Biatrial Cardioneuroablation Guided by Robotic Magnetic Navigation and Artificial Intelligence-Based Mapping in Vagal Bradyarrhythmias: A Controlled Observational Study

Biatrial Cardioneuroablation Guided by Robotic Magnetic Navigation and Artificial Intelligence-Based Mapping in Vagal Bradyarrhythmias: A Controlled Observational Study | 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 Biatrial Cardioneuroablation Guided by Robotic Magnetic Navigation and Artificial Intelligence-Based Mapping in Vagal Bradyarrhythmias: A Controlled Observational Study Fulvio Cacciapuoti, Salvatore Crispo, Saverio Ambrosino, Ciro Pirozzi, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8068513/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Jan, 2026 Read the published version in Journal of Interventional Cardiac Electrophysiology → Version 1 posted You are reading this latest preprint version Abstract Purpose Reflex bradyarrhythmias and syncope related to excessive vagal tone may be refractory to conservative therapy and significantly impair quality of life. Cardioneuroablation (CNA) has emerged as a device-sparing alternative, but real-world outcome data remain limited. Methods We retrospectively evaluated 12 consecutive patients (aged 23–55 years) with drug-refractory, vagally mediated bradyarrhythmias confirmed by tilt-table testing. All underwent biatrial CNA guided by ultra-high-density electroanatomical mapping with automated fragmented-electrogram detection and robotic magnetic navigation. A contemporaneous cohort of medically managed patients with comparable clinical profiles (n = 10) served as a control group. The primary outcome was freedom from syncope or clinically significant bradyarrhythmia without pacemaker implantation. Secondary outcomes included procedural metrics, heart-rate changes, and recurrence during follow-up. Results All CNA procedures were completed without acute complications and with minimal fluoroscopy exposure. Resting sinus rate increased substantially after ablation. Over a mean follow-up of approximately 12 months, most CNA-treated patients remained free of symptomatic bradyarrhythmia or syncope without requiring pacemaker implantation, whereas recurrence and pacemaker placement were less frequent compared with controls. No delayed complications were observed. Conclusions In this small, retrospective real-world cohort, biatrial CNA guided by automated electrogram analysis and robotic navigation was feasible, safe, and associated with mid-term symptomatic improvement in selected patients with vagally mediated bradyarrhythmias. These findings are exploratory and warrant confirmation in larger, prospective studies with longer follow-up to assess durability and reinnervation risk. Cardioneuroablation Robotic magnetic navigation Ganglionated plexi Vasovagal syncope High-density mapping Artificial intelligence Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Capsule Summary In a single-center observational cohort, biatrial cardioneuroablation guided by ultra-high-density mapping, automated electrogram analysis, and robotic navigation was feasible and safe, increased resting sinus rate, and achieved mid-term freedom from clinically significant bradyarrhythmia or pacemaker implantation in most selected patients. Introduction Reflex bradyarrhythmias and syncope mediated by excessive vagal tone represent a persistent clinical challenge, causing recurrent loss of consciousness and severely impairing quality of life [1]. Vasovagal syncope (VVS), affecting up to 1–3% of the general population with a lifetime prevalence approaching 40%, arises from an abnormal autonomic reflex in which ventricular mechanoreceptor activation triggers exaggerated parasympathetic discharge and sympathetic withdrawal, culminating in abrupt hypotension and bradycardia [2]. Related conditions, including vagally mediated sinus node dysfunction (SND) and functional atrioventricular (AV) block, share the same pathophysiological substrate of hypervagotonia in structurally normal conduction tissue [3]. Conventional therapies, including salt and fluid loading, counter-pressure maneuvers, and pharmacologic interventions, often fail to prevent recurrent, disabling episodes. Permanent pacing, although effective in selected cases, is unsatisfactory in otherwise young and structurally normal individuals [4,5]. Cardioneuroablation (CNA) has emerged as an innovative catheter-based therapy for vagally mediated bradyarrhythmias [6]. By delivering targeted radiofrequency lesions to atrial ganglionated plexi (GP), CNA attenuates parasympathetic input and restores autonomic balance [7,8]. While right atrial ablation can be sufficient in isolated sinus node dysfunction, accumulating evidence supports a biatrial strategy to achieve comprehensive denervation of both sinus and AV nodal inputs, thereby reducing the risk of reinnervation and recurrent events [9–11]. The left atrial component, however, necessitates transseptal puncture and carries procedure-specific risks, including pericardial effusion, thromboembolism, and iatrogenic atrial septal defects [12,13]. Recent technological advances have significantly improved both safety and precision. Robotic magnetic navigation (RMN) enables stable, atraumatic catheter control with constant low contact forces (~10 g), facilitating access to complex atrial regions while minimizing fluoroscopy [14–16]. Ultra–high-density three-dimensional mapping systems rapidly acquire millions of points, while artificial intelligence (AI) algorithms automatically detect fractionated electrograms corresponding to autonomic inputs [17,18]. Together, these tools allow lesion delivery to be confined to the most relevant targets, reducing unnecessary ablation, shortening procedure times, and limiting collateral risk. Aim: This retrospective, single-center observational analysis evaluates the feasibility, safety, and clinical outcomes of biatrial CNA using RMN and AI-enhanced ultra-high-density mapping in patients with drug-refractory vagally mediated bradyarrhythmias, including VVS, SND, and functional AV block. The study also presents a standardized procedural workflow based on exclusive use of RF-assisted transseptal access and automated detection of fragmented electrograms, and examines how these advanced techniques may improve lesion targeting and reduce procedural risk. Methods This retrospective, single-center observational study analyzed clinical and procedural data from patients treated between May 2024 and August 2025. Consecutive patients referred for recurrent, drug-refractory vagally mediated bradyarrhythmias (vasovagal syncope, vagally mediated sinus node dysfunction, and functional atrioventricular block) were screened. A total of 17 patients were initially identified, of whom 5 were excluded due to intrinsic conduction disease on baseline electrocardiography or electrophysiologic testing, structural heart disease on transthoracic echocardiography or cardiac magnetic resonance imaging, significant metabolic or endocrine disorders affecting heart rate, or refusal of invasive treatment. The remaining 12 patients (aged 23-55 years) constituted the study cohort (Table I). All included individuals had structurally normal hearts. Baseline 12-lead electrocardiograms showed stable sinus rhythm with preserved atrioventricular conduction and a mean heart rate (HR) of 60-65 bpm. Pre-procedural evaluation included 24-hour Holter or implantable loop recorder monitoring to document spontaneous bradyarrhythmic episodes (Fig. 1), tilt-table testing (TTT) to confirm vagal reflex involvement, and atropine challenge to evaluate autonomic responsiveness. A positive TTT result was required for inclusion; this consisted of reproduction of syncope or presyncope with characteristic cardioinhibitory or mixed responses and evidence of exaggerated parasympathetic activity. A control cohort was retrospectively identified from the institutional database, including patients with comparable baseline characteristics (age, sex, type of vagally mediated bradyarrhythmia, and positive TTT) who had declined or were deemed unsuitable for CNA during the same period (n = 10). These patients were managed with optimized medical therapy and, when indicated, permanent pacemaker implantation according to current guidelines. Follow-up data were collected in an identical manner to the ablation cohort. Patients were stratified into three predefined subgroups according to their predominant clinical presentation: recurrent