) and the NASR group (without ASR). A comparative assessment was performed to identify risk factors, encompassing the recurrent type of arrhythmia, CHA2DS2-VASc score, comorbidities, and pulmonary veins-left atrial (PVs-LA) reconnection, between two groups. RESULTS Of 1,786 screened patients, 102 met inclusion criteria (mean age: 61.0±10.0 years; 54% male), with 49 (48%) patients in the ASR group (mean age: 62.1±9.0 years; 45% male) and 53 (52%) in the NASR group (mean age: 61.0±10.0 years; 62% male). The ASR group had a higher CHA2DS2-VASc score, longer recurrence intervals, and a greater prevalence of recurrent persistent AF (PsAF). Notably, recurrent PsAF emerged as an independent risk factor for ASR (HR=2.66, 95%CI=1.05-6.73, P=0.04). Despite the presence of ASR, cardiac function remained preserved in both groups. CONCLUSIONS In PaAF patients with VLR, recurrent persistent AF is an independent risk factor for atrial substrate remodeling. These findings highlight the role of arrhythmia progression in driving structural-electrical remodeling, even in initially normal atrial substrates. Paroxysmal atrial fibrillation atrial substrate catheter ablation recurrence CHA2DS2-VASc score Figures Figure 1 Figure 2 KEY MESSAGES 1. Atrial substrate remodeling significantly contributes to very late PaAF recurrence. 2. The transition from PaAF to PsAF, as a standalone risk factor, accelerates atrial substrate remodeling. BACKGROUND Atrial fibrillation (AF), a growing cardiovascular epidemic in China, imposes substantial healthcare burdens, as previously reported [ 1 ]. Catheter ablation (CA) is a proven effective treatment for paroxysmal atrial fibrillation (PaAF) [ 2 ], however, its long-term efficacy is compromised by increasing recurrence rates during extended follow-up, particularly very late recurrence (VLR). The multifactorial determinants of VLR remain incompletely understood, with complex interactions among clinical, procedural, and substrate-related factors. Atrial substrate remodeling (ASR), a pathophysiological process encompassing both structural (e.g., low-voltage areas, left atrial enlargement) and electrical remodeling, has emerged as a critical predictor of VLR [ 3 – 6 ]. However, the mechanistic contributions of ASR to PaAF-VLR progression remains unclear [ 7 ], particularly regarding dynamic changes in electrical remodeling phenotypes. Additionally, while clinical factors such as obesity, metabolic syndrome, procedural outcomes [ 8 ], CHADS2 score [ 9 ], pericardial adipose tissue [ 10 ], and pulmonary vein-left atrium (PV-LA) reconnection [ 6 ] have been associated with AF-VLR, yet their impact on ASR development remains underinvestigated. Notably, existing studies have primarily focused on either structural or electrical remodeling in isolation, lacking integrative approaches to characterize their combined effects. Furthermore, the functional consequences of ASR on cardiac function remains poorly defined. To address these knowledge gap, we conducted a longitudinal investigation of ASR in PaAF patients with initially normal atrial substrate, specifically focusing on those who developed VLR during redo ablation procedures. The primary objective was to identify ASR-related risk factors associated with VLR in this well-defined patient cohort. METHODS Patient Selection. This is a single-center retrospective study. A total of 1786 consecutive PaAF patients undergoing CA between May 2006 and July 2023 in Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were screened. Patients were included if they had a normal atrial substrate at baseline, from which non-PVs foci was excluded. Normal atrial substrate was diagnosed when no abnormal low-voltage areas (LVA) through High Dynamic Electroanatomical Mapping (HDEM) during sinus rhythm (SR) and/or non-PV triggers under intravenous isoprotenerol infusion was identified. Cardiovert was performed when patients remain AF before mapping. Patients were excluded if they had abnormal atrial substrate and/or additional line ablation. Pulmonary vein isolation (PVI) was the only ablation protocol during first ablation. Those patients with AF/AT recurrence more than 12-month post-CA were enrolled and analyzed. Therefore, all the patients included in our study require a second ablation. Informed consent was obtained, and the study was approved by the hospital’s ethics committee and conformed to the Declaration of Helsinki. Patients were categorized into ASR (with atrial substrate remodeling) and NASR (without atrial substrate remodeling) groups based on ASR analysis criteria detailed in the ASR analysis section. Preoperative and intraoperative Procedures. All antiarrhythmic drugs were discontinued 5 half-lives before the procedure. Anti-coagulation drugs were stopped in the morning. Intracardiac thrombus was excluded via transesophageal echocardiography. A tenth electrode (Johnson Inc., New Jersey, USA) was inserted into the coronary sinus via right femoral vein. Double transseptal access was performed through the right femoral vein. Intravenous heparin was applied intraprocedurally aiming for an activated clotting time of 250–350 seconds. ASR Analysis ASR was defined by two aspects: (1) Structural remodeling (SR):Low-voltage areas (LVAs) were identified through HDEM in both the right atrium (RA) and left atrium (LA). Electrophysiological analysis was performed during sinus rhythm using CARTO XP system (Biosense Webster, 2005–2009) or CARTO3 system (Biosense Webster, 2010–2021), with bipolar voltage thresholds ≤ 0.5 mV defining abnormal regions. LVA exceeding 0.5 cm 2 in surface area were considered indicative of significant SR. To enable regional characterization, the LA was anatomically segmented into five distinct regions: anterior wall, posterior wall, inferior wall, lateral wall, and interatrial septum. (2) Electrical remodeling (ER): Comprehensive electroanatomical mapping revealed the following distribution patterns: The presence of newly identified non-pulmonary vein foci (NPVFs) associated with AF and/or AT recurrence. These arrhythmogenic substrates were localized outside the Pulmonary Veins ostia (PVs), as confirmed by targeted elimination and subsequent arrhythmia non-inducibility during electrophysiological study. Their distribution was mapped in LA (mitral isthmus, roof, anterior wall, left atrial appendage (LAA), small areas with fractionated potential, etc.) and RA (cavo-tricuspid isthmus (CTI), superior vena cave (SVC), right atrial appendage (RAA), crista terminalis, coronary sinus). Mapping procedures were performed using the CARTO 3 System with HDEM (Biosense Webster). Electrical cardioversion was performed to restore sinus rhythm if necessary. Bipolar voltages were recorded at 200 mm/s for analysis. Catheter Ablation Protocol and Follow-up. A 3.5 mm diameter irrigated Thermocool ablation catheter (Biosense Webster Inc.) was utilized for ablation, adhering to a standardized protocol with a temperature cap of 45°C, RF power ranging from 30–40 W, and irrigation flow maintained at 17–30 ml/min. Consistency was maintained across procedures, with power settings, lesion distance (2mm), and ablation time (20-30s) held constant from initial pulmonary vein isolation (PVI) to any subsequent ablation. Recurrent AF/AT was confirmed via 24-hour Holter monitoring, defined as AF/AT episodes lasting over 30 seconds. The time for Holter monitoring was prolonged in persistent AF. Persistent AF was diagnosed with the documentation of sustained AF for at least seven days through continuous Holter test. Very late recurrence (VLR) was categorized as AF/AT recurrence occurring more than 12-month post-CA. All the patients were followed up for every 1 year routinely, or interviewed when they have symptoms associated with AF (chest tightness, palpitation, and so on.) Statistical Analysis. Statistical analysis was conducted using SPSS 23.0. Data normality was assessed using Shapiro-Wilk tests. Normal distributed continuous data were reported as mean ± SD and assessed with Student’s t-test or variance analysis (ANOVA) as appropriate. Baseline between-group differences were evaluated using unpaired t tests. Between-group differences at repeat ablation were analyzed with unpaired t-tests, while repeat ablation between-group differences were similarly assessed. Within-group comparisons from baseline to repeat ablation were performed using paired t -tests. Skewed continuous data were presented as median with IQR (25th -75th percentile) and analyzed using nonparametric tests (Mann-Whitney U or Friedman M). Categorical data were expressed as counts and percentages, analyzed with Chi-square or Fisher’s exact tests. Variables with univariate P < 0.10 were further evaluated in multivariate Cox regression models. Statistical significance was set at p < 0.05. RESULTS Study Population. During a median follow-up period of 4 years, 102 patients undergoing repeat ablation procedures were enrolled, with exclusion criteria detailed in Fig. 1 . The cohort was stratified into an atrial substrate remodeling (ASR) group (n = 49, 48%; mean age: 62.0 ± 9.0 years, 45%male) and non-atrial substrate remodeling (NASR) group (n = 53, 52%; mean age: 61.0 ± 10.0 years, 62%male). Baseline Characteristics and Clinical Parameters. Baseline demographic and clinical characteristics are summarized in Table 1 . The two groups demonstrated comparable distributions of age, gender, body mass index (BMI), smoke, alcohol, combined diseases (hypertension, T2DM, heart failure, etc.), NT-pro-BNP, and average HAS-BLED score. Similarly, anti-arrhythmia medication profiles were similarly balanced between groups, including β-blocker use (55% vs. 59%, P = 0.73), amiodarone (57% vs. 74%, P = 0.08), and propafenone (18% vs. 13%, P = 0.47). Notably, the ASR group exhibited a significantly higher CHA 2 DS 2 -VASc score compared to the NASR group (2.5 ± 1.4 vs. 1.8 ± 1.6, P = 0.02) (Fig. 2 A), suggesting an elevated thromboembolic risk profile. Table 1 Baseline Characteristics of the PaAF Population undergoing repeat ablation procedure Total (n = 102) ASR group (n = 49) NASR group (n = 53) P Value Male (n, %) 55 (54%) 22 (45%) 33 (62%) 0.08 Age (yrs) 61 ± 10 62 ± 9 61 ± 10 0.49 Average BMI (kg/m 2 ) 25.0 ± 2.9 25.4 ± 2.6 24.8 ± 3.2 0.34 Smoke (n, %) 22(22%) 9 (18%) 13 (25%) 0.45 Alcohol (n, %) 22(22%) 12 (25%) 10 (19%) 0.50 Hypertension (n, %) 56(55%) 30 (61%) 26 (49%) 0.22 T2DM (n, %) 21(21%) 10 (20%) 11 (21%) 0.97 HF (n, %) 3(3%) 2 (4%) 1 (2%) 0.61 Average CHA 2 DS 2 -VASc score 2.1 ± 1.5 2.5 ± 1.4 1.8 ± 1.6 0.02 Average HAS-BLED score 1.9 ± 1.3 2.1 ± 1.2 1.7 ± 1.3 0.09 Beta-blocker (n, %) 58(57%) 27 (55%) 31 (59%) 0.73 Amiodarone (n, %) 67(66%) 28 (57%) 39 (74%) 0.08 Propafenone (n, %) 16(16%) 9 (18%) 7 (13%) 0.47 Values are mean ± SD or % or median (25th, 75th ). PaAF = Paroxysmal atrial fibrillation; ASR = Atrial substrate remodeling; NASR = No atrial substrate remodeling; BMI = body mass index; T2DM = Type 2 diabetes mellitus; HF = Heart failure; CHA2DS2-VASc = Congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke, transient ischemic attack, or thromboembolism, vascular disease, age 65–74 years, sex category (female); HAS-BLED score = Hypertension, abnormal renal and liver function, stroke, bleeding, labile INRs, elderly, drugs or alcohol. P value < 0.05 means statistically significant. Recurrence Patterns Post-Ablation. The median time to arrhythmia recurrence following the initial ablation was significantly prolonged in the ASR group (6 years vs. 3 years; P < 0.05; Fig. 2 B) compared to the NASR group, indicating a distinct delayed recurrence phenotype in ASR patients after catheter ablation (CA) . PVs-LA reconnection between ASR and NASR group. During repeat ablation procedures, PVs-LA reconnection was systematically analyzed. In the NASR group, 92 PVs-LA reconnection were identified, with 32 patients (60% of the NASR cohort) exhibiting PV recurrence. The recurrence distribution across individual PVs was as follows: right superior PV (RSPV, 16.3%; 15/92), right inferior PV (RIPV, 21.7%; 20/92), left superior PV (LSPV, 38.0%; 35/92) and left inferior PV (LIPV, 23.9%; 22/92)respectively, with LSPV demonstrating the highest recurrence frequency. In contrast, the ASR group exhibited significantly fewer PVs-LA reconnections compared to the NASR group (16 vs. 92 reconnections, P < 0.001). The recurrence rates for individual PVs in the ASR cohort were RSPV (18.8%; 3/16), RIPV (25.0%; 4/16), LSPV(37.5%; 6/16) and LIPV(18.8%; 3/16), with LSPV remaining the most recurrent PV. Notably, no statistically significant differences were observed in the recurrence rates of individual PVs between the ASR and NASR group (P > 0.05 for all comparisons). Recurrent Arrhythmia Profiles. Recurrent arrhythmias during follow-up were classified into four subtypes: paroxysmal atrial fibrillation (PaAF), persistent atrial fibrillation (PsAF), atrial tachycardia (AT), and combined AF/AT. The ASR group exhibited a significantly higher incidence of PsAF recurrence compared to the NASR group (20% [10/49] vs. 4% [2/53]; P < 0.05). Conversely, the NASR group demonstrated a higher predominance of PaAF recurrence (79% [42/53] vs. 33% [16/49] in the ASR group; P < 0.05). No significant intergroup difference was observed in isolated AT recurrence. However, a higher proportion of ASR patients experienced combined AF/AT recurrence compared to the NASR group(24% [12/49] vs. 9% [5/53]; P < 0.05; Fig. 2 C). Area distribution of ASR. In the ASR cohort (n = 65), all newly identified low-voltage areas (LVAs) were localized to the LA (Fig. 2 F) with no RA involvement. The LA anterior wall demonstrated the highest prevalence of structural remodeling (38.5%, 25/65), followed by the posterior (21.5%, 14/65) and inferior walls (21.5%, 14/65), lateral wall (13.8%, 9/65), and interatrial septum (4.6%,3/65), as depicted in Fig. 2 D. Non-PV foci were identified in 33 cases, with predominant RA distribution (66.7%, 22/33 vs. 33.3%, 11/33 in LA). RA foci clustered at the cavo tricuspid isthmus (CTI, 72.7%, 16/22), with sparse distribution at the right atrial appendage (RAA, 4.5%,1/22), superior vena cava (SVC, 9.1%,2/22), crista terminalis (4.5%,1/22), and RA septum (4.5%,1/22). LA foci primarily localized to the mitral isthmus (63.6%, 7/11), with additional sites at the roof (18.2%, 2/11), left atrial appendage( LAA,9.1%,1/11), and LA septum (9.1%,1/11), as showed in Fig. 2 E. Cardiac function Comparison Between ASR and NASR Cohorts. No intergroup difference was observed in baseline NT-proBNP levels ( P > 0.05), left atrium size (LA1: 38.6 ± 5.3mm vs. 38.5 ± 4.4mm, P = 0.86), and left ventricular ejection fraction (LVEF1: 65.3 ± 6.9% vs. 65.3 ± 4.4%, P = 0.95). Furthermore, at the repeat procedure, no significant difference was found in LA size (LA2: 39.9 ± 6.0 mm vs. 38.1 ± 4.4 mm, P = 0.11) and LVEF (LVEF2: 64.0 ± 5.1% vs. 65.6 ± 4.2%, P = 0.10). Longitudinal analysis revealed no significant changes in LA (△LA = LA2-LA1: 0.4(-3.7,6.5) mm vs. -0.9(-5.6,3.7) mm, P = 0.32) and LVEF (△LVEF = LVEF2-LVEF1: -0.1(-4.2,3.1)% vs. 0(-3,3.6)%, P = 0.50) between the ASR and NASR groups, suggesting that ASR did not impact the changes in LA size or LVEF (Table 2 ). Table 2 Type of recurrent arrhythmia and cardiac structure between ASR group and NASR group Total (n = 102) ASR group (n = 49) NASR group (n = 53) P Value Time interval of recurrence (y) [median(25th ,75th )] 4(3,8) 6.0 (3.0,7.5) 3.0 (1.0,5.0) < 0.001 Recurrent PsAF (n,%) 12(12%) 10(20%) 2(4%) 0.01 NT-proBNP (ng/ml)[median(25th ,75th )] 275(98,801) 248(75,650) 489(180,941) 0.06 LA1 (mm) 38.5 ± 4.9 38.6 ± 5.3 38.5 ± 4.4 0.86 LVEF1 (%) 65.3 ± 5.6 65.3 ± 6.9 65.3 ± 4.4 0.95 LA2 (mm) 39.0 ± 5.2 39.9 ± 6.0 38.1 ± 4.4 0.11 LVEF2 (%) 64.8 ± 4.7 64.0 ± 5.1 65.6 ± 4.2 0.10 △LA [median(25th ,75th )] - 0.4(-3.7,6.5) -0.9(-5.6,3.7) 0.32 △LVEF [median(25th ,75th )] - -0.1(-4.2,3.1) 0(-3,3.6) 0.50 Values are mean ± SD or % or median (25th ,75th ). ASR = Atrial substrate remodeling; NASR = No atrial substrate remodeling; PsAF = Persistent atrial fibrillation; LA = Left atrium; LVEF = Left ventricular ejection fraction;△LA = LA2-LA1; △LVEF = LVEF2-LVEF1. P value < 0.05 means statistically significant. Predictors of ASR in the VLR of PaAF population. The clinical factors associated with ASR are summarized in Table 3 . Cox regression analysis identified recurrent persistent AF (PsAF) as an independent predictor of ASR development: univariate association: HR = 6.54, 95% CI 1.35–31.57, P = 0.02, Multivariate adjustment (HR = 2.66, 95%CI = 1.05–6.73, P = 0.04). (adjusted for age, CHA2DS2-VASc score, and atrial dilatation status). Table 3 Risk factors associated with ASR in the VLR of PaAF population ASR group (n = 49) NASR group (n = 53) Univariate Multivariate HR 95%CI P HR 95%CI P Male (n,%) 22 (44.9%) 33 (62.3%) 2.03 0.92–4.47 0.08 0.75 0.30–1.91 0.55 CHA 2 DS 2 -VASc score > 2 26(53.1%) 17(39.5%) 2.39 1.07–5.35 0.03 2.319 0.79–6.84 0.13 HAS-BLED score > = 2 34(54.8%) 28(45.2%) 2.02 0.90–4.56 0.09 0.511 0.19–1.39 0.19 Recurrent PsAF (n,%) 10(20.0%) 2(4%) 6.54 1.35–31.57 0.02 2.660 1.05–6.73 0.04 NT-proBNP (ng/ml)[median(25th ,75th )] 247.8(75.3,650) 489(179.9,940.9) 1 1.00-1.11 0.63 - - - LA2 > = 40mm 23(46.9%) 13(36.1%) 3.25 0.81–13.05 0.10 1.011 0.44–2.35 0.98 ASR = Atrial substrate remodeling; NASR = No atrial substrate remodeling; CHA2DS2-VASc = Congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke, transient ischemic attack, or thromboembolism, vascular disease, age 65–74 years, sex category (female); HAS-BLED score = Hypertension, abnormal renal and liver function, stroke, bleeding, labile INRs, elderly, drugs or alcohol; PsAF = Persistent atrial fibrillation; LA = Left atrium; Factors with P < 0.10 in the univariate analysis were compared in the multivariate analysis. HR = Hazard Ratio; CI = Confidence Interval. P value < 0.05 means statistically significant. DISCUSSION The objective of our study was to elucidate the risk factors of long-term atrial substrate remodeling in the context of very late recurrence of PaAF. Atrial substrate remodeling and very late recurrence. In the context of AF interventions, ASR, featuring both structural and electrical remodeling, constitutes a critical prognostic determinant in catheter ablation outcomes for AF. While ASR is well-recognized as a principal mechanism underlying late recurrence in PsAF [ 4 ], its role in paroxysmal AF (PaAF) remains clinically significant. Notably, left atrial fibrosis prevalence is substantially higher in PsAF versus PaAF [ 11 ]. Low-voltage areas (LVAs, < 0.5 mV), serving as fibrosis surrogates, predict AF recurrence regardless of AF subtype [ 3 ]. Cardiac Magnetic Resonance Imaging (MRI) studies confirm progression atrial architectural disorganization correlates with worse ablation outcomes [ 5 , 6 ]. LVAs reflect regional discontinuity (CV < 0.3 m/s) and tissue de-coupling within heterogeneous cardiomyocytes bundles, establishing re-entrant substrate [ 2 , 6 ]. Non-pulmonary vein (non-PV) triggers (predominantly CTI/RAA origins) drive very late recurrence (> 5 years post-ablation) in 68% of cases [ 5 – 7 ]. The type of recurrent arrhythmia was different depending on different atrial substrate remodeling. In our study, patients without ASR had more PaAF recurrence, while patients with ASR harbored more AT and AF. Concordantly, our findings align with this understanding, demonstrating that PaAF patients experiencing progression of atrial substrate exhibit a notably prolonger time to recurrence, suggesting a delayed recurrence pattern in those with ASR following CA. Atrial substrate remodeling and PVs-LA electrical reconnection. Post-ablation AF recurrence arises from multifactorial pathophysiological interactions, with two predominant mechanisms: (1) pulmonary vein-left atrial (PV-LA) electrical reconnection and (2) progressive atrial substrate remodeling. While PVs-LA reconnection is established as a pivotal cause of early AF recurrence [ 12 ], its specific role in late recurrence remains uncertain. Intriguingly, patients with vs. without recurrence exhibit comparable PVs-LA reconnection prevalence [ 13 – 16 ]. Notably, we found no notable difference in PVs-LA reconnection between patients experiencing ASR and those without ASR, emphasizing the intricate interplay of diverse mechanisms and necessitating a deeper, multifaceted exploration of the contributors to AF recurrence post-ablation. Atrial substrate remodeling and related risk factors. In our cohort analysis, we identified several established clinical comorbidities associated with AF progression, including gender, age, hypertension, obesity, sleep apnea, left atrial enlargement, and left ventricular dysfunction [ 17 – 19 ]. Aligning with existing literature [ 9 ], ASR patients demonstrated significantly higher CHA2DS2-VASc score, a validated predictor of long-term ablation outcomes, compared to non-ASR counterparts. However, multivariate analysis failed to establish direct correlations between these risk factors and ASR development in PaAF patients. This apparent discrepancy may stem from our study’s statistical constraints, as the modest sample size potentially limited detection of subtle associations. To gain deeper insights into this, larger-scale studies are imperative. Current evidence implicates five-year AF recurrence patterns with LA dilatation, increased ectopic foci, and the progression to PsAF [ 20 ]. The pathophysiological continuum from PaAF to PsAF involves progressive atrial fibrotic remodeling, with histopathological studies demonstrating significantly greater fibrotic burden in PsAF versus PaAF patients [ 11 ]. Falkenberg et al. [ 21 ] particularly emphasized the temporal association between PsAF evolution and atrial substrate deterioration. Our findings corroborate this paradigm, revealing