Cardioneuroablation (CNA) is an emerging treatment for refractory vasovagal syncope (VVS). While biatrial approaches are common, the efficacy of a stepwise strategy—beginning with right-sided ablation and progressing to the left atrium only if necessary—remains incompletely defined. We conducted an observational, retrospective registry (2024–2025) of 57 patients (mean age 34.5 ± 16.8 years) with highly refractory cardioinhibitory (Vasovagal Syncope International Study 2A/2B, 77.2%) or mixed (Vasovagal Syncope International Study 1, 22.8%) VVS. All patients had normal intrinsic conduction verified by electrophysiological study and a positive atropine challenge. A fragmented electrogram-guided stepwise CNA was performed. Left-sided ablation was performed exclusively if right-sided ablation failed to meet predefined end points (fragmented electrogram elimination, heart rate [HR] increase >25%, and postablation atropine response <10%). Acute procedural success was achieved in 96.5% of cases. Right-sided ablation alone met denervation criteria in 30 patients (52.6%), while 27 (47.4%) required a subsequent biatrial approach. The requirement for a biatrial approach was not significantly predicted by the predominant rhythm disturbance (sinus slowing vs AV block). At a mean follow-up of 12.5 ± 6.0 months, there were 0% syncope recurrences. Significant improvements were observed at 6 months in mean HR (59.7 ± 9.9 to 79.6 ± 7.8 beat/min; p < 0.001) and in all time- and frequency-domain HR variability parameters, confirming sustained parasympathetic withdrawal. A stepwise, electrogram-guided CNA is a highly safe and effective therapy for carefully selected patients with functional VVS. Initial right-sided ablation is sufficient in over half of the cases, safely optimizing procedure time and avoiding unnecessary left atrial access without compromising clinical outcomes.
Cardioinhibitory vasovagal syncope (VVS), frequently characterized by prolonged asystole or high-grade atrioventricular (AV) block, represents a therapeutic challenge, particularly in younger patients. , Although VVS is a common condition that usually responds to conservative and noninvasive measures, current clinical guidelines have historically reserved permanent pacemaker implantation for patients older than 40 years or for highly refractory cases, given the generally benign but recurrent nature of the condition. In a small subset of patients with recurrent, severe, and treatment-refractory episodes, cardioneuroablation (CNA) has emerged as a potential etiological treatment strategy. CNA targets atrial ganglionated plexi (GPs), which mediate excessive parasympathetic input to the sinus node, resulting in bradyarrhythmia, and to the AV node, leading to supra-Hisian block.
Appropriate patient selection is essential, requiring confirmation of a functional, vagally mediated substrate and exclusion of intrinsic conduction system disease, as CNA is not intended as first-line therapy. While sinus node innervation is predominantly right-sided, AV nodal innervation involves both right and left atrial GPs, including the left posteromedial GP. Most published series describe a biatrial ablation strategy, although some have proposed right-sided ablation alone. Whether a stepwise approach beginning with right-sided ablation and proceeding to the left atrium only if predefined denervation end points are not achieved is sufficient in a significant proportion of patients remains incompletely defined. Accordingly, this study aimed to evaluate the efficacy of a stepwise CNA strategy in patients with cardioinhibitory and mixed VVS, identifying clinical predictors for right-sided versus biatrial success, and to characterize postprocedural autonomic modulation using heart rate variability analysis.
Methodology
Study design and population
An observational, retrospective, multicenter study was conducted, including a consecutive series of patients aged 15 to 70 years of both sexes with recurrent VVS. During the study period (2024–2025), a total of 452 patients were evaluated for VVS at our institution; of these, 57 highly refractory cases (12.6%) were selected for CNA. While a cardioinhibitory mechanism does not define refractoriness, it indicates the appropriateness of considering cardioneuroablation; therefore, in our cohort, refractoriness was defined by the failure of standard therapy rather than by the absolute number of syncopal events. Failure of established treatment was defined as recurrent syncope despite patient education, trigger avoidance, increased fluid and salt intake, physical counterpressure maneuvers, and at least one pharmacological agent. CNA was not a first-line therapy and was considered only after thorough evaluation and exclusion of conduction system disease.
Classification of VVS subtypes was rigorously defined according to the Vasovagal Syncope International Study classification. Patients were classified as Type 1 (mixed response: HR falls but does not drop <40 beat/min for >10 seconds, or falls <40 beat/min for <10 seconds without asystole >3 seconds), Type 2A (cardioinhibitory without asystole: HR falls <40 beat/min for >10 s, but asystole is <3 seconds), or Type 2B (cardioinhibitory with asystole: asystole >3 seconds).
Notably, all patients (n = 57) underwent a Head-Up Tilt Test (HUTT), which served as the indispensable standard used to establish the VASIS classification in 100% of the analyzed cases. The tests included both those performed within our institution and those conducted externally before patient referral, thereby ensuring the absence of bias due to a lack of standardization in the screening test.