cardioinhibitory or mixed syncope confirmed by TTT (VVS); documented sinus pauses >3 s or resting sinus bradycardia <40 bpm associated with symptoms (SND); paroxysmal AV block with preserved His–Purkinje conduction and positive vagal features on testing (AVB). Subgroup comparisons were performed for changes in resting sinus rate, recurrence of clinically significant bradyarrhythmia, and need for pacemaker implantation. Continuous variables were compared using ANOVA or Kruskal–Wallis tests as appropriate, and categorical outcomes with Fisher’s exact test. Procedures were performed under conscious sedation with continuous surface electrocardiographic (Fig. 2), hemodynamic, and oxygen saturation monitoring. After venous access, intravenous heparin was administered to maintain an activated clotting time (ACT) of 300-350 s. Left atrial access was obtained by intracardiac echocardiography (ICE)-guided, radiofrequency-assisted transseptal puncture (Versacross system, Baylis Medical, Canada), a technique shown to shorten puncture time and improve first-pass success compared to the conventional Brockenbrough method (Fig. 3) [19]. Electroanatomical mapping was performed with the Rhythmia HDx platform (Boston Scientific, USA) using the IntellaMap Orion catheter; the band-pass filter was set at 200-500 Hz to highlight high-frequency fractionated electrograms (Fig. 4). Putative ganglionated plexi (GP) were automatically identified using the Lumipoint AI module, which highlights signals with amplitude < 0.7 mV and ≥ 4 deflections (Fig. 5) [20,21]. This automated electrogram-based strategy allows more precise targeting and reduces the limitations of high-frequency stimulation, including false positives and arrhythmia induction [22]. Radiofrequency energy was delivered through an irrigated, magnetically navigated Magnoflush G4 catheter (MedFact Engineering GmbH, Germany) (Fig. 6) under robotic magnetic navigation (RMN; Genesis, Stereotaxis, USA). RMN provided stable catheter control with predictable contact force (~10 g), enabling creation of focal and durable lesions [23,24]. Ablation was directed at left atrial GP clusters around the pulmonary vein antra and the ligament of Marshall, and at right-sided GP approached from the left atrium at the anterior wall of the right superior pulmonary vein. Direct right atrial ablation was systematically avoided to minimize the risk of phrenic nerve injury. RF delivery at each site was continued until fractionated electrograms were abolished or attenuated and the resting sinus rate increased by 20–30 bpm or matched the value observed during atropine testing. Acute vagal responses (transient sinus slowing or asystole) consistently confirmed accurate targeting of autonomic sites (Fig. 7, Fig. 8). At the conclusion of each procedure, echocardiography was used to exclude pericardial effusion and assess the interatrial septum. Post-procedural management included anticoagulation for at least eight weeks and proton-pump inhibitor prophylaxis for four weeks. Clinical follow-up consisted of scheduled outpatient visits, 24-hour Holter monitoring, or interrogation of implantable loop recorders to detect recurrent bradyarrhythmias or atrial tachyarrhythmias. The primary endpoint was freedom from syncope or clinically significant bradyarrhythmia without pacemaker implantation. Secondary endpoints included total procedure duration, fluoroscopy exposure, and incidence of acute or delayed complications. Statistical analysis: Continuous variables are presented as mean ± standard deviation, while categorical variables are shown as counts and percentages. Changes in resting heart rate before and after ablation were analyzed using a paired t-test. The incidence of syncope recurrence and pacemaker implantation during follow-up was tracked and reported as cumulative occurrence rates. Procedural and safety outcomes were summarized descriptively. To identify independent predictors of clinical recurrence or pacemaker implantation, a stepwise logistic regression model was applied including the following baseline and procedural variables. age, sex, bradyarrhythmia subtype (VVS, SND, AVB), baseline resting heart rate, resting HR increase post-CNA, number of ablation lesions, total procedure duration, and fluoroscopy exposure. Given the small sample size, the model was limited to a maximum of three covariates per step to prevent overfitting. Odds ratios (OR) with 95% confidence intervals (CI) were calculated. A p-value <0.05 was considered statistically significant. Results Twelve patients met inclusion criteria and underwent biatrial cardioneuroablation. All procedures were successfully completed without major complications such as pericardial effusion, tamponade, thromboembolism, or phrenic nerve injury. Of the 12 patients, 5 (41.7%) had cardioinhibitory vasovagal syncope, 4 (33.3%) had vagally mediated sinus node dysfunction, and 3 (25.0%) had functional AV block. Post-procedural heart rate increase was similar across subgroups (VVS: +26 ± 3 bpm; SND: +24 ± 4 bpm; AVB: +25 ± 5 bpm; p = 0.68). At 12-month follow-up, freedom from recurrence or pacemaker implantation was 80% for VVS, 100% for SND, and 66.7% for AVB (p = 0.41). The only pacemaker implantation occurred in a patient with functional AV block. No significant differences were observed in procedure duration, fluoroscopy exposure, or complication rates among subgroups. These findings suggest that CNA efficacy and safety were consistent across distinct vagally mediated phenotypes, although larger cohorts are required to confirm differential responses. Procedural efficiency was high (Table II). Mean total procedure time was 141 ± 22 min (95% CI 127–155), with minimal fluoroscopy exposure (3 ± 1 min, 95% CI 2.4–3.6). Average radiofrequency power was 37 ± 3 W (95% CI 35.1–38.9), with 8 ± 4 lesions (95% CI 6.5–9.5) delivered per patient. Acute autonomic confirmation was achieved in all cases, evidenced by transient sinus slowing or brief asystole during ablation. Automated electrogram detection using the AI module identified an average of 5.8 ± 1.2 autonomic clusters per patient, predominantly located around the left superior and inferior pulmonary veins and the ligament of Marshall. Operator review confirmed 94% concordance with visually assessed fractionation patterns, supporting algorithmic reliability. Resting sinus rate increased significantly from baseline, with a mean post-ablation rise of 25 ± 4 bpm (95% CI 22.5–27.5; p = 2.3 × 10⁻¹⁰), indicating effective parasympathetic attenuation. At a median follow-up of 12.6 ± 1.7 months, 10 of 12 patients (83.3%, 95% CI 51.6–97.9) remained free of syncope or clinically significant bradyarrhythmia and required no pacemaker implantation. Two patients (16.7%, 95% CI 2.1–48.4) experienced recurrent symptomatic bradyarrhythmia; one (8.3%, 95% CI 0.2–38.5) ultimately underwent permanent pacemaker implantation. No late procedural complications occurred. Compared with the control group, patients undergoing CNA showed significantly greater freedom from recurrent syncope or bradyarrhythmia (83.3% vs 40.0%; p = 0.04) and a lower need for pacemaker implantation (8.3% vs 30.0%; p = 0.03) during a comparable mean follow-up of 12.4 ± 1.8 months. In the combined cohort (CNA and control, n = 22), multivariate logistic regression identified two independent predictors of recurrence or pacemaker implantation: absence of significant post-procedural heart rate increase (< 20 bpm) (OR 8.6; 95% CI 1.3–57.1; p = 0.02) and functional atrioventricular block subtype (OR 6.9; 95% CI 1.1–43.5; p = 0.04). Neither age, sex, baseline HR, nor total procedure time were independently associated with recurrence (p > 0.2 for all). In patients achieving a heart rate increase ≥ 25 bpm post-ablation, the probability of remaining free from clinically significant bradyarrhythmia at 12 months was 91% (vs 50% in those below this threshold; p = 0.03 by Kaplan–Meier analysis). These data suggest that effective parasympathetic attenuation, reflected by a substantial HR rise, is the most robust marker of durable CNA response. Overall, these findings suggest that biatrial cardioneuroablation, when guided by ultra-high-density mapping and automated electrogram identification under robotic control, can produce sustained improvements in resting heart rate and symptom control, while maintaining a favorable safety profile even in a real-world, drug-refractory population of vagally mediated bradyarrhythmias (Fig. 9 ; Table III). Limitations