differential recurrence patterns: the ASR group showed predominant PsAF recurrence (n = 10) versus predominantly PaAF recurrence in non-ASR controls (n = 2). Cox proportional hazards modeling identified PsAF recurrence as the sole independent predictor of ASR. This may be attributed to PsAF’s discontinuous fibrillation beats, fostering inflammatory cells infiltration, extracellular matrix synthesis, and ultimately, atrial substrate fibrosis. However, the comparisons (10 vs. 2 PsAF cases) are quite small due to the small sample size in our study. The role of PsAF should be carefully considered in another prospective cohort study with larger sample size. Nevertheless, definitive conclusions are constrained by the limited PsAF cases in our cohort, necessitating validation through prospective multicenter studies. Serial assessment of atrial substrate characteristics becomes crucial when managing patients demonstrating AF progression from paroxysmal to persistent forms. This phenotypic transition not only signifies disease advancement but also underscores the need for aggressive rhythm control strategies to interrupt the "AF begets AF" cycle. Early intervention targeting substrate modification may potentially attenuate fibrotic progression and improve long-term outcomes. Area distribution of atrial substrate progression. Consistent with prior studies [ 22 ], our high-density mapping analysis preferential low-voltage area (LVA) formation in the posterior and anterior LA walls. The anterior LA region demonstrated particular arrhythmogenic susceptibility, with 38.5% of sustained atrial tachycardias originating from this zone. This area’s intricate anatomy, including multiple endocardial/epicardial layers and muscular bridges like the Bachmann's bundle, predispose it to arrhythmogenicity [ 23 ]. These anatomical features likely contribute to the anterior LA’s electrical vulnerability, underscoring the need for targeted therapies focused on this region. Patients with very late AF recurrence often require ablation beyond PV isolation compared to late recurrence [ 16 ]. Prior studies focused SVC, interatrial septum, foramen ovale, and LA posterior wall as prevalent non-PV foci, which might elevate the AF recurrence risk [ 24 ]. Our study identified 33 novel non-PV foci in PaAF patients with very late recurrence, 22 in RA and 11 in LA, predominantly in the cavo-tricuspid isthmus. This underscores the importance of a comprehensive ablation strategy targeting PVs and non-PV foci, especially cavo-tricuspid isthmus, for effective AF recurrence management. Atrial substrate remodeling and cardiac function. The left atrium (LA) plays a pivotal hemodynamic role in ventricular filling, contributing 30% of total cardiac output through its reservoir, conduit, and contractile functions [ 25 ]. In atrial substrate remodeling (ASR), LA mechanical dysfunction manifests as impaired contractile performance, quantified through reduced reservoir and conduit strain parameters. Longitudinal AF progression from paroxysmal (PaAF) to persistent forms correlates with deteriorating LA emptying efficiency and progressive chamber dilatation [ 26 ]. Notably, fibrotic atrial cardiomyopathy (FACM) represents a distinct pathological entity characterized by diffuse interstitial fibrosis, differing fundamentally from the electrical remodeling observed in early PaAF [ 27 ]. Our cohort analysis revealed no significant associations between ASR in NT-proBNP levels, LA size, or LVEF. These findings suggest preserved ventricular systolic function and mitigated heart failure risk in PaAF patients experiencing very late recurrence. This apparent dissociation may arise from the compartmentalized nature of atrial remodeling, where electrical/structural LA alterations occur independently from ventricular functional deterioration - a phenomenon corroborated by clinical reports of maintained LVEF in PaAF patients with advanced atrial substrate abnormalities. LIMITATIONS Our study faces three main limitations. Firstly, changes in catheter technology, systems, and techniques between procedures may have introduced variability. Secondly, periodic follow-up could have delayed arrhythmia recurrence detection, including bias into the data. Thirdly, as a single-center retrospective analysis with a small sample, larger multi-center randomized controlled trials are needed to comprehensively understand atrial substrate remodeling’s real-world impact on AF. Lastly, owing to the relationship that ASR may predispose patients to PsAF, the conclusion of our study should be further evidenced via prospective study with larger sample size. CONCLUSIONS Recurrent PsAF independently increases the risk of atrial substrate remodeling in very late recurrence post-catheter ablation for paroxysmal AF. This highlights the importance of monitoring and managing recurrent PsAF to prevent or minimize remodeling, which can complicate long-term AF management. Declarations 1. Funding: This work was supported from Ji-Fang Ma by The Medical Science and Technology Commission Foundation of Henan Province (Grant numbers [LHGJ20231349]) and from Juan Hu by The Natural Science Foundation of Henan Province (Grant numbers [232300421282]). 2. Authors' contributions: Ji-Fang Ma, Jian Sun, and Yi-Gang Li contributed to conception and design of the study. Ji-Fang Ma, Yi-Chi Yu, Mu Chen organized the database. Juan Hu, You Zhou, and Peng-Pai Zhang performed the statistical analysis. Ji-fang Ma wrote the first draft of the manuscript. Hai-Xia Fu, Qun-Shan Wang wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version. 3. Conflicts of interest/Competing interests ： The authors have no relevant financial or non-financial interests to disclose. 4. Ethics approval and consent to participate: The study was approved by the human ethics committee of Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine.The authors affirm that human research participants provided informed consent for publications. 5. Clinical trial number: not applicable. 6. Data Availability: All data included in this study are available upon request by contact with the corresponding author. References Chen M, Li C, Liao P, et al. Epidemiology, management, and outcomes of atrial fibrillation among 30 million citizens in Shanghai, China from 2015 to 2020: A medical insurance database study. Lancet Reg Health West Pac. 2022;23:100470. doi:10.1016/j.lanwpc.2022.100470. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021;42(5):373-498. doi:10.1093/eurheartj/ehaa612 . Musat DL, Milstein NS, Bhatt A, et al. Incidence and Predictors of Very Late Recurrence of Atrial Fibrillation Following Cryoballoon Pulmonary Vein Isolation. Circ Arrhythm Electrophysiol . 2020;13(9):e008646. doi:10.1161/CIRCEP.120.008646. Sotomi Y, Inoue K, Tanaka K, et al. Persistent left atrial remodeling after catheter ablation for non-paroxysmal atrial fibrillation is associated with very late recurrence. J Cardiol. 2015;66:370–376. doi: 10.1016/j. jjcc.2015.03.007. McGann C, Akoum N, Patel A, et al. Atrial fibrillation ablation outcome is predicted by left atrial remodeling on MRI. Circ Arrhythm Electrophysiol. 2014;7(1):23-30. doi:10.1161/CIRCEP.113.000689. Khurram IM, Habibi M, Gucuk Ipek E, et al. Left Atrial LGE and Arrhythmia Recurrence Following Pulmonary Vein Isolation for Paroxysmal and Persistent AF. JACC Cardiovasc Imaging. 2016;9(2):142-148. doi:10.1016/j.jcmg.2015.10.015. Erhard N, Metzner A, Fink T. Late arrhythmia recurrence after atrial fibrillation ablation: incidence, mechanisms and clinical implications. Herzschrittmacherther Elektrophysiol. 2022;33(1):71-76. doi:10.1007/s00399-021-00836-6. Magnussen C, Niiranen TJ, Ojeda FM, et al. Sex Differences and Similarities in Atrial Fibrillation Epidemiology, Risk Factors, and Mortality in Community Cohorts: Results From the BiomarCaRE Consortium (Biomarker for Cardiovascular Risk Assessment in Europe). Circulation. 2017;136(17):1588-1597. doi:10.1161/CIRCULATIONAHA.117.028981. Jacobs V, May HT, Bair TL, et al. The impact of risk score (CHADS2 versus CHA2DS2-VASc) on long-term outcomes after atrial fibrillation ablation. Heart Rhythm. 2015;12(4):681-686. doi:10.1016/j.hrthm.2014.12.034. Gökoğlan Y, Mohanty S, Güneş MF, Trivedi C, Santangeli P, Gianni C, Asfour IK, Bai R, Burkhardt JD, Horton R, et al. Pulmonary vein antrum isolation in patients with paroxysmal atrial fibrillation: more than a decade of follow-up. Circ Arrhythm Electrophysiol. 2016;9:e003660. DOI: 10.1161/CIRCEP.115.003660. Kim HD, Cho DH, Kim MN, et al. Left Atrial Dysfunction, Fibrosis and the Risk of Thromboembolism in Patients With Paroxysmal and Persistent Atrial Fibrillation. Int J Heart Fail. 2022;4(1):42-53. doi:10.36628/ijhf.2021.0043. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm. 2017;14(10):e275-e444. doi:10.1016/j.hrthm.2017.05.012. Mohanty S, Trivedi C, Horton P, et al. Natural History of Arrhythmia After Successful Isolation of Pulmonary Veins, Left Atrial Posterior Wall, and Superior Vena Cava in Patients With Paroxysmal Atrial Fibrillation: A Multi-Center Experience. J Am Heart Assoc . 2021;10(11):e020563. doi:10.1161/JAHA.120.020563. Farrell M, Yoneda Z, Montgomery J, et al. Non-pulmonary vein mediated atrial fibrillation: a novel sub-phenotype. PLoS One. 2017;12:e0184354. DOI: 10.1371/journal.pone.0184354. Nery PB, Belliveau D, Nair GM, Bernick J, Redpath CJ, Szczotka A, Sadek MM, Green MS, Wells G, Birnie DH. Relationship between pulmonary vein reconnection and atrial fibrillation recurrence: a systematic review and meta-analysis. JACC Clin Electrophysiol. 2016;2:474–483. DOI: 10.1016/j.jacep.2016.02.003. Sotomi Y, Inoue K, Ito N, et al. Cause of very late recurrence of atrial fibrillation or flutter after catheter ablation for atrial fibrillation. Am J Cardiol. 2013;111(4):552-556. doi:10.1016/j.amjcard.2012.10.040. De Maat GE, Mulder BA, Berretty WL, et al. Obesity is associated with impaired long-term success of pulmonary vein isolation: a plea for risk factor management before ablation. Open Heart. 2018;5(1):e000771. doi:10.1136/openhrt-2017-000771. Pathak RK, Middeldorp ME, Lau DH, et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. J Am Coll Cardiol. 2014;64(21):2222-2231. doi:10.1016/j.jacc.2014.09.028. Onishi N, Kaitani K, Amano M, et al. Relationship between left ventricular diastolic dysfunction and very late recurrences after multiple procedures for atrial fibrillation ablation. Heart Vessels. 2018;33(1):41-48. doi:10.1007/s00380-017-1027-y. Tzou WS, Marchlinski FE, Zado ES, et al. Long-term outcome after successful catheter ablation of atrial fibrillation. Circ Arrhythm Electrophysiol. 2010;3(3):237-242. doi:10.1161/CIRCEP.109.923771. Falkenberg M, Ford AJ, Li AC, et al. Unified mechanism of local drivers in a percolation model of atrial fibrillation. Phys Rev E. 2019;100(6-1):062406. doi:10.1103/PhysRevE.100.062406 Wong GR, Nalliah CJ, Lee G, et al. Dynamic Atrial Substrate During High-Density Mapping of Paroxysmal and Persistent AF: Implications for Substrate Ablation. JACC Clin Electrophysiol . 