Vasovagal syncope (VVS) is a prevalent condition, with approximately 42% of women and 32% of men experiencing at least one episode by the age of 60.1 Despite its generally benign nature, the recurrence rate is considerable, impacting morbidity and quality of life.2,3 Traditional treatments encompass lifestyle modifications, increased salt and water intake, physical counterpressure manoeuvres and pharmacological therapies, such as fludrocortisone or midodrine.4 Notably, a subset of patients over 40 years of age with primarily cardioinhibitory responses may derive benefit from dual-chamber pacemaker implantation.5 However, even with these interventions, many patients still face therapy-refractory VVS episodes.6
The past two decades have witnessed the emergence of cardioneuroablation (CNA) as a promising therapy for VVS.7 This technique targets the intrinsic cardiac autonomic nervous system (ANS), specifically the ganglionated plexi (GPs) located outside the pulmonary vein–left atrial junction and within the epicardial atrial fat pads.8–10 These GPs, which play a pivotal role in connecting preganglionic and postganglionic nerve fibres, influence heart rate and cardiac function.11 CNA involves the localisation and ablation of these GPs. Various methodologies targeting the right or left atrium or the use of biatrial procedures have been documented for GP identification and ablation.12–14
Despite the encouraging preliminary data in the treatment of VVS with CNA, its broad applicability remains hindered by challenges such as patient selection, ablation strategies and long-term outcome data.14
This review integrates findings from diverse studies to provide a comprehensive perspective on the methodology of CNA, centred around the anatomical and physiological rationale, including the concept of selected GP sites that serve as gateways to the sinoatrial (SA) node and atrioventricular (AV) node. This concept of gateway GPs that can be accessed and potentially ablated from either the right or left atrium, may provide a unifying hypothesis to explain how the widely varying methods can achieve similarly highly successful outcomes in VVS.
Basis of Cardioneuroablation in the Management of Vasovagal Syncope
Dysregulation of the ANS underpins VVS, making it an appropriate therapeutic target.15 The cardiac ANS includes both sympathetic and parasympathetic divisions.9 These divisions have distinct neurotransmitters and can either activate or inhibit target tissues. These components of the nervous system converge at GPs housed in epicardial fat pads to exert their influence on cardiac physiology.9 These GPs are complex integration centres that communicate both efferent and afferent feedback.9 The localised ablation of these GPs through CNA has shown promising results in the treatment of VVS (Table 1), but the exact mechanism of CNA efficacy remains to be understood.
Anatomy and Physiology of the Cardiac Autonomic Nervous System
The neurocardiac axis forms a complex hierarchical network that serves as the interface between the ANS and the cardiovascular system. This understanding is essential for developing mechanism-guided approaches to VVS therapy. Originating from the brain cortex, brainstem and spinal cord, the central ANS exerts its influence through intrathoracic extracardiac innervation characterised by sympathetic chain ganglia and the vagus nerve.16
By contrast, the intrinsic cardiac autonomic system is primarily composed of GPs in epicardial fat pads. These GPs are strategically located in anatomically well-defined regions in the heart, specifically near the four pulmonary vein–atrial junctions and around critical cardiac structures, such as the SA and AV nodes.8,9,17,18 They comprise an extensive neural network densely innervated by adrenergic and cholinergic nerve fibres (Figure 1).8,9,19 Adrenergic nerve fibres increase heart rate and strengthen cardiac contractility, while cholinergic nerve fibres decrease heart rate and reduce cardiac contractility. The number of intrinsic cardiac neurons ranges between 43,000 and 94,000 with the density of nerve cells in ganglia decreasing with age.20 These GPs play a pivotal role in modulating cardiovascular parameters such as heart rate, conduction velocity, contractility, refractory periods and relaxation, and communicate information via afferents back to the central nervous system, but they also activate reflex arcs such as the Bezold–Jarisch cardioinhibitory reflex.8,9

The intricate interplay between the sympathetic and parasympathetic components allows for nuanced regulation of cardiac function. CNA almost certainly affects both components and may specifically diminish the parasympathetic overactivity that typically triggers the cardioinhibitory reflex associated with VVS, while also preventing excessive sympathetic withdrawal.