This study has several important limitations. First, its retrospective, single-center design and the small sample size inherently limit statistical power and generalizability. Although the inclusion of a contemporaneous control cohort provides a comparative framework, residual selection bias cannot be excluded, as treatment allocation was not randomized. Second, while the integration of AI-based electrogram analysis improved objectivity in identifying autonomic targets, the algorithm parameters were partially proprietary and validated internally; external reproducibility should be confirmed in independent datasets. Third, the multivariate analysis must be interpreted cautiously due to the low event rate and the limited number of covariates included to avoid model overfitting. The identified predictors—namely functional AV block and limited heart rate response—should therefore be viewed as hypothesis-generating rather than definitive and do not establish superiority over conventional pacing strategies. Fourth, although subgroup comparisons (VVS, SND, AVB) revealed similar trends, the small numbers preclude reliable detection of subtle phenotype-specific differences. Fifth, follow-up duration averaged 12.6 ± 1.7 months, insufficient to assess potential late reinnervation or autonomic remodeling, which may influence long-term efficacy. Lastly, autonomic function was inferred indirectly through heart rate response rather than formal autonomic testing (e.g., heart rate variability, baroreflex sensitivity), limiting mechanistic insight. Larger, multicenter prospective studies with extended follow-up, standardized AI algorithms, and direct autonomic measurements are warranted to validate these preliminary observations. Discussion This retrospective, single-center observational study suggests that biatrial CNA performed with ultra–high-density electroanatomical mapping, AI-assisted electrogram analysis, and robotic magnetic navigation (RMN) is feasible and can be executed with a favorable procedural safety profile in patients with drug-refractory vagally mediated bradyarrhythmias, including cardioinhibitory VVS, vagally mediated SND, and functional AV block. Importantly, no randomization or treatment-assignment control was performed, and outcomes therefore reflect real-world clinical practice rather than controlled experimental conditions. All procedures were completed without acute complications, and a consistent increase in resting sinus rate was observed, supporting effective parasympathetic attenuation. At approximately one year of follow-up, most patients remained free from clinically significant bradyarrhythmia or pacemaker implantation. These findings suggest potential mid-term clinical benefit in appropriately selected patients; however, the small sample size and observational design limit the strength of causal inference. Our results are consistent with prior prospective series and meta-analyses reporting symptom improvement and autonomic modulation following CNA [ 25 – 27 ]. Moreover, the ROMAN randomized trial demonstrated a substantial reduction in syncope recurrence compared with conservative management [ 28 ]. The use of a biatrial approach in this study aligns with the 2024 EHRA/HRS/APHRS/LAHRS consensus statement [ 13 ], which emphasizes comprehensive denervation of sinus and AV nodal innervation to reduce the risk of incomplete neuromodulation and potential reinnervation reported after right-sided ablation alone. A notable feature of our workflow is the combined use of ultra–high-density mapping and AI-based electrogram analysis to aid in the identification of ganglionated plexi [ 29 ], together with RMN, which provided stable catheter control with minimal fluoroscopy. This strategy may help avoid excessive or anatomically imprecise ablation and could potentially lower the risk of collateral injury, including esophageal, phrenic nerve, or pulmonary vein injury [ 30 , 31 ]. While promising, these technical advantages should be interpreted with caution, as systematic comparative data are not yet available. Left atrial access remains a key procedural step. RF-assisted transseptal puncture under ICE guidance was used systematically in this cohort, consistent with evidence from the TRAVERSE-LA randomized trial demonstrating shorter access time and reduced mechanical complications compared with conventional needle puncture [ 19 , 32 ]. The absence of TSP-related complications in this series may reflect the standardized use of RF-assisted access and continuous anticoagulation; however, the study is underpowered to assess procedural safety comprehensively. From a mechanistic standpoint, the observed clinical improvements support the hypothesis that hypervagotonia was the dominant driver of symptoms. Ablation of left- and right-sided autonomic inputs resulted in a sustained increase in resting sinus rate, which may reflect durable attenuation of parasympathetic efferent pathways [ 33 ]. In this cohort, right-sided autonomic targets were approached from the left atrium, avoiding direct right atrial ablation and potentially reducing the risk of phrenic nerve injury; however, whether this approach provides equivalent or superior long-term autonomic modulation requires further investigation. Tilt-table testing (TTT) was used as a prerequisite for inclusion and served as an essential tool for confirming reflex-mediated physiology prior to CNA [ 34 ]. By distinguishing parasympathetic-mediated bradyarrhythmia from conditions such as orthostatic intolerance or structural conduction disease, TTT supported more precise candidate selection and may have contributed to the low recurrence and complication rates observed [ 35 ]. Nonetheless, TTT-based selection criteria vary across centers, and further standardization is needed. This study has several limitations. The retrospective, non-randomized design introduces potential selection bias, and the control cohort may differ from the CNA group in symptom severity or treatment preference. The small sample size limits statistical power, particularly for subgroup analysis and multivariable modeling. Follow-up duration was approximately one year, which is insufficient to determine long-term durability or the potential for autonomic reinnervation. Accordingly, these findings should be regarded as exploratory and hypothesis-generating. Overall, this real-world experience supports the feasibility of integrating advanced mapping and robotic navigation technologies into CNA workflows and highlights the importance of careful patient selection. Larger, prospective, multicenter studies with longer follow-up are needed to validate durability, refine procedural endpoints, and define optimal patient selection criteria. Conclusions Biatrial CNA performed with ultra–high-density mapping, AI-assisted electrogram analysis, and RMN represents a feasible, safe, and radiation-sparing strategy for the management of drug-refractory vagally mediated bradyarrhythmias. By enabling comprehensive vagal denervation while minimizing procedural risks, particularly those related to transseptal puncture, this approach offers a device-sparing alternative to permanent pacemaker implantation and is consistent with current international recommendations. Looking forward, integration of advanced AI and machine-learning algorithms may allow real-time identification of the fossa ovalis and high-probability GP sites, improving safety and dynamically tailoring lesion sets. Fusion of pre-procedural imaging with high-density mapping could provide individualized roadmaps, while novel devices such as RF-enabled or pressure-sensing needles, in combination with robotic navigation, may further reduce access-related complications. Long-term monitoring with implantable loop recorders will be essential to clarify the durability of vagal denervation and to guide potential reintervention. Future research should also explore expanding CNA indications to mixed vasodepressor–cardioinhibitory syncope and vagally mediated atrial fibrillation, as well as testing novel energy sources such as pulsed-field ablation, which may enhance both safety and efficiency. Large-scale, multicenter randomized trials with long-term follow-up will be crucial to standardize procedural endpoints, refine patient selection, and establish CNA as a cornerstone of modern autonomic modulation therapy. Collectively, these findings provide real-world support for integrating advanced mapping and robotic technologies in CNA practice and may