2019;5(11):1265-1277. doi:10.1016/j.jacep.2019.06.002. de Groot N, van der Does L, Yaksh A, et al. Direct Proof of Endo-Epicardial Asynchrony of the Atrial Wall During Atrial Fibrillation in Humans. Circ Arrhythm Electrophysiol. 2016;9(5):e003648. doi:10.1161/CIRCEP.115.003648. Takigawa M, Takahashi A, Kuwahara T, et al. Impact of Non-Pulmonary Vein Foci on the Outcome of the Second Session of Catheter Ablation for Paroxysmal Atrial Fibrillation. J Cardiovasc Electrophysiol. 2015;26(7):739-746. doi:10.1111/jce.12681. Badano LP, Kolias TJ, Muraru D, et al. Standardization of left atrial, right ventricular, and right atrial deformation imaging using two-dimensional speckle tracking echocardiography: a consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging [published correction appears in Eur Heart J Cardiovasc Imaging. 2018 Jul 1;19(7):830-833]. Eur Heart J Cardiovasc Imaging. 2018;19(6):591-600. doi:10.1093/ehjci/jey042 Peters DC, Duncan JS, Grunseich K, et al. CMR-Verified Lower LA Strain in the Presence of Regional Atrial Fibrosis in Atrial Fibrillation. JACC Cardiovasc Imaging . 2017;10(2):207-208. doi:10.1016/j.jcmg.2016.01.015 Goette A, Kalman JM, Aguinaga L, et al. EHRA/HRS/APHRS/SOLAECE expert consensus on Atrial cardiomyopathies: Definition, characterisation, and clinical implication. J Arrhythm . 2016;32(4):247-278. doi:10.1016/j.joa.2016.05.002 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 24 Sep, 2025 Read the published version in BMC Cardiovascular Disorders → Version 1 posted Editorial decision: Revision requested 16 Apr, 2025 Editor assigned by journal 16 Apr, 2025 Reviews received at journal 14 Apr, 2025 Reviewers agreed at journal 09 Apr, 2025 Reviews received at journal 07 Apr, 2025 Reviewers agreed at journal 07 Apr, 2025 Reviewers agreed at journal 07 Apr, 2025 Reviewers agreed at journal 07 Apr, 2025 Reviewers invited by journal 07 Apr, 2025 Submission checks completed at journal 07 Apr, 2025 First submitted to journal 07 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5778159","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":439835788,"identity":"f083590f-2363-48c7-9411-55b61ac474cf","order_by":0,"name":"Ji-Fang Ma","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ji-Fang","middleName":"","lastName":"Ma","suffix":""},{"id":439835789,"identity":"5156ca0b-d7d2-4340-a144-f6f7eabdc84d","order_by":1,"name":"Juan Hu","email":"","orcid":"","institution":"Fuwai Central China Cardiovascular Hospital","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Hu","suffix":""},{"id":439835790,"identity":"fb1322c9-3bd9-4626-9a51-111b85fed2a6","order_by":2,"name":"Hai-Xia Fu","email":"","orcid":"","institution":"Fuwai Central China Cardiovascular Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hai-Xia","middleName":"","lastName":"Fu","suffix":""},{"id":439835792,"identity":"8d1989f0-e8f0-435a-91c2-1cb74a706a5b","order_by":3,"name":"You Zhou","email":"","orcid":"","institution":"Fuwai Central China Cardiovascular Hospital","correspondingAuthor":false,"prefix":"","firstName":"You","middleName":"","lastName":"Zhou","suffix":""},{"id":439835794,"identity":"66d4995c-0d9d-4b01-a2e1-a61d79488b8e","order_by":4,"name":"Mu Chen","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Mu","middleName":"","lastName":"Chen","suffix":""},{"id":439835795,"identity":"6ecc87ea-c3a1-4ec1-a775-af4b218d65a4","order_by":5,"name":"Peng-Pai Zhang","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Peng-Pai","middleName":"","lastName":"Zhang","suffix":""},{"id":439835797,"identity":"6cdab015-17bb-4e46-9826-96ef22aedac8","order_by":6,"name":"Yi-Chi Yu","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yi-Chi","middleName":"","lastName":"Yu","suffix":""},{"id":439835798,"identity":"69c90502-130d-4567-b5db-79772081feb4","order_by":7,"name":"Qun-Shan Wang","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Qun-Shan","middleName":"","lastName":"Wang","suffix":""},{"id":439835800,"identity":"a176a4d5-eda2-4078-95ed-c822fb2c728a","order_by":8,"name":"Jian Sun","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIiWNgGAWjYJACgwQGBjkGZgY2CPcAkVqMSdMCAokNDMRqkZ+Re6DgQc2d9A3HeY895qnZJsd3gPnhoxsMdnk4HXUjL8Eg4diz3JnNfOnGPMduG0seYDM2zmFILsapRSLHwCCB7XBuPzOPmTQP2+3EDQd42KRzGA6AnIrDYSAt/w6ns4G1/LtdT1ALww2glsS2wwn8IC28bbcTDAhpMTjzBqil77DhzGYeM8m5fbcNZx4G+cUgGbfD2nPMDH98OyxvcP6MmcSbb7fl+Y43P3ycU2GH22HA6DBA5TODbcetHqTkAV7pUTAKRsEoGAUAyoRUOIHIcCEAAAAASUVORK5CYII=","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Jian","middleName":"","lastName":"Sun","suffix":""},{"id":439835804,"identity":"caa4b416-5efc-4148-9a6b-2eb27ac5db76","order_by":9,"name":"Yi-Gang Li","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yi-Gang","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2025-01-07 05:53:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5778159/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5778159/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12872-025-04809-2","type":"published","date":"2025-09-24T15:57:39+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":80285323,"identity":"116fc4f2-285e-4e90-b5ad-ad7467b57767","added_by":"auto","created_at":"2025-04-10 06:39:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":99950,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe protocol and flow of our study\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5778159/v1/13af84ea1aae2c7aa877d988.png"},{"id":80284303,"identity":"6da38acc-90d5-4730-9322-e27f89c430e6","added_by":"auto","created_at":"2025-04-10 06:31:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":141827,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e. Patients in ASR group had significantly higher average CHA\u003csub\u003e2\u003c/sub\u003eDS\u003csub\u003e2\u003c/sub\u003e-VASc score than that in NASR group. \u003cstrong\u003eB\u003c/strong\u003e. PaAF patients with atrial substrate remodeling (ASR group) had longer time interval post 1\u003csup\u003est\u003c/sup\u003e CPVI ablation than NASR group (P\u0026lt;0.001) via violin plot. \u003cstrong\u003eC.\u003c/strong\u003e The recurrent type of arrhythmia made no significant difference between ASR group and NASR group. PaAF was the most common type of recurrent arrhythmia post 1\u003csup\u003est\u003c/sup\u003e ablation procedure. \u003cstrong\u003eD\u003c/strong\u003e. The distribution of abnormal atrial substrate areas in ASR group. \u003cstrong\u003eE\u003c/strong\u003e. The distribution of non-pulmonary foci of RA and LA in ASR group. \u003cstrong\u003eF\u003c/strong\u003e. A representative figure of low voltage area (bipolar voltage \u0026lt;0.5 mV, tagged by yellow circle) locating at the LA posterior wall on CARTO system. ASR=Atrial Substrate Remodeling; NASR= No Atrial Substrate Remodeling; PaAF = paroxysmal atrial fibrillation; PsAF = persistent atrial fibrillation; AT= Atrial tachycardia; LA=Left atrium; CTI=Cavo tricuspid isthmus; RA=Right atrium; LAA=Left atrial appendage; SVC=Superior vena cava; RAA=Right atrial appendage. P value\u0026lt;0.05 means significant difference by arterisk.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5778159/v1/6e5e8b4d6129ce14c4466c7f.png"},{"id":92430624,"identity":"1e9b7fca-0347-414d-9f29-3dd48870fad8","added_by":"auto","created_at":"2025-09-29 16:06:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1186969,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5778159/v1/24839e72-2cee-41f0-935b-4bf4d08ceac1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The risk factors of Atrial Substrate Remodeling in the Patients of Paroxysmal Atrial Fibrillation following Pulmonary Vein Isolation","fulltext":[{"header":"KEY MESSAGES","content":"\u003cp\u003e1. Atrial substrate remodeling significantly contributes to very late PaAF recurrence.\u003c/p\u003e\n\u003cp\u003e2. The transition from PaAF to PsAF, as a standalone risk factor, accelerates atrial substrate remodeling.\u003c/p\u003e"},{"header":"BACKGROUND","content":"\u003cp\u003eAtrial fibrillation (AF), a growing cardiovascular epidemic in China, imposes substantial healthcare burdens, as previously reported [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Catheter ablation (CA) is a proven effective treatment for paroxysmal atrial fibrillation (PaAF) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], however, its long-term efficacy is compromised by increasing recurrence rates during extended follow-up, particularly very late recurrence (VLR). The multifactorial determinants of VLR remain incompletely understood, with complex interactions among clinical, procedural, and substrate-related factors. Atrial substrate remodeling (ASR), a pathophysiological process encompassing both structural (e.g., low-voltage areas, left atrial enlargement) and electrical remodeling, has emerged as a critical predictor of VLR [\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, the mechanistic contributions of ASR to PaAF-VLR progression remains unclear [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], particularly regarding dynamic changes in electrical remodeling phenotypes. Additionally, while clinical factors such as obesity, metabolic syndrome, procedural outcomes [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], CHADS2 score [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], pericardial adipose tissue [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], and pulmonary vein-left atrium (PV-LA) reconnection [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] have been associated with AF-VLR, yet their impact on ASR development remains underinvestigated.\u003c/p\u003e \u003cp\u003eNotably, existing studies have primarily focused on either structural or electrical remodeling in isolation, lacking integrative approaches to characterize their combined effects. Furthermore, the functional consequences of ASR on cardiac function remains poorly defined. To address these knowledge gap, we conducted a longitudinal investigation of ASR in PaAF patients with initially normal atrial substrate, specifically focusing on those who developed VLR during redo ablation procedures. The primary objective was to identify ASR-related risk factors associated with VLR in this well-defined patient cohort.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e \u003cb\u003ePatient Selection.