The presence of afferent (sensory) neurons, efferent (motor) neurons and interconnecting (local circuit) neurons in these GPs adds further complexity to this nuanced regulation of cardiac function. Their unique composition enables them to express both cholinergic and adrenergic effects, and their extensive interconnections pave the way for integrated communication between the parasympathetic and sympathetic divisions of the ANS.16 In a recent case report, CNA was used to treat severe mixed pattern VVS and orthostatic tachycardia without cardioinhibition, demonstrating the potential of CNA to treat VVS by modulating the extracardiac ANS through cardiac ganglionic plexus ablation, probably through modulation of the efferent neurons.21
Stavrakis and Po commented on the pivotal role of GPs in both arrhythmogenesis and autonomic regulation of cardiac function.22 The GPs harbour a diverse array of neuropeptides and neuromodulators, including calcitonin gene-related peptide and vasoactive intestinal polypeptide, which underscores the intricate nature of their autonomic regulatory influence.23,24 This complexity supports the hypothesis that disrupting aberrant autonomic feedback loops may be critical to the efficacy of CNA in treating vasovagal VVS.
The intricate organisation of this neurocardiac axis, including the central and intrinsic cardiac components, facilitates the complex interplay of autonomic reflexes. Input from other autonomic reflex arcs, such as the baroreflex (in response to changes in blood pressure, leading to adjustments in heart rate and vessel dilation) and renal nerves (in response to changes in fluid balance, influencing blood volume and pressure), can also influence this global and regional autonomic tone, thereby enabling direct communication between the ANS and the cardiovascular system.9,16,25
In the treatment of VVS, GPs are chosen as the principal targets for CNA because they are functionally significant in physiology and their anatomical sites are convenient to access with an ablation catheter.26
Targets for Cardioneuroablation
In 2005, Pachon et al. introduced CNA as an innovative therapeutic approach for managing patients with a dominantly adverse parasympathetic autonomic drive.7 They used a unique spectral analysis method to pinpoint areas of atrial myocardium that were heavily innervated, but widespread application was restricted by the necessity for specialised pre-amplifiers and spectral analysis software. Their method divided the atrial myocardium into two types: compact (housing well-connected cells and with a homogenous spectral profile of around 40 Hz); and fibrillar (interlaced with neural fibres and with a fragmented and elevated frequency spectrum exceeding 100 Hz). The principal limitation of this spectral-guided approach was in the specialised hardware and software required, which were not readily available in all electrophysiological laboratories. Subsequently, modifications were made to the spectral analysis technique, enabling the identification of both the major GPs and multiple minor GPs without requiring specialised equipment.27
Scanavacca et al. applied high-frequency stimulation (HFS) to localise GPs in patients with frequent VVS episodes, and their methodology was subsequently validated by Yao et al. in a series of clinical cases.28,29 Unlike Pachon et al.’s biatrial ablation approach, Yao et al. proposed a targeted technique of linear ablation in the left atrium alone, where vagal reflexes were frequently observed during AF ablation.7,29 Their long-term efficacy results in 57 VVS patients indicated a 91.2% syncope-free rate over a 36-month follow-up period.30 The success rates of the HFS-guided and anatomical approaches were statistically comparable, both in terms of syncope recurrence and prodromal symptoms.
Although anatomical approaches have been used, these do not always specifically target the GPs due to the variability in GP position between patients.9,31,32 Debruyne et al. leveraged both CT and electroanatomic mapping for more precise GP localisation, focusing on the ablation of the superior parasagittal ganglionic plexus in a more specific ablation approach.33 This was based on previous work showing clinical changes following ablation of this region.33 The localised strategy showed comparable therapeutic efficacy and further validated the importance of the superior paraseptal ganglionated plexus (SPSGP), as confirmed by subsequent studies (Table 1). However, recent meta-analyses have suggested lower success rates for right atrium-only ablation compared with left atrium-only or biatrial approaches, underscoring the need for randomised controlled trials (RCTs) to resolve these discrepancies.14
Aksu et al. offered a simplified methodology by targeting fractionated electrograms at conventional GP locations, which was achieved with standard electrophysiological equipment through simple filter setting adjustments.34 This technique evaluated bipolar endocardial atrial electrograms for amplitude and number of deflections, aiding in more effective GP targeting using conventional electrophysiological equipment.
Pachon et al. explored a method of extracardiac vagal stimulation via the jugular vein. This stimulation typically causes AV block or asystole, which provides a clearly defined functional endpoint for CNA procedures.35
Piotrowski et al. conducted the first RCT on CNA for VVS, which found a significantly lower rate of syncope recurrence in the intervention group compared with the non-pharmacological control group after 2 years, thus significantly strengthening the evidence for CNA’s efficacy.36
Despite the use of diverse strategies for locating and ablating GP sites in the treatment of VVS, studies on CNA have consistently reported favourable outcomes (Table 1).