serve as a foundation for multicenter efforts to standardize workflows, define procedural endpoints, and validate long-term clinical outcomes. Abbreviations SD standard deviation bpm beats per minute HR heart rate CMR cardiac magnetic resonance TTT tilt-table test. Declarations Funding: The authors did not receive support from any organization for the submitted work. Competing interests: The authors have no relevant financial or non-financial interests to disclose. Ethics approval: The study was conducted in accordance with the Declaration of Helsinki. The Institutional Ethics Committee of “A. Cardarelli” Hospital, Naples, reviewed the study protocol and waived the requirement for formal approval, as the analysis involved only anonymized retrospective data. Consent to participate: Not applicable owing to the retrospective design with anonymized data and absence of identifiable images. Data availability: The data that support the findings of this study are available from the corresponding author upon reasonable request. Authors’ contributions: Conceptualization: Fulvio Cacciapuoti and Mario Volpicelli; Methodology: Fulvio Cacciapuoti and Mario Volpicelli; Investigation: Fulvio Cacciapuoti, Mario Volpicelli, Salvatore Crispo, Saverio Ambrosino, Ciro Pirozzi, Orlando Munciguerra, Carmine Nappo and Nicoletta Caccavale; Formal analysis: Fulvio Cacciapuoti, Flavia Casolaro and Mario Volpicelli; Writing—original draft: Fulvio Cacciapuoti and Mario Volpicelli; Writing—review & editing: Fulvio Cacciapuoti, Mario Volpicelli and Ciro Pirozzi; Supervision: Fulvio Cacciapuoti and Mario Volpicelli. References Aydin MA, Salukhe TV, Wilke I, Willems S. Management and therapy of vasovagal syncope: A review. World J Cardiol. 2010;2(10):308–15. 10.4330/wjc.v2.i10.308 . PMID: 21160608; PMCID: PMC2998831. van Dijk JG, van Rossum IA, Thijs RD. The pathophysiology of vasovagal syncope: Novel insights. Auton Neurosci. 2021;236:102899. 10.1016/j.autneu.2021.102899 . Epub 2021 Oct 18. PMID: 34688189. Mai W, Kusumoto F. 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Supplementary Files Tables.docx Cite Share Download PDF Status: Published Journal Publication published 24 Jan, 2026 Read the published version in Journal of Interventional Cardiac Electrophysiology → Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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09:59:10","extension":"png","order_by":26,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":703535,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage9.png","url":"https://assets-eu.researchsquare.com/files/rs-8068513/v1/872fdff8aa3d4aee5cdd3846.png"},{"id":96968376,"identity":"678d8598-1905-42e5-83b9-00e18aa6d012","added_by":"auto","created_at":"2025-11-28 07:00:37","extension":"xml","order_by":27,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":122069,"visible":true,"origin":"","legend":"","description":"","filename":"538a9b3cf5a747409847dd3040446f0d1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8068513/v1/3c4c5b2380456f8c5b202569.xml"},{"id":96968383,"identity":"cc8bcde6-005a-4ec8-b96c-a14a90b261bd","added_by":"auto","created_at":"2025-11-28 07:00:37","extension":"html","order_by":28,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":132939,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8068513/v1/75f3f7299a4779c368af371a.html"},{"id":96968344,"identity":"e9ba9d2a-6db4-4ea7-93fe-1d9d32f426e0","added_by":"auto","created_at":"2025-11-28 07:00:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":98071,"visible":true,"origin":"","legend":"\u003cp\u003eImplantable loop recorder tracing demonstrating a prolonged cardioinhibitory reflex during a spontaneous vasovagal syncope episode. Consecutive pauses exceed 2 seconds, with intermittent ventricular and atrial activity followed by asystolic periods longer than 2 seconds (\u0026gt;2000 ms), consistent with vagally mediated functional atrioventricular block.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8068513/v1/f43230b3311b216fd99b2e7c.png"},{"id":96968345,"identity":"56a24161-14e0-406f-9a2d-d8c281db54e5","added_by":"auto","created_at":"2025-11-28 07:00:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":585505,"visible":true,"origin":"","legend":"\u003cp\u003eBaseline 12-lead electrocardiogram. Surface ECG at rest shows sinus rhythm at approximately 64 bpm with normal atrioventricular conduction, representative of the baseline status of the patients prior to cardioneuroablation.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8068513/v1/2bb23d560cbd1edc4444adf4.png"},{"id":96968348,"identity":"3154646e-f7e3-4008-8655-f093e2ef579f","added_by":"auto","created_at":"2025-11-28 07:00:36","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":681588,"visible":true,"origin":"","legend":"\u003cp\u003eIntraprocedural fluoroscopic and intracardiac echocardiographic (ICE) imaging during left atrial access.\u003c/p\u003e\n\u003cp\u003eFluoroscopic view showing radiofrequency-assisted transseptal puncture with visualization of the transseptal sheath and mapping catheter positioned in the right atrium. The radiofrequency wire tip is aligned toward the fossa ovalis under ICE guidance (inset, lower right), ensuring precise puncture trajectory and minimizing the risk of aortic or posterior wall injury. Continuous ICE monitoring confirms tenting of the interatrial septum and successful entry into the left atrium prior to catheter advancement for electroanatomical mapping.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8068513/v1/60292c0036ee5b4ac189b52d.png"},{"id":96968357,"identity":"936fc5a2-d9cc-4062-9dc4-6cdbb5089d49","added_by":"auto","created_at":"2025-11-28 07:00:36","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":368295,"visible":true,"origin":"","legend":"\u003cp\u003eUltra–high-density three-dimensional left atrial voltage mapping. The anterior (A) and posterior (B) projections show detailed reconstruction with color-coded voltage distribution. High-resolution mapping allows precise delineation of atrial anatomy and identification of regions potentially harboring ganglionated plexi.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8068513/v1/f4fc0fb4b8ab1308c4ddb10c.png"},{"id":96968356,"identity":"e33871fb-ac6c-4ce2-beea-fef2a0adb1c2","added_by":"auto","created_at":"2025-11-28 07:00:36","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":416490,"visible":true,"origin":"","legend":"\u003cp\u003eHigh-density electroanatomical map with AI-based fragmented potential analysis. Three-dimensional left atrial reconstruction obtained during sinus rhythm. The AI-based electrogram analysis module (band-pass 200–500 Hz) automatically highlights areas of fractionated electrograms (\u0026gt;4 deflections, amplitude \u0026lt;0.7 mV) corresponding to candidate ganglionated plexi (light blue). Red tags indicate radiofrequency applications delivered with robotic magnetic navigation.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-8068513/v1/ba02a8ad8322b938f34007c7.png"},{"id":96968358,"identity":"ec92d982-9475-4cc6-9915-7ccb15ed3b38","added_by":"auto","created_at":"2025-11-28 07:00:36","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":429861,"visible":true,"origin":"","legend":"\u003cp\u003eFluoroscopic image showing the irrigated, magnetically navigated catheter during biatrial cardioneuroablation.\u003c/p\u003e\n\u003cp\u003eThe catheter is visualized in the left atrium under robotic magnetic navigation, with stable positioning achieved using the magnetic field vectors. The image illustrates precise control and orientation of the ablation catheter along with diagnostic multipolar catheters positioned in the coronary sinus and right atrium.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-8068513/v1/a343735b0aae2b652bfa377c.png"},{"id":96968374,"identity":"b87bd596-ef5c-41e1-8e40-b04f2a8d7d34","added_by":"auto","created_at":"2025-11-28 07:00:37","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":457572,"visible":true,"origin":"","legend":"\u003cp\u003eIntraprocedural vagal response during right atrial ganglionated plexus ablation. Intracardiac electrograms demonstrate a pronounced sinus slowing during radiofrequency application on a right-sided ganglionated plexus, confirming effective vagal stimulation and accurate localization of the ablation target.