\u003c/b\u003e This is a single-center retrospective study. A total of 1786 consecutive PaAF patients undergoing CA between May 2006 and July 2023 in Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were screened. Patients were included if they had a normal atrial substrate at baseline, from which non-PVs foci was excluded. Normal atrial substrate was diagnosed when no abnormal low-voltage areas (LVA) through High Dynamic Electroanatomical Mapping (HDEM) during sinus rhythm (SR) and/or non-PV triggers under intravenous isoprotenerol infusion was identified. Cardiovert was performed when patients remain AF before mapping. Patients were excluded if they had abnormal atrial substrate and/or additional line ablation. Pulmonary vein isolation (PVI) was the only ablation protocol during first ablation. Those patients with AF/AT recurrence more than 12-month post-CA were enrolled and analyzed. Therefore, all the patients included in our study require a second ablation. Informed consent was obtained, and the study was approved by the hospital\u0026rsquo;s ethics committee and conformed to the Declaration of Helsinki. Patients were categorized into ASR (with atrial substrate remodeling) and NASR (without atrial substrate remodeling) groups based on ASR analysis criteria detailed in the ASR analysis section.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePreoperative and intraoperative Procedures.\u003c/b\u003e All antiarrhythmic drugs were discontinued 5 half-lives before the procedure. Anti-coagulation drugs were stopped in the morning. Intracardiac thrombus was excluded via transesophageal echocardiography. A tenth electrode (Johnson Inc., New Jersey, USA) was inserted into the coronary sinus via right femoral vein. Double transseptal access was performed through the right femoral vein. Intravenous heparin was applied intraprocedurally aiming for an activated clotting time of 250\u0026ndash;350 seconds.\u003c/p\u003e \u003cp\u003e \u003cb\u003eASR Analysis\u003c/b\u003e ASR was defined by two aspects:\u003c/p\u003e \u003cp\u003e(1) Structural remodeling (SR):Low-voltage areas (LVAs) were identified through HDEM in both the right atrium (RA) and left atrium (LA). Electrophysiological analysis was performed during sinus rhythm using CARTO XP system (Biosense Webster, 2005\u0026ndash;2009) or CARTO3 system (Biosense Webster, 2010\u0026ndash;2021), with bipolar voltage thresholds\u0026thinsp;\u0026le;\u0026thinsp;0.5 mV defining abnormal regions. LVA exceeding 0.5 cm\u003csup\u003e2\u003c/sup\u003e in surface area were considered indicative of significant SR. To enable regional characterization, the LA was anatomically segmented into five distinct regions: anterior wall, posterior wall, inferior wall, lateral wall, and interatrial septum.\u003c/p\u003e \u003cp\u003e(2) Electrical remodeling (ER): Comprehensive electroanatomical mapping revealed the following distribution patterns: The presence of newly identified non-pulmonary vein foci (NPVFs) associated with AF and/or AT recurrence. These arrhythmogenic substrates were localized outside the Pulmonary Veins ostia (PVs), as confirmed by targeted elimination and subsequent arrhythmia non-inducibility during electrophysiological study. Their distribution was mapped in LA (mitral isthmus, roof, anterior wall, left atrial appendage (LAA), small areas with fractionated potential, etc.) and RA (cavo-tricuspid isthmus (CTI), superior vena cave (SVC), right atrial appendage (RAA), crista terminalis, coronary sinus). Mapping procedures were performed using the CARTO 3 System with HDEM (Biosense Webster). Electrical cardioversion was performed to restore sinus rhythm if necessary. Bipolar voltages were recorded at 200 mm/s for analysis.\u003c/p\u003e \u003cp\u003e \u003cb\u003eCatheter Ablation Protocol and Follow-up.\u003c/b\u003e A 3.5 mm diameter irrigated Thermocool ablation catheter (Biosense Webster Inc.) was utilized for ablation, adhering to a standardized protocol with a temperature cap of 45\u0026deg;C, RF power ranging from 30\u0026ndash;40 W, and irrigation flow maintained at 17\u0026ndash;30 ml/min. Consistency was maintained across procedures, with power settings, lesion distance (2mm), and ablation time (20-30s) held constant from initial pulmonary vein isolation (PVI) to any subsequent ablation. Recurrent AF/AT was confirmed via 24-hour Holter monitoring, defined as AF/AT episodes lasting over 30 seconds. The time for Holter monitoring was prolonged in persistent AF. Persistent AF was diagnosed with the documentation of sustained AF for at least seven days through continuous Holter test.\u003c/p\u003e \u003cp\u003eVery late recurrence (VLR) was categorized as AF/AT recurrence occurring more than 12-month post-CA. All the patients were followed up for every 1 year routinely, or interviewed when they have symptoms associated with AF (chest tightness, palpitation, and so on.)\u003c/p\u003e \u003cp\u003e \u003cb\u003eStatistical Analysis.\u003c/b\u003e Statistical analysis was conducted using SPSS 23.0. Data normality was assessed using Shapiro-Wilk tests. Normal distributed continuous data were reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD and assessed with Student\u0026rsquo;s t-test or variance analysis (ANOVA) as appropriate. Baseline between-group differences were evaluated using unpaired t tests. Between-group differences at repeat ablation were analyzed with unpaired t-tests, while repeat ablation between-group differences were similarly assessed. Within-group comparisons from baseline to repeat ablation were performed using paired \u003cem\u003et\u003c/em\u003e-tests. Skewed continuous data were presented as median with IQR (25th -75th percentile) and analyzed using nonparametric tests (Mann-Whitney U or Friedman M). Categorical data were expressed as counts and percentages, analyzed with Chi-square or Fisher\u0026rsquo;s exact tests. Variables with univariate P\u0026thinsp;\u0026lt;\u0026thinsp;0.10 were further evaluated in multivariate Cox regression models. Statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e \u003cb\u003eStudy Population.\u003c/b\u003e During a median follow-up period of 4 years, 102 patients undergoing repeat ablation procedures were enrolled, with exclusion criteria detailed in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The cohort was stratified into an atrial substrate remodeling (ASR) group (n\u0026thinsp;=\u0026thinsp;49, 48%; mean age: 62.0\u0026thinsp;\u0026plusmn;\u0026thinsp;9.0 years, 45%male) and non-atrial substrate remodeling (NASR) group (n\u0026thinsp;=\u0026thinsp;53, 52%; mean age: 61.0\u0026thinsp;\u0026plusmn;\u0026thinsp;10.0 years, 62%male).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eBaseline Characteristics and Clinical Parameters.\u003c/b\u003e Baseline demographic and clinical characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The two groups demonstrated comparable distributions of age, gender, body mass index (BMI), smoke, alcohol, combined diseases (hypertension, T2DM, heart failure, etc.), NT-pro-BNP, and average HAS-BLED score. Similarly, anti-arrhythmia medication profiles were similarly balanced between groups, including β-blocker use (55% vs. 59%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.73), amiodarone (57% vs. 74%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.08), and propafenone (18% vs. 13%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.47). Notably, the ASR group exhibited a significantly higher CHA\u003csub\u003e2\u003c/sub\u003eDS\u003csub\u003e2\u003c/sub\u003e-VASc score compared to the NASR group (2.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4 vs. 1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA), suggesting an elevated thromboembolic risk profile.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Characteristics of the PaAF Population undergoing repeat ablation procedure\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;102)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eASR group (n\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNASR group (n\u0026thinsp;=\u0026thinsp;53)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 (54%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (45%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33 (62%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (yrs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAverage BMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoke (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22(22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (18%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlcohol (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22(22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (19%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56(55%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (61%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (49%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2DM (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21(21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHF (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3(3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.61\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAverage CHA\u003csub\u003e2\u003c/sub\u003eDS\u003csub\u003e2\u003c/sub\u003e-VASc score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAverage HAS-BLED score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBeta-blocker (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58(57%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (55%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31 (59%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmiodarone (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67(66%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (57%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39 (74%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePropafenone (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16(16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (18%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eValues are mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or % or median (25th, 75th ). PaAF\u0026thinsp;=\u0026thinsp;Paroxysmal atrial fibrillation; ASR\u0026thinsp;=\u0026thinsp;Atrial substrate remodeling; NASR\u0026thinsp;=\u0026thinsp;No atrial substrate remodeling; BMI\u0026nbsp;=\u0026nbsp;body mass index; T2DM\u0026nbsp;= Type 2 diabetes mellitus; HF\u0026nbsp;= Heart failure; CHA2DS2-VASc =\u0026nbsp;Congestive heart failure, hypertension, age\u0026nbsp;\u0026ge;75 years, diabetes mellitus, prior stroke,\u0026nbsp;transient ischemic attack, or\u0026nbsp;thromboembolism, vascular disease, age 65\u0026ndash;74 years, sex category (female); HAS-BLED score\u0026thinsp;=\u0026thinsp;Hypertension, abnormal renal and liver function, stroke, bleeding, labile INRs, elderly, drugs or alcohol. P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 means statistically significant.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eRecurrence Patterns Post-Ablation.\u003c/b\u003e The median time to arrhythmia recurrence following the initial ablation was significantly prolonged in the ASR group (6 years vs. 3 years; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB) compared to the NASR group, indicating a distinct delayed recurrence phenotype in ASR patients after catheter ablation (CA) .