There appears to be a pivotal role of the SPSGP and inferior paraseptal ganglionated plexus (IPSGP) in mediating sinus arrest or AV block, respectively, which leads to cardioinhibitory VVS. Hu et al. previously proposed the SPSGP as the primary target during CNA, demonstrating its significance in modulating the sinus node rate.37 Although targeting of the SPSGP appears sufficient for most patients, Ascione et al. highlighted the importance of additional ablation of the IPSGP, perhaps to abolish the vagal inputs into the AV node, which can lead to transient AV block and thence to bradycardia.38 Indeed, most studies of cardioneural ablation target one or both of these GP sites (Table 1), implying that there may be distinct gateway GPs that modulate autonomic outputs to the SA and AV nodes.
Malcolme-Lawes et al. showed that applying continuous HFS at specific GP sites across the left atrium led to a transient AV block in AF (short-lived AF was typically triggered during HFS).39 This AV block effect for all GP sites across the atrium was notably abolished after ablating only a single GP: the IPSGP. This suggests that the IPSGP serves as a critical node or gateway to the AV node, through which the other GPs across the heart affect AV nodal function (Figure 2). Conversely, AV nodal GP responses to HFS were not significantly altered after ablating GP sites other than the IPSGP. Given the anatomical location of the IPSGP, its fibres can be denervated by ablation in both the right atrium and left atrium, which could explain why both approaches have shown positive results (Figure 3). This finding is supported by Hu et al., who noted that during ablation of the SPSGP, heart rate increased from 61.3±12.2 BPM to 82.4±14.7 BPM (p<0.001), whereas during ablation of other GPs only vagal responses were observed without any heart rate increase, implying that the SPSGP may be a functional gateway to the SA node.37
Similarly, Malcolme-Lawes et al. also reported significant changes in heart rate variability (HRV; a key measure of autonomic modulation of the sinus node) following ablation at a specific GP site: the SPSGP. Both high-frequency and low-frequency HRV parameters decreased substantially after ablation at the SPSGP, whereas no significant alterations in HRV parameters were observed after ablation for other GP sites, including the IPSGP site (the gateway to the AV node).39 These observations suggest that the SPSGP acts as a gateway for modulating autonomic input to the SA node in humans, and this particular GP may play a significant role in patients in whom sinus arrest is the dominant pathophysiological mechanism causing VVS.
The gateway GP theory and the distinctive roles of GP sites such as the IPSGP and SPSGP offer a potential explanation for the generally favourable outcomes for VVS seen across various CNA trials despite differing ablation strategies. This consistent success, regardless of the ablation techniques used, including left atrial-only or right atrial-only CNA, may be explained by the fact that these GPs can be targeted from either atrium, and that the major gateway GPs may be functionally consistent across patients, but equally may be characterised easily by using techniques such as high-frequency endocardial stimulation, and which can be further verified by extracardiac vagal stimulation in the neck.35
Such studies could prove invaluable for refining existing CNA methods and establishing a standardised approach beneficial to future research. Such exploration would be instrumental in refining existing CNA methodologies and establishing a standardised approach for future trials.
The existing literature is marked by a lack of sham-controlled RCTs. For broader acceptance and application, large, multicentre, sham-controlled RCTs are urgently needed, which would entail a consensus on a standardised protocol among the few centres currently offering CNA.40
Selecting Patients and Standardising Care
Regarding patient selection for CNA, various studies offer insights into the efficacy across age group and syncope type. Notably, previous double-blinded RCTs such as VPS II and SYNPACE, which focused on pacemaker implantation in patients over 18 years of age, showed no pacing benefits in relatively younger patients.41,42 However, these studies were limited by the inclusion of mixed syncope types and short follow-up periods.
Subsequent RCTs targeting older patients (mean age of 63 years), such as ISSUE 3, SPAIN and BioSync reported better results with pacing.43–45 In ISSUE 3, patients were randomly assigned to ‘pacemaker on’ or to ‘pacemaker off’ with a dual-chamber pacemaker with rate drop response or sensing only; this showed a 57% relative reduction in the risk of syncope recurrence rather than complete abolition of symptoms, implying an additional mechanism sustaining VVS beyond cardioinhibition. CNA outcomes appear consistently much higher, across many studies, which may imply a mechanism of action that goes beyond abolishing cardioinhibtion.14,46 We speculate that one additional way, beyond cardioinhibition, in which CNA may reduce syncope and presyncope is by modifying reflex arcs that may be initiated through autonomic afferent communication arising from inside the heart.