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-8068513/v1/1eacf47bdee7795015174275.png"},{"id":96968381,"identity":"476f556f-f420-46d7-b4e5-1a57c2db75dc","added_by":"auto","created_at":"2025-11-28 07:00:37","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":525923,"visible":true,"origin":"","legend":"\u003cp\u003eTwelve-lead surface ECG and intracardiac recordings demonstrate a marked sinus pause of 7.8 s (corresponding to a transient ventricular rate of 7 bpm) during radiofrequency delivery at a left atrial ganglionated plexus site. The pause is followed by a rapid resumption of sinus rhythm, confirming effective vagal stimulation and successful localization of autonomic inputs.\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-8068513/v1/f4c42c9167c31eccdef8a75a.png"},{"id":97136605,"identity":"1bd88894-7b57-4edb-a32d-d7a232e78ab2","added_by":"auto","created_at":"2025-12-01 09:56:49","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":99809,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves for freedom from clinically significant bradyarrhythmia or pacemaker implantation comparing the CNA (blue) and control (red) groups.\u003c/p\u003e\n\u003cp\u003eThe CNA cohort demonstrated significantly higher event-free survival (83.3% vs 40.0%; p = 0.04 by log-rank test).\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-8068513/v1/32d77d7c537138e3fc687e6e.png"},{"id":101153046,"identity":"62e89fd2-83c2-4c77-ae4b-ee11956d7d7e","added_by":"auto","created_at":"2026-01-26 16:14:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4356696,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8068513/v1/5c0ea65d-fddf-46dd-afcc-56320c41c114.pdf"},{"id":96968347,"identity":"0fc4c740-5b45-410d-8dc8-27678ecdb728","added_by":"auto","created_at":"2025-11-28 07:00:36","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":168288,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8068513/v1/568d695a6180d18f213f8176.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Biatrial Cardioneuroablation Guided by Robotic Magnetic Navigation and Artificial Intelligence-Based Mapping in Vagal Bradyarrhythmias: A Controlled Observational Study","fulltext":[{"header":"Capsule Summary","content":"\u003cp\u003eIn a single-center observational cohort, biatrial cardioneuroablation guided by ultra-high-density mapping, automated electrogram analysis, and robotic navigation was feasible and safe, increased resting sinus rate, and achieved mid-term freedom from clinically significant bradyarrhythmia or pacemaker implantation in most selected patients.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eReflex bradyarrhythmias and syncope mediated by excessive vagal tone represent a persistent clinical challenge, causing recurrent loss of consciousness and severely impairing quality of life [1]. Vasovagal syncope (VVS), affecting up to 1\u0026ndash;3% of the general population with a lifetime prevalence approaching 40%, arises from an abnormal autonomic reflex in which ventricular mechanoreceptor activation triggers exaggerated parasympathetic discharge and sympathetic withdrawal, culminating in abrupt hypotension and bradycardia [2]. Related conditions, including vagally mediated sinus node dysfunction (SND) and functional atrioventricular (AV) block, share the same pathophysiological substrate of hypervagotonia in structurally normal conduction tissue [3].\u003c/p\u003e\n\u003cp\u003eConventional therapies, including salt and fluid loading, counter-pressure maneuvers, and pharmacologic interventions, often fail to prevent recurrent, disabling episodes. Permanent pacing, although effective in selected cases, is unsatisfactory in otherwise young and structurally normal individuals [4,5].\u003c/p\u003e\n\u003cp\u003eCardioneuroablation (CNA) has emerged as an innovative catheter-based therapy for vagally mediated bradyarrhythmias [6]. By delivering targeted radiofrequency lesions to atrial ganglionated plexi (GP), CNA attenuates parasympathetic input and restores autonomic balance [7,8]. While right atrial ablation can be sufficient in isolated sinus node dysfunction, accumulating evidence supports a biatrial strategy to achieve comprehensive denervation of both sinus and AV nodal inputs, thereby reducing the risk of reinnervation and recurrent events [9\u0026ndash;11]. The left atrial component, however, necessitates transseptal puncture and carries procedure-specific risks, including pericardial effusion, thromboembolism, and iatrogenic atrial septal defects [12,13].\u003c/p\u003e\n\u003cp\u003eRecent technological advances have significantly improved both safety and precision. Robotic magnetic navigation (RMN) enables stable, atraumatic catheter control with constant low contact forces (~10 g), facilitating access to complex atrial regions while minimizing fluoroscopy [14\u0026ndash;16]. Ultra\u0026ndash;high-density three-dimensional mapping systems rapidly acquire millions of points, while artificial intelligence (AI) algorithms automatically detect fractionated electrograms corresponding to autonomic inputs [17,18]. Together, these tools allow lesion delivery to be confined to the most relevant targets, reducing unnecessary ablation, shortening procedure times, and limiting collateral risk.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAim:\u003c/strong\u003e This retrospective, single-center observational analysis evaluates the feasibility, safety, and clinical outcomes of biatrial CNA using RMN and AI-enhanced ultra-high-density mapping in patients with drug-refractory vagally mediated bradyarrhythmias, including VVS, SND, and functional AV block. The study also presents a standardized procedural workflow based on exclusive use of RF-assisted transseptal access and automated detection of fragmented electrograms, and examines how these advanced techniques may improve lesion targeting and reduce procedural risk.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis retrospective, single-center observational study analyzed clinical and procedural data from patients treated between May 2024 and August 2025. Consecutive patients referred for recurrent, drug-refractory vagally mediated bradyarrhythmias (vasovagal syncope, vagally mediated sinus node dysfunction, and functional atrioventricular block) were screened. A total of 17 patients were initially identified, of whom 5 were excluded due to intrinsic conduction disease on baseline electrocardiography or electrophysiologic testing, structural heart disease on transthoracic echocardiography or cardiac magnetic resonance imaging, significant metabolic or endocrine disorders affecting heart rate, or refusal of invasive treatment. The remaining 12 patients (aged 23-55 years) constituted the study cohort (Table I).\u003c/p\u003e\n\u003cp\u003eAll included individuals had structurally normal hearts. Baseline 12-lead electrocardiograms showed stable sinus rhythm with preserved atrioventricular conduction and a mean heart rate (HR) of 60-65 bpm. Pre-procedural evaluation included 24-hour Holter or implantable loop recorder monitoring to document spontaneous bradyarrhythmic episodes (Fig. 1), tilt-table testing (TTT) to confirm vagal reflex involvement, and atropine challenge to evaluate autonomic responsiveness. A positive TTT result was required for inclusion; this consisted of reproduction of syncope or presyncope with characteristic cardioinhibitory or mixed responses and evidence of exaggerated parasympathetic activity.\u003c/p\u003e\n\u003cp\u003eA control cohort was retrospectively identified from the institutional database, including patients with comparable baseline characteristics (age, sex, type of vagally mediated bradyarrhythmia, and positive TTT) who had declined or were deemed unsuitable for CNA during the same period (n = 10).\u003c/p\u003e\n\u003cp\u003eThese patients were managed with optimized medical therapy and, when indicated, permanent pacemaker implantation according to current guidelines. Follow-up data were collected in an identical manner to the ablation cohort.\u003c/p\u003e\n\u003cp\u003ePatients were stratified into three predefined subgroups according to their predominant clinical presentation: recurrent cardioinhibitory or mixed syncope confirmed by TTT (VVS); documented sinus pauses \u0026gt;3 s or resting sinus bradycardia \u0026lt;40 bpm associated with symptoms (SND); paroxysmal AV block with preserved His\u0026ndash;Purkinje conduction and positive vagal features on testing (AVB).\u003c/p\u003e\n\u003cp\u003eSubgroup comparisons were performed for changes in resting sinus rate, recurrence of clinically significant bradyarrhythmia, and need for pacemaker implantation. Continuous variables were compared using ANOVA or Kruskal\u0026ndash;Wallis tests as appropriate, and categorical outcomes with Fisher\u0026rsquo;s exact test.