\u003c/p\u003e \u003cp\u003e \u003cb\u003ePVs-LA reconnection between ASR and NASR group.\u003c/b\u003e During repeat ablation procedures, PVs-LA reconnection was systematically analyzed. In the NASR group, 92 PVs-LA reconnection were identified, with 32 patients (60% of the NASR cohort) exhibiting PV recurrence. The recurrence distribution across individual PVs was as follows: right superior PV (RSPV, 16.3%; 15/92), right inferior PV (RIPV, 21.7%; 20/92), left superior PV (LSPV, 38.0%; 35/92) and left inferior PV (LIPV, 23.9%; 22/92)respectively, with LSPV demonstrating the highest recurrence frequency.\u003c/p\u003e \u003cp\u003eIn contrast, the ASR group exhibited significantly fewer PVs-LA reconnections compared to the NASR group (16 vs. 92 reconnections, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The recurrence rates for individual PVs in the ASR cohort were RSPV (18.8%; 3/16), RIPV (25.0%; 4/16), LSPV(37.5%; 6/16) and LIPV(18.8%; 3/16), with LSPV remaining the most recurrent PV. Notably, no statistically significant differences were observed in the recurrence rates of individual PVs between the ASR and NASR group (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all comparisons).\u003c/p\u003e \u003cp\u003e \u003cb\u003eRecurrent Arrhythmia Profiles.\u003c/b\u003e Recurrent arrhythmias during follow-up were classified into four subtypes: paroxysmal atrial fibrillation (PaAF), persistent atrial fibrillation (PsAF), atrial tachycardia (AT), and combined AF/AT. The ASR group exhibited a significantly higher incidence of PsAF recurrence compared to the NASR group (20% [10/49] vs. 4% [2/53]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Conversely, the NASR group demonstrated a higher predominance of PaAF recurrence (79% [42/53] vs. 33% [16/49] in the ASR group; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). No significant intergroup difference was observed in isolated AT recurrence. However, a higher proportion of ASR patients experienced combined AF/AT recurrence compared to the NASR group(24% [12/49] vs. 9% [5/53]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003e \u003cb\u003eArea distribution of ASR.\u003c/b\u003e In the ASR cohort (n\u0026thinsp;=\u0026thinsp;65), all newly identified low-voltage areas (LVAs) were localized to the LA (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF) with no RA involvement. The LA anterior wall demonstrated the highest prevalence of structural remodeling (38.5%, 25/65), followed by the posterior (21.5%, 14/65) and inferior walls (21.5%, 14/65), lateral wall (13.8%, 9/65), and interatrial septum (4.6%,3/65), as depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD.\u003c/p\u003e \u003cp\u003eNon-PV foci were identified in 33 cases, with predominant RA distribution (66.7%, 22/33 vs. 33.3%, 11/33 in LA). RA foci clustered at the cavo tricuspid isthmus (CTI, 72.7%, 16/22), with sparse distribution at the right atrial appendage (RAA, 4.5%,1/22), superior vena cava (SVC, 9.1%,2/22), crista terminalis (4.5%,1/22), and RA septum (4.5%,1/22). LA foci primarily localized to the mitral isthmus (63.6%, 7/11), with additional sites at the roof (18.2%, 2/11), left atrial appendage( LAA,9.1%,1/11), and LA septum (9.1%,1/11), as showed in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE.\u003c/p\u003e \u003cp\u003e \u003cb\u003eCardiac function Comparison Between ASR and NASR Cohorts.\u003c/b\u003e No intergroup difference was observed in baseline NT-proBNP levels (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05), left atrium size (LA1: 38.6\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3mm vs. 38.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4mm, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.86), and left ventricular ejection fraction (LVEF1: 65.3\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9% vs. 65.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.95). Furthermore, at the repeat procedure, no significant difference was found in LA size (LA2: 39.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.0 mm vs. 38.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4 mm, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.11) and LVEF (LVEF2: 64.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1% vs. 65.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.10). Longitudinal analysis revealed no significant changes in LA (△LA\u0026thinsp;=\u0026thinsp;LA2-LA1: 0.4(-3.7,6.5) mm vs. -0.9(-5.6,3.7) mm, P\u0026thinsp;=\u0026thinsp;0.32) and LVEF (△LVEF\u0026thinsp;=\u0026thinsp;LVEF2-LVEF1: -0.1(-4.2,3.1)% vs. 0(-3,3.6)%, P\u0026thinsp;=\u0026thinsp;0.50) between the ASR and NASR groups, suggesting that ASR did not impact the changes in LA size or LVEF (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eType of recurrent arrhythmia and cardiac structure between ASR group and NASR group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;102)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eASR group (n\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNASR group (n\u0026thinsp;=\u0026thinsp;53)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eTime interval of recurrence (y) [median(25th ,75th )]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(3,8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.0 (3.0,7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.0 (1.0,5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eRecurrent PsAF (n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12(12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10(20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2(4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNT-proBNP (ng/ml)[median(25th ,75th )]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e275(98,801)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e248(75,650)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e489(180,941)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eLA1 (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38.6\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e38.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eLVEF1 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.3\u0026thinsp;\u0026plusmn;\u0026thinsp;5.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65.3\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e65.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eLA2 (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e38.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eLVEF2 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e64.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e65.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e△LA [median(25th ,75th )]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.4(-3.7,6.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.9(-5.6,3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e△LVEF [median(25th ,75th )]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.1(-4.2,3.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0(-3,3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eValues are mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or % or median (25th ,75th ). ASR\u0026thinsp;=\u0026thinsp;Atrial substrate remodeling; NASR\u0026thinsp;=\u0026thinsp;No atrial substrate remodeling; PsAF\u0026nbsp;=\u0026nbsp;Persistent atrial fibrillation; LA\u0026nbsp;=\u0026nbsp;Left atrium; LVEF\u0026nbsp;=\u0026nbsp;Left ventricular ejection fraction;△LA\u0026nbsp;=\u0026nbsp;LA2-LA1; △LVEF\u0026thinsp;=\u0026thinsp;LVEF2-LVEF1.\u0026nbsp;P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 means statistically significant.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003ePredictors of ASR in the VLR of PaAF population.\u003c/b\u003e The clinical factors associated with ASR are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Cox regression analysis identified recurrent persistent AF (PsAF) as an independent predictor of ASR development: univariate association: HR\u0026thinsp;=\u0026thinsp;6.54, 95% CI 1.35\u0026ndash;31.57, P\u0026thinsp;=\u0026thinsp;0.02, Multivariate adjustment (HR\u0026thinsp;=\u0026thinsp;2.66, 95%CI\u0026thinsp;=\u0026thinsp;1.05\u0026ndash;6.73, P\u0026thinsp;=\u0026thinsp;0.04). (adjusted for age, CHA2DS2-VASc score, and atrial dilatation status).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRisk factors associated with ASR in the VLR of PaAF population\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eASR group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNASR group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;53)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95%CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e95%CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale (n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (44.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (62.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.92\u0026ndash;4.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.30\u0026ndash;1.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCHA\u003csub\u003e2\u003c/sub\u003eDS\u003csub\u003e2\u003c/sub\u003e-VASc score\u0026thinsp;\u0026gt;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26(53.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17(39.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.07\u0026ndash;5.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.319\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.79\u0026ndash;6.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHAS-BLED score\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34(54.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28(45.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.90\u0026ndash;4.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.511\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.19\u0026ndash;1.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrent PsAF (n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10(20.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.35\u0026ndash;31.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.660\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.05\u0026ndash;6.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNT-proBNP (ng/ml)[median(25th ,75th )]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e247.8(75.3,650)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e489(179.9,940.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.00-1.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLA2\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;40mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23(46.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13(36.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.81\u0026ndash;13.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.44\u0026ndash;2.