Atropine challenge and electrophysiological study
To ensure patients possessed a purely functional substrate rather than intrinsic disease, an atropine challenge was performed before the procedure (dose: 0.04 mg/kg for weight <50 kg; 2 mg otherwise) under electrocardiographic monitoring. The test was considered positive if the baseline HR increased by >25%. , A standard Electrophysiological Study was performed to measure conduction intervals: a normal AH interval was defined as 55 to 125 ms, a normal His-Ventricular (HV) interval as 35 to 55 ms, , and the AV node refractory period as 250 to 400 ms. A decapolar catheter was introduced into the coronary sinus, and a quadripolar catheter was used for His bundle recording.
Mapping and localization of GPs
Anatomical and activation maps were generated using the CARTO 3 System (Biosense Webster), the Rhythmia HDx platform (Boston Scientific), or the EnSite X EP System (Abbott), employing the Pentaray (Biosense Webster), Orion (Boston Scientific), or HD Grid (Abbott) mapping catheters, respectively. GP localization was achieved through manual registration of low-amplitude Fragmented Electrograms (FEGM) with 4 to 8 deflections, obtained using high-frequency filters recorded at filter settings of 100 to 500 Hz and a sweep speed of 200 mm/s, according to Aksu et al. If adequate results were not obtained following right-sided GP ablation, a transseptal puncture was performed under intracardiac echocardiography guidance. A deflectable sheath (Agilis, Abbott) was introduced, through which the multipoint and ablation catheters were advanced to localize FEGMs. Activation mapping was used to localize the sinus node, followed by phrenic nerve delimitation via stimulation at 25 mA with a cycle length of 1000 ms (its course was marked with black points); nerve capture was defined as diaphragmatic contraction upon stimulation. Activated clotting time (ACT) was measured, and heparin was administered every 30 minutes to maintain an ACT >300 seconds.
Radiofrequency ablation technique
Ablation was performed using contact force (CF) sensing catheters SmartTouch (Biosense Webster), TactiCath (Abbott), and IntellaNav (Boston Scientific). Ablation parameters were standardized to achieve an Ablation Index (AI) of 400 to 450 and a lesion size index of 3.5 to 5, with a CF of 10 to 20 g, power of 30 to 35 W, a maximum temperature of 43°C, an irrigation flow rate of 30 mL/min, and a local impedance drop of 15 to 20 ohms. Ablation always commenced at the right superior GP followed by the right inferior GP. Acute success parameters were defined as an HR elevation of >25% from baseline, elimination of FEGMs (<0.05 mV), and a postablation atropine response with an HR elevation of no more than 10%. If HR elevation was not achieved after right-sided ablation as described, ablation was then performed on the left side, targeting the left superior ganglionated plexus (LSGP) and the posteromedial GPs of the left atrium. Left-sided ablation was performed using the same parameters mentioned above.
Follow-up and autonomic evaluation
Clinical follow-up was conducted at 3, 6, and 12 months through interrogation for syncopal episodes and Holter monitoring to assess minimum, average, and maximum heart rates. Heart rate variability (HRV) parameters were analyzed in the time domain (SDNN [ms], SDANN [ms], pNN50 [%], rMSSD [ms]; normal values considered >100 ms, >100 ms, >5%, and >20 ms, respectively) and in the frequency domain (low frequency/high frequency [LF/HF] ratio; normal value 1.5–2.0).
Results
Fifty-seven consecutive patients underwent CNA between 2024 and 2025. The cohort included 40 (70.2%) women, with a mean age of 34.5 ± 16.8 years. Following strict adherence to diagnostic criteria, 44 patients (77.2%) presented with cardioinhibitory VVS (VASIS Type 2A/2B), and 13 (22.8%) with mixed VVS (VASIS Type 1). Notably, one patient initially classified as mixed VVS was reclassified to Type 2B due to the documentation of pauses >3 seconds.
Continuous ECG documentation during a spontaneous syncopal episode in the ambulatory setting was available in only 18 patients (31.5%), revealing sinus arrest in 12, high-grade AV block in 4, and profound sinus bradycardia in 2. However, the rhythm disturbance recorded during the HUTT for the entire cohort was sinus slowing.
A positive atropine test was documented in 42 (73.6%) patients; in the total group, the heart rate increase was 33.5 ± 9.5 beat/min. Mean conduction intervals were: (1) AH interval 104.5 ± 10.3 ms, (2) His-Ventricular interval 49.4 ± 4.2 ms, and (3) Effective Refractory Period of the AV Node (ERP-AVN) 354.5 ± 21.9 ms for the entire population. Voltage and activation mapping utilized CARTO, Rhythmia, and EnSite systems in 41 (71.9%), 8 (14.0%), and 8 (14.0%) patients, respectively. GP localization was based on FEGM mapping in all patients. Right-sided ganglia were localized in all patients (100%), while the LSGP and LIGP were identified in 27 (47.3%) and 6 (10.5%), respectively ( Table 1 ).