\u003c/p\u003e\n\u003cp\u003eProcedures were performed under conscious sedation with continuous surface electrocardiographic (Fig. 2), hemodynamic, and oxygen saturation monitoring. After venous access, intravenous heparin was administered to maintain an activated clotting time (ACT) of 300-350 s. Left atrial access was obtained by intracardiac echocardiography (ICE)-guided, radiofrequency-assisted transseptal puncture (Versacross system, Baylis Medical, Canada), a technique shown to shorten puncture time and improve first-pass success compared to the conventional Brockenbrough method (Fig. 3) [19].\u003c/p\u003e\n\u003cp\u003eElectroanatomical mapping was performed with the Rhythmia HDx platform (Boston Scientific, USA) using the IntellaMap Orion catheter; the band-pass filter was set at 200-500 Hz to highlight high-frequency fractionated electrograms (Fig. 4). Putative ganglionated plexi (GP) were automatically identified using the Lumipoint AI module, which highlights signals with amplitude \u0026lt; 0.7 mV and \u0026ge; 4 deflections (Fig. 5) [20,21]. This automated electrogram-based strategy allows more precise targeting and reduces the limitations of high-frequency stimulation, including false positives and arrhythmia induction [22].\u003c/p\u003e\n\u003cp\u003eRadiofrequency energy was delivered through an irrigated, magnetically navigated Magnoflush G4 catheter (MedFact Engineering GmbH, Germany) (Fig. 6) under robotic magnetic navigation (RMN; Genesis, Stereotaxis, USA). RMN provided stable catheter control with predictable contact force (~10 g), enabling creation of focal and durable lesions [23,24]. Ablation was directed at left atrial GP clusters around the pulmonary vein antra and the ligament of Marshall, and at right-sided GP approached from the left atrium at the anterior wall of the right superior pulmonary vein. Direct right atrial ablation was systematically avoided to minimize the risk of phrenic nerve injury. RF delivery at each site was continued until fractionated electrograms were abolished or attenuated and the resting sinus rate increased by 20\u0026ndash;30 bpm or matched the value observed during atropine testing. Acute vagal responses (transient sinus slowing or asystole) consistently confirmed accurate targeting of autonomic sites (Fig. 7, Fig. 8).\u003c/p\u003e\n\u003cp\u003eAt the conclusion of each procedure, echocardiography was used to exclude pericardial effusion and assess the interatrial septum. Post-procedural management included anticoagulation for at least eight weeks and proton-pump inhibitor prophylaxis for four weeks.\u003c/p\u003e\n\u003cp\u003eClinical follow-up consisted of scheduled outpatient visits, 24-hour Holter monitoring, or interrogation of implantable loop recorders to detect recurrent bradyarrhythmias or atrial tachyarrhythmias. The primary endpoint was freedom from syncope or clinically significant bradyarrhythmia without pacemaker implantation. Secondary endpoints included total procedure duration, fluoroscopy exposure, and incidence of acute or delayed complications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis:\u0026nbsp;\u003c/strong\u003eContinuous variables are presented as mean \u0026plusmn; standard deviation, while categorical variables are shown as counts and percentages. Changes in resting heart rate before and after ablation were analyzed using a paired t-test. The incidence of syncope recurrence and pacemaker implantation during follow-up was tracked and reported as cumulative occurrence rates. Procedural and safety outcomes were summarized descriptively.\u003c/p\u003e\n\u003cp\u003eTo identify independent predictors of clinical recurrence or pacemaker implantation, a stepwise logistic regression model was applied including the following baseline and procedural variables. age, sex, bradyarrhythmia subtype (VVS, SND, AVB), baseline resting heart rate, resting HR increase post-CNA, number of ablation lesions, total procedure duration, and fluoroscopy exposure.\u003c/p\u003e\n\u003cp\u003eGiven the small sample size, the model was limited to a maximum of three covariates per step to prevent overfitting. Odds ratios (OR) with 95% confidence intervals (CI) were calculated. A p-value \u0026lt;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eTwelve patients met inclusion criteria and underwent biatrial cardioneuroablation. All procedures were successfully completed without major complications such as pericardial effusion, tamponade, thromboembolism, or phrenic nerve injury.\u003c/p\u003e\u003cp\u003eOf the 12 patients, 5 (41.7%) had cardioinhibitory vasovagal syncope, 4 (33.3%) had vagally mediated sinus node dysfunction, and 3 (25.0%) had functional AV block.\u003c/p\u003e\u003cp\u003ePost-procedural heart rate increase was similar across subgroups (VVS: +26\u0026thinsp;\u0026plusmn;\u0026thinsp;3 bpm; SND: +24\u0026thinsp;\u0026plusmn;\u0026thinsp;4 bpm; AVB: +25\u0026thinsp;\u0026plusmn;\u0026thinsp;5 bpm; p\u0026thinsp;=\u0026thinsp;0.68).\u003c/p\u003e\u003cp\u003eAt 12-month follow-up, freedom from recurrence or pacemaker implantation was 80% for VVS, 100% for SND, and 66.7% for AVB (p\u0026thinsp;=\u0026thinsp;0.41).\u003c/p\u003e\u003cp\u003eThe only pacemaker implantation occurred in a patient with functional AV block. No significant differences were observed in procedure duration, fluoroscopy exposure, or complication rates among subgroups.\u003c/p\u003e\u003cp\u003eThese findings suggest that CNA efficacy and safety were consistent across distinct vagally mediated phenotypes, although larger cohorts are required to confirm differential responses.\u003c/p\u003e\u003cp\u003eProcedural efficiency was high (Table II). Mean total procedure time was 141\u0026thinsp;\u0026plusmn;\u0026thinsp;22 min (95% CI 127\u0026ndash;155), with minimal fluoroscopy exposure (3\u0026thinsp;\u0026plusmn;\u0026thinsp;1 min, 95% CI 2.4\u0026ndash;3.6). Average radiofrequency power was 37\u0026thinsp;\u0026plusmn;\u0026thinsp;3 W (95% CI 35.1\u0026ndash;38.9), with 8\u0026thinsp;\u0026plusmn;\u0026thinsp;4 lesions (95% CI 6.5\u0026ndash;9.5) delivered per patient. Acute autonomic confirmation was achieved in all cases, evidenced by transient sinus slowing or brief asystole during ablation.\u003c/p\u003e\u003cp\u003eAutomated electrogram detection using the AI module identified an average of 5.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2 autonomic clusters per patient, predominantly located around the left superior and inferior pulmonary veins and the ligament of Marshall. Operator review confirmed 94% concordance with visually assessed fractionation patterns, supporting algorithmic reliability.\u003c/p\u003e\u003cp\u003eResting sinus rate increased significantly from baseline, with a mean post-ablation rise of 25\u0026thinsp;\u0026plusmn;\u0026thinsp;4 bpm (95% CI 22.5\u0026ndash;27.5; p\u0026thinsp;=\u0026thinsp;2.3 \u0026times; 10⁻\u0026sup1;⁰), indicating effective parasympathetic attenuation.\u003c/p\u003e\u003cp\u003eAt a median follow-up of 12.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7 months, 10 of 12 patients (83.3%, 95% CI 51.6\u0026ndash;97.9) remained free of syncope or clinically significant bradyarrhythmia and required no pacemaker implantation. Two patients (16.7%, 95% CI 2.1\u0026ndash;48.4) experienced recurrent symptomatic bradyarrhythmia; one (8.3%, 95% CI 0.2\u0026ndash;38.5) ultimately underwent permanent pacemaker implantation. No late procedural complications occurred.\u003c/p\u003e\u003cp\u003eCompared with the control group, patients undergoing CNA showed significantly greater freedom from recurrent syncope or bradyarrhythmia (83.3% vs 40.0%; p\u0026thinsp;=\u0026thinsp;0.04) and a lower need for pacemaker implantation (8.3% vs 30.0%; p\u0026thinsp;=\u0026thinsp;0.03) during a comparable mean follow-up of 12.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8 months.\u003c/p\u003e\u003cp\u003eIn the combined cohort (CNA and control, n\u0026thinsp;=\u0026thinsp;22), multivariate logistic regression identified two independent predictors of recurrence or pacemaker implantation: absence of significant post-procedural heart rate increase (\u0026lt;\u0026thinsp;20 bpm) (OR 8.6; 95% CI 1.3\u0026ndash;57.1; p\u0026thinsp;=\u0026thinsp;0.02) and functional atrioventricular block subtype (OR 6.9; 95% CI 1.1\u0026ndash;43.5; p\u0026thinsp;=\u0026thinsp;0.04).