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e \u003cp\u003eASR\u0026thinsp;=\u0026thinsp;Atrial substrate remodeling; NASR\u0026thinsp;=\u0026thinsp;No atrial substrate remodeling; CHA2DS2-VASc =\u0026nbsp;Congestive heart failure, hypertension, age\u0026nbsp;\u0026ge;75 years, diabetes mellitus, prior stroke,\u0026nbsp;transient ischemic attack, or\u0026nbsp;thromboembolism, vascular disease, age 65\u0026ndash;74 years, sex category (female); HAS-BLED score\u0026thinsp;=\u0026thinsp;Hypertension, abnormal renal and liver function, stroke, bleeding, labile INRs, elderly, drugs or alcohol; PsAF\u0026nbsp;=\u0026nbsp;Persistent atrial fibrillation; LA\u0026nbsp;=\u0026nbsp;Left atrium; Factors with P\u0026thinsp;\u0026lt;\u0026thinsp;0.10 in the univariate analysis were compared in the multivariate analysis. HR\u0026thinsp;=\u0026thinsp;Hazard Ratio; CI\u0026thinsp;=\u0026thinsp;Confidence Interval.\u0026nbsp;P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 means statistically significant.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe objective of our study was to elucidate the risk factors of long-term atrial substrate remodeling in the context of very late recurrence of PaAF.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAtrial substrate remodeling and very late recurrence.\u003c/b\u003e In the context of AF interventions, ASR, featuring both structural and electrical remodeling, constitutes a critical prognostic determinant in catheter ablation outcomes for AF. While ASR is well-recognized as a principal mechanism underlying late recurrence in PsAF [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], its role in paroxysmal AF (PaAF) remains clinically significant. Notably, left atrial fibrosis prevalence is substantially higher in PsAF versus PaAF [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Low-voltage areas (LVAs, \u0026lt;\u0026thinsp;0.5 mV), serving as fibrosis surrogates, predict AF recurrence regardless of AF subtype [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Cardiac Magnetic Resonance Imaging (MRI) studies confirm progression atrial architectural disorganization correlates with worse ablation outcomes [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. LVAs reflect regional discontinuity (CV\u0026thinsp;\u0026lt;\u0026thinsp;0.3 m/s) and tissue de-coupling within heterogeneous cardiomyocytes bundles, establishing re-entrant substrate [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Non-pulmonary vein (non-PV) triggers (predominantly CTI/RAA origins) drive very late recurrence (\u0026gt;\u0026thinsp;5 years post-ablation) in 68% of cases [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The type of recurrent arrhythmia was different depending on different atrial substrate remodeling. In our study, patients without ASR had more PaAF recurrence, while patients with ASR harbored more AT and AF.\u003c/p\u003e \u003cp\u003eConcordantly, our findings align with this understanding, demonstrating that PaAF patients experiencing progression of atrial substrate exhibit a notably prolonger time to recurrence, suggesting a delayed recurrence pattern in those with ASR following CA.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAtrial substrate remodeling and PVs-LA electrical reconnection.\u003c/b\u003e Post-ablation AF recurrence arises from multifactorial pathophysiological interactions, with two predominant mechanisms: (1) pulmonary vein-left atrial (PV-LA) electrical reconnection and (2) progressive atrial substrate remodeling. While PVs-LA reconnection is established as a pivotal cause of early AF recurrence [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], its specific role in late recurrence remains uncertain. Intriguingly, patients with vs. without recurrence exhibit comparable PVs-LA reconnection prevalence [\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNotably, we found no notable difference in PVs-LA reconnection between patients experiencing ASR and those without ASR, emphasizing the intricate interplay of diverse mechanisms and necessitating a deeper, multifaceted exploration of the contributors to AF recurrence post-ablation.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAtrial substrate remodeling and related risk factors.\u003c/b\u003e In our cohort analysis, we identified several established clinical comorbidities associated with AF progression, including gender, age, hypertension, obesity, sleep apnea, left atrial enlargement, and left ventricular dysfunction [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Aligning with existing literature [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], ASR patients demonstrated significantly higher CHA2DS2-VASc score, a validated predictor of long-term ablation outcomes, compared to non-ASR counterparts. However, multivariate analysis failed to establish direct correlations between these risk factors and ASR development in PaAF patients. This apparent discrepancy may stem from our study\u0026rsquo;s statistical constraints, as the modest sample size potentially limited detection of subtle associations. To gain deeper insights into this, larger-scale studies are imperative.\u003c/p\u003e \u003cp\u003eCurrent evidence implicates five-year AF recurrence patterns with LA dilatation, increased ectopic foci, and the progression to PsAF [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The pathophysiological continuum from PaAF to PsAF involves progressive atrial fibrotic remodeling, with histopathological studies demonstrating significantly greater fibrotic burden in PsAF versus PaAF patients [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Falkenberg et al. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] particularly emphasized the temporal association between PsAF evolution and atrial substrate deterioration. Our findings corroborate this paradigm, revealing differential recurrence patterns: the ASR group showed predominant PsAF recurrence (n\u0026thinsp;=\u0026thinsp;10) versus predominantly PaAF recurrence in non-ASR controls (n\u0026thinsp;=\u0026thinsp;2). Cox proportional hazards modeling identified PsAF recurrence as the sole independent predictor of ASR. This may be attributed to PsAF\u0026rsquo;s discontinuous fibrillation beats, fostering inflammatory cells infiltration, extracellular matrix synthesis, and ultimately, atrial substrate fibrosis. However, the comparisons (10 vs. 2 PsAF cases) are quite small due to the small sample size in our study. The role of PsAF should be carefully considered in another prospective cohort study with larger sample size. Nevertheless, definitive conclusions are constrained by the limited PsAF cases in our cohort, necessitating validation through prospective multicenter studies.\u003c/p\u003e \u003cp\u003eSerial assessment of atrial substrate characteristics becomes crucial when managing patients demonstrating AF progression from paroxysmal to persistent forms. This phenotypic transition not only signifies disease advancement but also underscores the need for aggressive rhythm control strategies to interrupt the \"AF begets AF\" cycle. Early intervention targeting substrate modification may potentially attenuate fibrotic progression and improve long-term outcomes.\u003c/p\u003e \u003cp\u003e \u003cb\u003eArea distribution of atrial substrate progression.\u003c/b\u003e Consistent with prior studies [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], our high-density mapping analysis preferential low-voltage area (LVA) formation in the posterior and anterior LA walls. The anterior LA region demonstrated particular arrhythmogenic susceptibility, with 38.5% of sustained atrial tachycardias originating from this zone. This area\u0026rsquo;s intricate anatomy, including multiple endocardial/epicardial layers and muscular bridges like the Bachmann's bundle, predispose it to arrhythmogenicity [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. These anatomical features likely contribute to the anterior LA\u0026rsquo;s electrical vulnerability, underscoring the need for targeted therapies focused on this region.\u003c/p\u003e \u003cp\u003ePatients with very late AF recurrence often require ablation beyond PV isolation compared to late recurrence [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Prior studies focused SVC, interatrial septum, foramen ovale, and LA posterior wall as prevalent non-PV foci, which might elevate the AF recurrence risk [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Our study identified 33 novel non-PV foci in PaAF patients with very late recurrence, 22 in RA and 11 in LA, predominantly in the cavo-tricuspid isthmus. This underscores the importance of a comprehensive ablation strategy targeting PVs and non-PV foci, especially cavo-tricuspid isthmus, for effective AF recurrence management.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAtrial substrate remodeling and cardiac function.\u003c/b\u003e The left atrium (LA) plays a pivotal hemodynamic role in ventricular filling, contributing 30% of total cardiac output through its reservoir, conduit, and contractile functions [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In atrial substrate remodeling (ASR), LA mechanical dysfunction manifests as impaired contractile performance, quantified through reduced reservoir and conduit strain parameters. Longitudinal AF progression from paroxysmal (PaAF) to persistent forms correlates with deteriorating LA emptying efficiency and progressive chamber dilatation [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Notably, fibrotic atrial cardiomyopathy (FACM) represents a distinct pathological entity characterized by diffuse interstitial fibrosis, differing fundamentally from the electrical remodeling observed in early PaAF [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur cohort analysis revealed no significant associations between ASR in NT-proBNP levels, LA size, or LVEF. These findings suggest preserved ventricular systolic function and mitigated heart failure risk in PaAF patients experiencing very late recurrence. This apparent dissociation may arise from the compartmentalized nature of atrial remodeling, where electrical/structural LA alterations occur independently from ventricular functional deterioration - a phenomenon corroborated by clinical reports of maintained LVEF in PaAF patients with advanced atrial substrate abnormalities.\u003c/p\u003e"},{"header":"LIMITATIONS","content":"\u003cp\u003eOur study faces three main limitations. Firstly, changes in catheter technology, systems, and techniques between procedures may have introduced variability. Secondly, periodic follow-up could have delayed arrhythmia recurrence detection, including bias into the data. Thirdly, as a single-center retrospective analysis with a small sample, larger multi-center randomized controlled trials are needed to comprehensively understand atrial substrate remodeling\u0026rsquo;s real-world impact on AF. Lastly, owing to the relationship that ASR may predispose patients to PsAF, the conclusion of our study should be further evidenced via prospective study with larger sample size.