Table 1
Baseline and clinical characteristics according to ablation strategy (n = 57)
| Variable | Total population (n = 57) | Right-sided only (n = 30) | Biatrial (n = 27) | p-value |
|---|---|---|---|---|
| Sex, n (%) | ||||
| Male | 17 (29.8) | 8 (26.6) | 9 (33.3) | 0.584 |
| Female | 40 (70.2) | 22 (73.4) | 18 (66.6) | 0.427 |
| Age, years (mean ± SD) | 34.5 ± 16.8 | 33.2 ± 15.1 | 35.9 ± 18.5 | 0.537 |
| Type Syncope (VASIS) | ||||
| Type 1 | 13 (22.8) | 8 (26.6) | 5 (18.5) | 0.362 |
| Type 2A/2B | 44 (77.2) | 22 (73.3) | 22 (81.4) | 0.265 |
| Predominant Rhythm Disturbance | ||||
| Predominant Sinus Slowing, n (%) | 53 (92.9) | 29 (96.6) | 24 (88.8) | 0.417 |
| Predominant AV Block, n (%) | 4 (7.1) | 1 (3.4) | 3 (11.1) | 0.447 |
| Number of syncope episodes, median [IQR] | 5 [3–6] | 5 [3–6] | 4.5 [3–5] | 0.353 |
| Positive atropine test (>25%), n (%) | 42 (73.6) | 24 (80.0) | 18 (66.6) | 0.254 |
| HR increase with atropine vs baseline | 33.5 ± 9.5 | 34.2 ± 8.5 | 32.7 ± 10.5 | 0.551 |
Stepwise cardioneuroablation strategy and anatomical-electrical outcomes
To highlight the efficacy of our stepwise protocol, patients were analyzed based on the required ablation strategy. GP ablation on the right side alone achieved the prespecified success endpoints in 30 patients (52.6%). The remaining 27 patients (47.4%) required a subsequent biatrial approach to achieve denervation end points ( Table 2 ).
Table 2
Procedural and follow-up characteristics according to ablation strategy
| Variable | Total population (n = 57) | Right-sided only (n = 30) | Biatrial (n = 27) | p-value |
|---|---|---|---|---|
| Baseline resting HR (bpm, mean ± SD) | 50.1 ± 8.5 | 51.2 ± 7.8 | 48.8 ± 9.1 | 0.291 |
| AH interval (ms, mean ± SD) | 104.5 ± 10.3 | 103.5 ± 9.8 | 105.6 ± 10.9 | 0.453 |
| HV interval (ms, mean ± SD) | 49.4 ± 4.2 ms | 49.0 ± 4.0 | 49.8 ± 4.4 | 0.482 |
| AVN effective refractory period (ms, mean ± SD) | 354.5 ± 21.9 | 353.0 ± 20.5 | 356.2 ± 23.4 | 0.586 |
| Mapping system/ Mapping catheter/ Ablation catheter, n (%) | ||||
| CARTO 3/ Pentaray/ SmartTouch | 41 (71.9) | 22 (73.3) | 19 (70.3) | NS |
| Rhythmia/ Orion/ IntellaNav | 8 (14.0) | 4 (13.3) | 4 (14.8) | NS |
| EnSite/ HD Grid/ TactiCath | 8 (14.0) | 4 (13.3) | 4 (14.8) | NS |
| Ganglia targeted, n (%) | ||||
| RSGP | 57 (100) | 30 (100) | 27 (100) | NS |
| RIGP | 57 (100) | 30 (100) | 27 (100) | NS |
| LSGP | 27 (47.3) | 0 (0.0) | 27 (100) | <0.001 |
| LIGP | 6 (10.5) | 0 (0.0) | 6 (22.2) | <0.001 |
| Ablation parameters (mean ± SD) | ||||
| Power (W) | 34.2 ± 4.9 | 33.8 ± 4.5 | 34.6 ± 5.3 | 0.540 |
| Ablation Index | 457.0 ± 17.5 | 456.0 ± 16.5 | 458.0 ± 18.6 | NS |
| Lesion Size Index (LSI) | 3.7 ± 0.3 | 3.6 ± 0.2 | 3.8 ± 0.4 | NS |
| Local impedance drop (Ω) | 17.5 ± 3.5 | 17.0 ± 3.0 | 18.0 ± 4.0 | NS |
| Duration (s) | 52.3 ± 5.6 | 51.8 ± 5.2 | 64.8 ± 6.0 | 0.264 |
| Mean temperature (°C) | 48.0 ± 7.0 | 47.5 ± 6.5 | 48.5 ± 7.5 | 0.589 |
| Total procedure time (min) | 54.7 ± 22.1 | 45.0 ± 15.5 | 65.5 ± 24.2 | <0.05 |
| Complications, n (%) | 0 (0.0) | – | – | – |
| Postablation outcomes | ||||
| HR increase from baseline to postablation (bpm) | 25.7 ± 7.0 | 26.5 ± 6.5 | 24.8 ± 7.5 | NS |
| HR increase with atropine <10%, n (%) | 55 (96.5) | 30 (100) | 25 (92.5) | 0.134 |
| Follow-up duration (months) | 12.5 ± 6.0 | 12.2 ± 5.5 | 12.8 ± 6.6 | NS |
| Syncope recurrence, n (%) | 0 (0.0) | – | – | – |
| Redo ablation, n (%) | 0 (0.0) | – | – | – |
| Pacemaker implantation required, n (%) | 0 (0.0) | – | – | – |
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