\u003c/p\u003e\u003cp\u003eNeither age, sex, baseline HR, nor total procedure time were independently associated with recurrence (p\u0026thinsp;\u0026gt;\u0026thinsp;0.2 for all).\u003c/p\u003e\u003cp\u003eIn patients achieving a heart rate increase\u0026thinsp;\u0026ge;\u0026thinsp;25 bpm post-ablation, the probability of remaining free from clinically significant bradyarrhythmia at 12 months was 91% (vs 50% in those below this threshold; p\u0026thinsp;=\u0026thinsp;0.03 by Kaplan\u0026ndash;Meier analysis).\u003c/p\u003e\u003cp\u003eThese data suggest that effective parasympathetic attenuation, reflected by a substantial HR rise, is the most robust marker of durable CNA response.\u003c/p\u003e\u003cp\u003eOverall, these findings suggest that biatrial cardioneuroablation, when guided by ultra-high-density mapping and automated electrogram identification under robotic control, can produce sustained improvements in resting heart rate and symptom control, while maintaining a favorable safety profile even in a real-world, drug-refractory population of vagally mediated bradyarrhythmias (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003e; Table III).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003cp\u003eThis study has several important limitations. First, its retrospective, single-center design and the small sample size inherently limit statistical power and generalizability. Although the inclusion of a contemporaneous control cohort provides a comparative framework, residual selection bias cannot be excluded, as treatment allocation was not randomized.\u003c/p\u003e\u003c/p\u003e\u003cp\u003eSecond, while the integration of AI-based electrogram analysis improved objectivity in identifying autonomic targets, the algorithm parameters were partially proprietary and validated internally; external reproducibility should be confirmed in independent datasets.\u003c/p\u003e\u003cp\u003eThird, the multivariate analysis must be interpreted cautiously due to the low event rate and the limited number of covariates included to avoid model overfitting. The identified predictors\u0026mdash;namely functional AV block and limited heart rate response\u0026mdash;should therefore be viewed as hypothesis-generating rather than definitive and do not establish superiority over conventional pacing strategies.\u003c/p\u003e\u003cp\u003eFourth, although subgroup comparisons (VVS, SND, AVB) revealed similar trends, the small numbers preclude reliable detection of subtle phenotype-specific differences.\u003c/p\u003e\u003cp\u003eFifth, follow-up duration averaged 12.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7 months, insufficient to assess potential late reinnervation or autonomic remodeling, which may influence long-term efficacy.\u003c/p\u003e\u003cp\u003eLastly, autonomic function was inferred indirectly through heart rate response rather than formal autonomic testing (e.g., heart rate variability, baroreflex sensitivity), limiting mechanistic insight.\u003c/p\u003e\u003cp\u003eLarger, multicenter prospective studies with extended follow-up, standardized AI algorithms, and direct autonomic measurements are warranted to validate these preliminary observations.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis retrospective, single-center observational study suggests that biatrial CNA performed with ultra\u0026ndash;high-density electroanatomical mapping, AI-assisted electrogram analysis, and robotic magnetic navigation (RMN) is feasible and can be executed with a favorable procedural safety profile in patients with drug-refractory vagally mediated bradyarrhythmias, including cardioinhibitory VVS, vagally mediated SND, and functional AV block. Importantly, no randomization or treatment-assignment control was performed, and outcomes therefore reflect real-world clinical practice rather than controlled experimental conditions.\u003c/p\u003e\u003cp\u003eAll procedures were completed without acute complications, and a consistent increase in resting sinus rate was observed, supporting effective parasympathetic attenuation. At approximately one year of follow-up, most patients remained free from clinically significant bradyarrhythmia or pacemaker implantation. These findings suggest potential mid-term clinical benefit in appropriately selected patients; however, the small sample size and observational design limit the strength of causal inference.\u003c/p\u003e\u003cp\u003eOur results are consistent with prior prospective series and meta-analyses reporting symptom improvement and autonomic modulation following CNA [\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Moreover, the ROMAN randomized trial demonstrated a substantial reduction in syncope recurrence compared with conservative management [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The use of a biatrial approach in this study aligns with the 2024 EHRA/HRS/APHRS/LAHRS consensus statement [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], which emphasizes comprehensive denervation of sinus and AV nodal innervation to reduce the risk of incomplete neuromodulation and potential reinnervation reported after right-sided ablation alone.\u003c/p\u003e\u003cp\u003eA notable feature of our workflow is the combined use of ultra\u0026ndash;high-density mapping and AI-based electrogram analysis to aid in the identification of ganglionated plexi [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], together with RMN, which provided stable catheter control with minimal fluoroscopy. This strategy may help avoid excessive or anatomically imprecise ablation and could potentially lower the risk of collateral injury, including esophageal, phrenic nerve, or pulmonary vein injury [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. While promising, these technical advantages should be interpreted with caution, as systematic comparative data are not yet available.\u003c/p\u003e\u003cp\u003eLeft atrial access remains a key procedural step. RF-assisted transseptal puncture under ICE guidance was used systematically in this cohort, consistent with evidence from the TRAVERSE-LA randomized trial demonstrating shorter access time and reduced mechanical complications compared with conventional needle puncture [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The absence of TSP-related complications in this series may reflect the standardized use of RF-assisted access and continuous anticoagulation; however, the study is underpowered to assess procedural safety comprehensively.\u003c/p\u003e\u003cp\u003eFrom a mechanistic standpoint, the observed clinical improvements support the hypothesis that hypervagotonia was the dominant driver of symptoms. Ablation of left- and right-sided autonomic inputs resulted in a sustained increase in resting sinus rate, which may reflect durable attenuation of parasympathetic efferent pathways [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In this cohort, right-sided autonomic targets were approached from the left atrium, avoiding direct right atrial ablation and potentially reducing the risk of phrenic nerve injury; however, whether this approach provides equivalent or superior long-term autonomic modulation requires further investigation.\u003c/p\u003e\u003cp\u003eTilt-table testing (TTT) was used as a prerequisite for inclusion and served as an essential tool for confirming reflex-mediated physiology prior to CNA [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. By distinguishing parasympathetic-mediated bradyarrhythmia from conditions such as orthostatic intolerance or structural conduction disease, TTT supported more precise candidate selection and may have contributed to the low recurrence and complication rates observed [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Nonetheless, TTT-based selection criteria vary across centers, and further standardization is needed.\u003c/p\u003e\u003cp\u003eThis study has several limitations. The retrospective, non-randomized design introduces potential selection bias, and the control cohort may differ from the CNA group in symptom severity or treatment preference. The small sample size limits statistical power, particularly for subgroup analysis and multivariable modeling. Follow-up duration was approximately one year, which is insufficient to determine long-term durability or the potential for autonomic reinnervation. Accordingly, these findings should be regarded as exploratory and hypothesis-generating.