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eRecurrent PsAF independently increases the risk of atrial substrate remodeling in very late recurrence post-catheter ablation for paroxysmal AF. This highlights the importance of monitoring and managing recurrent PsAF to prevent or minimize remodeling, which can complicate long-term AF management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e1. Funding:\u003c/strong\u003e This work was supported from Ji-Fang Ma by The Medical Science and Technology Commission Foundation of Henan Province (Grant numbers [LHGJ20231349]) and from Juan Hu by The Natural Science Foundation of Henan Province (Grant numbers [232300421282]).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. Authors' contributions:\u0026nbsp;\u003c/strong\u003eJi-Fang Ma, Jian Sun, and Yi-Gang Li contributed to conception and design of the study. Ji-Fang Ma, Yi-Chi Yu, Mu Chen organized the database. Juan Hu, You Zhou, and Peng-Pai Zhang performed the statistical analysis. Ji-fang Ma wrote the first draft of the manuscript. Hai-Xia Fu, Qun-Shan Wang wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Conflicts of interest/Competing interests\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eThe study was approved by the human ethics committee of Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine.The authors affirm that human research participants provided informed consent for publications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5. Clinical trial number:\u003c/strong\u003e not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e6. Data Availability:\u003c/strong\u003e All data included in this study are available upon request by contact with the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eChen M, Li C, Liao P, et al. 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Heart Rhythm. 2017;14(10):e275-e444. doi:10.1016/j.hrthm.2017.05.012.\u003c/li\u003e\n \u003cli\u003eMohanty S, Trivedi C, Horton P, et al. Natural History of Arrhythmia After Successful Isolation of Pulmonary Veins, Left Atrial Posterior Wall, and Superior Vena Cava in Patients With Paroxysmal Atrial Fibrillation: A Multi-Center Experience. \u003cem\u003eJ Am Heart Assoc\u003c/em\u003e. 2021;10(11):e020563. doi:10.1161/JAHA.120.020563.\u003c/li\u003e\n \u003cli\u003eFarrell M, Yoneda Z, Montgomery J, et al. Non-pulmonary vein mediated atrial fibrillation: a novel sub-phenotype. PLoS One. 2017;12:e0184354. DOI: 10.1371/journal.pone.0184354.\u003c/li\u003e\n \u003cli\u003eNery PB, Belliveau D, Nair GM, Bernick J, Redpath CJ, Szczotka A, Sadek MM, Green MS, Wells G, Birnie DH. Relationship between pulmonary vein reconnection and atrial fibrillation recurrence: a systematic review and meta-analysis. JACC Clin Electrophysiol. 2016;2:474\u0026ndash;483. DOI: 10.1016/j.jacep.2016.02.003.\u003c/li\u003e\n \u003cli\u003eSotomi Y, Inoue K, Ito N, et al. Cause of very late recurrence of atrial fibrillation or flutter after catheter ablation for atrial fibrillation. Am J Cardiol. 2013;111(4):552-556. doi:10.1016/j.amjcard.2012.10.040.\u003c/li\u003e\n \u003cli\u003eDe Maat GE, Mulder BA, Berretty WL, et al. Obesity is associated with impaired long-term success of pulmonary vein isolation: a plea for risk factor management before ablation. Open Heart. 2018;5(1):e000771. doi:10.1136/openhrt-2017-000771.\u003c/li\u003e\n \u003cli\u003ePathak RK, Middeldorp ME, Lau DH, et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. J Am Coll Cardiol. 2014;64(21):2222-2231. doi:10.1016/j.jacc.2014.09.028.\u003c/li\u003e\n \u003cli\u003eOnishi N, Kaitani K, Amano M, et al. Relationship between left ventricular diastolic dysfunction and very late recurrences after multiple procedures for atrial fibrillation ablation. Heart Vessels. 2018;33(1):41-48. doi:10.1007/s00380-017-1027-y.\u003c/li\u003e\n \u003cli\u003eTzou WS, Marchlinski FE, Zado ES, et al. Long-term outcome after successful catheter ablation of atrial fibrillation. Circ Arrhythm Electrophysiol. 2010;3(3):237-242. doi:10.1161/CIRCEP.109.923771.\u003c/li\u003e\n \u003cli\u003eFalkenberg M, Ford AJ, Li AC, et al. Unified mechanism of local drivers in a percolation model of atrial fibrillation. Phys Rev E. 2019;100(6-1):062406. doi:10.1103/PhysRevE.100.062406\u003c/li\u003e\n \u003cli\u003eWong GR, Nalliah CJ, Lee G, et al. Dynamic Atrial Substrate During High-Density Mapping of Paroxysmal and Persistent AF: Implications for Substrate Ablation. \u003cem\u003eJACC Clin Electrophysiol\u003c/em\u003e. 2019;5(11):1265-1277. doi:10.1016/j.jacep.2019.06.002.\u003c/li\u003e\n \u003cli\u003ede Groot N, van der Does L, Yaksh A, et al. Direct Proof of Endo-Epicardial Asynchrony of the Atrial Wall During Atrial Fibrillation in Humans. Circ Arrhythm Electrophysiol. 2016;9(5):e003648. doi:10.1161/CIRCEP.115.003648.\u003c/li\u003e\n \u003cli\u003eTakigawa M, Takahashi A, Kuwahara T, et al. Impact of Non-Pulmonary Vein Foci on the Outcome of the Second Session of Catheter Ablation for Paroxysmal Atrial Fibrillation. J Cardiovasc Electrophysiol. 2015;26(7):739-746. doi:10.1111/jce.12681.\u003c/li\u003e\n \u003cli\u003eBadano LP, Kolias TJ, Muraru D, et al. Standardization of left atrial, right ventricular, and right atrial deformation imaging using two-dimensional speckle tracking echocardiography: a consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging [published correction appears in Eur Heart J Cardiovasc Imaging. 2018 Jul 1;19(7):830-833]. Eur Heart J Cardiovasc Imaging. 2018;19(6):591-600. doi:10.1093/ehjci/jey042\u003c/li\u003e\n \u003cli\u003ePeters DC, Duncan JS, Grunseich K, et al. CMR-Verified Lower LA Strain in the Presence of Regional Atrial Fibrosis in Atrial Fibrillation. \u003cem\u003eJACC Cardiovasc Imaging\u003c/em\u003e. 2017;10(2):207-208. doi:10.1016/j.jcmg.2016.01.015\u003c/li\u003e\n \u003cli\u003eGoette A, Kalman JM, Aguinaga L, et al. EHRA/HRS/APHRS/SOLAECE expert consensus on Atrial cardiomyopathies: Definition, characterisation, and clinical implication. \u003cem\u003eJ Arrhythm\u003c/em\u003e. 2016;32(4):247-278. doi:10.1016/j.joa.2016.05.002\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Paroxysmal atrial fibrillation, atrial substrate, catheter ablation, recurrence, CHA2DS2-VASc score","lastPublishedDoi":"10.21203/rs.3.rs-5778159/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5778159/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBACKGROUND\u003c/strong\u003e Atrial substrate remodeling (ASR) was emerged as a critical determinant of very late recurrence (VLR) in paroxysmal atrial fibrillation (PaAF). However, the multifaceted risk factors driving ASR progression and their interplay with clinical outcomes remain incompletely characterized. This study aimed to identify clinical, electrophysiological, and structural risk factors associated with ASR in PaAF patients experiencing VLR after catheter ablation (CA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMETHODS \u003c/strong\u003eA total of 1786 consecutive patients with PaAF who underwent catheter ablation at Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine between May 2006 and July 2023 were screened. Patients with normal atrial substrate at baseline who subsequently experienced recurrent AF were enrolled and categorized into two cohorts: the ASR group (with ASR) and the NASR group (without ASR). A comparative assessment was performed to identify risk factors, encompassing the recurrent type of arrhythmia, CHA2DS2-VASc score, comorbidities, and pulmonary veins-left atrial (PVs-LA) reconnection, between two groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRESULTS\u003c/strong\u003e Of 1,786 screened patients, 102 met inclusion criteria (mean age: 61.0±10.0 years; 54% male), with 49 (48%) patients in the ASR group (mean age: 62.1±9.0 years; 45% male) and 53 (52%) in the NASR group (mean age: 61.0±10.0 years; 62% male). The ASR group had a higher CHA2DS2-VASc score, longer recurrence intervals, and a greater prevalence of recurrent persistent AF (PsAF). Notably, recurrent PsAF emerged as an independent risk factor for ASR (HR=2.66, 95%CI=1.05-6.73, P=0.04). Despite the presence of ASR, cardiac function remained preserved in both groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONCLUSIONS\u003c/strong\u003e In PaAF patients with VLR, recurrent persistent AF is an independent risk factor for atrial substrate remodeling. These findings highlight the role of arrhythmia progression in driving structural-electrical remodeling, even in initially normal atrial substrates.\u003c/p\u003e","manuscriptTitle":"The risk factors of Atrial Substrate Remodeling in the Patients of Paroxysmal Atrial Fibrillation following Pulmonary Vein Isolation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-10 06:22:56","doi":"10.21203/rs.3.rs-5778159/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-16T10:00:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-16T09:56:52+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-15T02:06:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"251098032094225357727118993928696785111","date":"2025-04-09T22:24:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-08T03:43:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"271991478349325339012883676209254648542","date":"2025-04-08T03:21:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"222810917185857250275382877559256150469","date":"2025-04-07T13:29:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"255462249780134388526626877727769739415","date":"2025-04-07T13:21:36+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-07T13:17:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-07T11:10:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cardiovascular Disorders","date":"2025-04-07T05:27:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"952c801f-d3b9-4c3c-905c-2745cc3f045b","owner":[],"postedDate":"April 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-29T16:03:17+00:00","versionOfRecord":{"articleIdentity":"rs-5778159","link":"https://doi.org/10.1186/s12872-025-04809-2","journal":{"identity":"bmc-cardiovascular-disorders","isVorOnly":false,"title":"BMC Cardiovascular Disorders"},"publishedOn":"2025-09-24 15:57:39","publishedOnDateReadable":"September 24th, 2025"},"versionCreatedAt":"2025-04-10 06:22:56","video":"","vorDoi":"10.1186/s12872-025-04809-2","vorDoiUrl":"https://doi.org/10.1186/s12872-025-04809-2","workflowStages":[]},"version":"v1","identity":"rs-5778159","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5778159","identity":"rs-5778159","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}