Head-up tilt testing (HUTT) remains a crucial tool for patient selection in CNA, providing valuable insights into the haemodynamic patterns of VVS. Recent studies have underscored the significance of HUTT in differentiating VVS subtypes and guiding treatment decisions. Russo et al. demonstrated that patients with classical VVS have higher HUTT positivity rates and a distinct cardioinhibitory response pattern compared with those with non-classical VVS, emphasising the importance of continuing HUTT until syncope occurs, rather than terminating at presyncope to capture patients who have a cardioinhibitory response.47
Furthermore, van Dijk et al. used HUTT to show how ‘vasodepression’ can encompass both diminished arterial constriction and increased venous pooling.48 HUTT also identifies age-dependent shift in VVS mechanisms, characterised by attenuated cardioinhibition and augmented vasodepression in older patients.49 This age-related transition in pathophysiology may explain the reduced efficacy of cardiac pacing interventions in the elderly, highlighting the necessity of considering the balance between cardioinhibitory and vasodepressor components when formulating a treatment strategy, particularly when selecting candidates for CNA.
CNA has shown promise, particularly in younger patients. A retrospective study conducted by Pachon et al. in 2011 reported that 93% of 43 VVS patients (mean age: 32.9 years) remained syncope-free after CNA after a mean follow-up of 45 months.50 Similar high success rates were confirmed by Hu et al. in a retrospective analysis of CNA in 115 patients with a mean age of 43 years.37 For older populations, the available data are sparse, suggesting that pacemaker implantation remains a reasonable first-line treatment in this age group given its proven efficacy in RCTs.46
When comparing treatment options for middle-aged patients (40–60 years old), a personalised approach that considers both CNA and pacemaker implantation seems prudent.46 For patients over 60 years of age, especially those with potential comorbidities, a pacemaker may be the initial intervention of choice, with CNA as an alternative if the patient prefers it and responds positively to atropine. In younger patients, those unresponsive to atropine may be better candidates for pacemakers because of potential intrinsic sinus node issues.46
Aksu et al. proposed a treatment algorithm for VVS that begins with patient education and lifestyle modifications, coupled with the recommendation of physical counter-pressure manoeuvres.46 To ascertain the cardioinhibitory mechanism, the HUTT test is used. For patients with spontaneous syncope with an asystolic pause exceeding 3 seconds, treatment is age dependent: CNA is primarily suggested for those under 40 years of age; an individualised approach is recommended for those aged 40–60 years; and patients over 60 years are initially directed towards closed-loop stimulation dual chamber pacemakers (Figure 4).
Although CNA has a high success rate in treating VVS, it is worth noting that the evidence is still limited, comprising mostly single-centre studies and one unblinded RCT (Table 1). Patients suitable for RCTs should have recurrent, severe VVS refractory to conventional treatments and exhibit a documented cardioinhibitory response.40 Patient selection for CNA varies: the literature shows that younger patients have particularly high success rates with CNA, whereas older populations might benefit more from pacemaker implantation.
Conclusion
CNA has emerged as a promising technique to manage VVS through interventions targeting GP sites. Various methods, ranging from anatomically guided approaches, spectral analysis and HFS, have been used to locate and ablate these sites, with studies consistently reporting favourable outcomes using these different techniques. An explanation for the ability of these differing techniques to generate similar outcomes is the concept of gateway plexi: specifically, the IPSGP as the gateway to the AV node and the SPSGP as the gateway to the SA node, both of which can be accessed from either the left or right atrium. There is a pressing need to consolidate efforts to run multicentre, sham-controlled RCTs with consistent methodology to enable CNA to be more widely accepted and to be incorporated into syncope guidelines.
Clinical Perspective
- Cardioneuroablation (CNA) is emerging as a promising technique for managing vasovagal syncope (VVS), offering an effective treatment option for patients with refractory VVS.
- The efficacy of CNA appears to vary with age. Younger patients (under 40 years) have had higher success rates with CNA, while older patients may benefit more from traditional pacemaker implantation; an individualised approach is crucial in patient selection.
- There is an urgent need for large, multicentre, sham-controlled randomised controlled trials and the establishment of standardised protocols for CNA, given that current evidence primarily comes from single-centre studies and retrospective analyses.