\u003c/p\u003e\u003cp\u003eOverall, this real-world experience supports the feasibility of integrating advanced mapping and robotic navigation technologies into CNA workflows and highlights the importance of careful patient selection. Larger, prospective, multicenter studies with longer follow-up are needed to validate durability, refine procedural endpoints, and define optimal patient selection criteria.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eBiatrial CNA performed with ultra\u0026ndash;high-density mapping, AI-assisted electrogram analysis, and RMN represents a feasible, safe, and radiation-sparing strategy for the management of drug-refractory vagally mediated bradyarrhythmias. By enabling comprehensive vagal denervation while minimizing procedural risks, particularly those related to transseptal puncture, this approach offers a device-sparing alternative to permanent pacemaker implantation and is consistent with current international recommendations.\u003c/p\u003e\u003cp\u003eLooking forward, integration of advanced AI and machine-learning algorithms may allow real-time identification of the fossa ovalis and high-probability GP sites, improving safety and dynamically tailoring lesion sets. Fusion of pre-procedural imaging with high-density mapping could provide individualized roadmaps, while novel devices such as RF-enabled or pressure-sensing needles, in combination with robotic navigation, may further reduce access-related complications. Long-term monitoring with implantable loop recorders will be essential to clarify the durability of vagal denervation and to guide potential reintervention.\u003c/p\u003e\u003cp\u003eFuture research should also explore expanding CNA indications to mixed vasodepressor\u0026ndash;cardioinhibitory syncope and vagally mediated atrial fibrillation, as well as testing novel energy sources such as pulsed-field ablation, which may enhance both safety and efficiency. Large-scale, multicenter randomized trials with long-term follow-up will be crucial to standardize procedural endpoints, refine patient selection, and establish CNA as a cornerstone of modern autonomic modulation therapy.\u003c/p\u003e\u003cp\u003eCollectively, these findings provide real-world support for integrating advanced mapping and robotic technologies in CNA practice and may serve as a foundation for multicenter efforts to standardize workflows, define procedural endpoints, and validate long-term clinical outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003estandard deviation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ebpm\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ebeats per minute\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eheart rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCMR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecardiac magnetic resonance\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTTT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003etilt-table test.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThe authors did not receive support from any organization for the submitted work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u0026nbsp;\u003c/strong\u003eThe study was conducted in accordance with the Declaration of Helsinki. The Institutional Ethics Committee of \u0026ldquo;A. Cardarelli\u0026rdquo; Hospital, Naples, reviewed the study protocol and waived the requirement for formal approval, as the analysis involved only anonymized retrospective data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u0026nbsp;\u003c/strong\u003eNot applicable owing to the retrospective design with anonymized data and absence of identifiable images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e The data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u003c/strong\u003e Conceptualization: Fulvio Cacciapuoti and Mario Volpicelli; Methodology: Fulvio Cacciapuoti and Mario Volpicelli; Investigation: Fulvio Cacciapuoti, Mario Volpicelli, Salvatore Crispo, Saverio Ambrosino, Ciro Pirozzi, Orlando Munciguerra, Carmine Nappo and Nicoletta Caccavale; Formal analysis: Fulvio Cacciapuoti, Flavia Casolaro and Mario Volpicelli; Writing\u0026mdash;original draft: Fulvio Cacciapuoti and Mario Volpicelli; Writing\u0026mdash;review \u0026amp; editing: Fulvio Cacciapuoti, Mario Volpicelli and Ciro Pirozzi; Supervision: Fulvio Cacciapuoti and Mario Volpicelli.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAydin MA, Salukhe TV, Wilke I, Willems S. 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PMID: 12679218.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFedorowski A, Kulakowski P, Brignole M, de Lange FJ, Kenny RA, Moya A, Rivasi G, Sheldon R, Van Dijk G, Sutton R, Deharo JC. Twenty-five years of research on syncope. Europace. 2023;25(8):euad163. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/europace/euad163\u003c/span\u003e\u003cspan address=\"10.1093/europace/euad163\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 37622579; PMCID: PMC10450792.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Cardioneuroablation, Robotic magnetic navigation, Ganglionated plexi, Vasovagal syncope, High-density mapping, Artificial intelligence","lastPublishedDoi":"10.21203/rs.3.rs-8068513/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8068513/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eReflex bradyarrhythmias and syncope related to excessive vagal tone may be refractory to conservative therapy and significantly impair quality of life. Cardioneuroablation (CNA) has emerged as a device-sparing alternative, but real-world outcome data remain limited.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe retrospectively evaluated 12 consecutive patients (aged 23\u0026ndash;55 years) with drug-refractory, vagally mediated bradyarrhythmias confirmed by tilt-table testing. All underwent biatrial CNA guided by ultra-high-density electroanatomical mapping with automated fragmented-electrogram detection and robotic magnetic navigation. A contemporaneous cohort of medically managed patients with comparable clinical profiles (n\u0026thinsp;=\u0026thinsp;10) served as a control group. The primary outcome was freedom from syncope or clinically significant bradyarrhythmia without pacemaker implantation. Secondary outcomes included procedural metrics, heart-rate changes, and recurrence during follow-up.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAll CNA procedures were completed without acute complications and with minimal fluoroscopy exposure. Resting sinus rate increased substantially after ablation. Over a mean follow-up of approximately 12 months, most CNA-treated patients remained free of symptomatic bradyarrhythmia or syncope without requiring pacemaker implantation, whereas recurrence and pacemaker placement were less frequent compared with controls. No delayed complications were observed.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eIn this small, retrospective real-world cohort, biatrial CNA guided by automated electrogram analysis and robotic navigation was feasible, safe, and associated with mid-term symptomatic improvement in selected patients with vagally mediated bradyarrhythmias. These findings are exploratory and warrant confirmation in larger, prospective studies with longer follow-up to assess durability and reinnervation risk.\u003c/p\u003e","manuscriptTitle":"Biatrial Cardioneuroablation Guided by Robotic Magnetic Navigation and Artificial Intelligence-Based Mapping in Vagal Bradyarrhythmias: A Controlled Observational Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-28 07:00:31","doi":"10.21203/rs.3.rs-8068513/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5e62d05b-11dd-41a9-a860-6d7729bacbdd","owner":[],"postedDate":"November 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-26T16:12:08+00:00","versionOfRecord":{"articleIdentity":"rs-8068513","link":"https://doi.org/10.1007/s10840-026-02241-w","journal":{"identity":"journal-of-interventional-cardiac-electrophysiology","isVorOnly":false,"title":"Journal of Interventional Cardiac Electrophysiology"},"publishedOn":"2026-01-24 15:59:22","publishedOnDateReadable":"January 24th, 2026"},"versionCreatedAt":"2025-11-28 07:00:31","video":"","vorDoi":"10.1007/s10840-026-02241-w","vorDoiUrl":"https://doi.org/10.1007/s10840-026-02241-w","workflowStages":[]},"version":"v1","identity":"rs-8068513","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8068513","identity":"rs-8068513","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}