Cardiac physiological function is regulated by the epicardial autonomic ganglia of the heart. Cardiac innervation of the autonomic nervous system converges at multiple ganglionated plexi (GPs) that contain sympathetic and parasympathetic neurons (Armour et al., 1997; Chiou et al., 1997). Autonomic perturbation of parasympathetic overactivity may induce the onset of vasovagal syncope (VVS), functional sinus node dysfunction (SND), and functional atrioventricular block (FAVB) (Manolis et al., 2021). These patients are at a high risk of injury and severe impacts on quality of life if undergone hemodynamic disturbance, may be refractory to conventional therapies, and require pacemaker implantation to prevent sudden fatal events (Kusumoto et al., 2019; Glikson et al., 2021).

Cardioneuroablation (CNA) is an emerging interventional therapy that localizes vagal GPs via electroanatomical mapping and damages nerve fibers via radiofrequency ablation. It can blunt the excessive vagal activation of the heart and thus eliminate or improve the pathological conditions related to high vagal tone (Pachon et al., 2005). CNA has been used successfully in preliminary studies in refractory VVS patients, particularly in treating the cardioinhibitory type (significant decrease in heart rate during syncope, occasionally accompanied with paroxysmal abnormal rhythm such as sinus bradycardia, sinus arrest, and atrioventricular block), and may enable patients to avoid the complications and financial burdens of long-term cardiac pacing (Pachon et al., 2005; Pachon et al., 2011; Yao et al., 2012; Aksu et al., 2016; Debruyne et al., 2018; Hu et al., 2019; Aksu et al., 2020; Pachon et al., 2020; Aksu et al., 2021; Debruyne et al., 2021; Tu et al., 2022).

Previous studies exploring the therapeutic effects of CNA in vagal-induced bradycardia and conduction disorders have suggested CNA as an alternative treatment strategy for patients with functional SND and FAVB after pharmacological interventions have failed (Pachon et al., 2005; Zhao et al., 2015; Aksu et al., 2016; Qin et al., 2017; Debruyne et al., 2018; Aksu et al., 2020; Aksu et al., 2021; Debruyne et al., 2021). SND encompasses a range of electrophysiological and arrhythmic disturbances resulting from abnormalities of the sinus node and atrial impulse formation and propagation (Kusumoto et al., 2019).

The clinical manifestations of SND can vary from insidious symptoms to a state of frequent discomfort such as a constant feeling of fatigue or recurrent syncope (Kusumoto et al., 2019). Among the extrinsic factors (autonomic perturbation, metabolism, and medication) affecting sinus node function, vagal overactivity may play the most important role (Kusumoto et al., 2019); in this review, functional SND refers to vagally induced SND. Although symptomatic SND is an indication for pacemaker implantation, the premise is that other potential treatable or reversible etiologies have been excluded (Kusumoto et al., 2019; Glikson et al., 2021). Determining whether an abnormal heart rhythm is caused by the relatively reversible autonomic imbalance, that is, distinguishing between symptom-related vagal overactivity and sinus node intrinsic damage accurately, is the focus and difficulty of rational and effective application of CNA in SND patients. Thus, when making therapeutic decisions for SND patients, in addition to the need to obtain a clear symptom-rhythm correlation, quantifying the cardiac vagal tone and clarifying the nature of sinus node lesions are equally important. In this review, we provide an overview of the knowledge regarding symptomatic vagal-induced SND, therapy choices for refractory patients, and the strengths and limitations of different diagnostic tools for evaluating the function of the sinus node or cardiac autonomic nervous system.

The sympathetic and parasympathetic nervous systems, the two core arms of the autonomic nervous system, regulate the basic physiological activities of any visceral organ, and interact at each hierarchical level, including brain centers, brainstem, spinal cord, stellate ganglia, and intrinsic visceral nerves and ganglia (Manolis et al., 2021). The cardiac autonomic nervous system is also divided into two parts: the extrinsic part, derived from the central nervous system and its emanated axons, mediates connections between the heart and the autonomic ganglia of the cervical and thoracic spinal cord (sympathetic connections) and the medulla oblongata (parasympathetic connections, the vagus nerve carrying parasympathetic preganglionic fibers); the intrinsic part is located in the periatrial epicardial fat pads that contain the autonomic ganglia and the downstream autonomic nerve fibers, mainly innervating the sinus node, atrial muscle, atrioventricular node, and ventricular muscle. Besides acting as a relay-station that processes efferent signals to the heart, it is also involved in the local reflex loop that regulates cardiac function independently of the control of higher autonomic centers (Armour et al., 1997; Chiou et al., 1997; Manolis et al., 2021). Cardiac motor neurons exert their effect via a fine balance between cholinergic (parasympathetic postganglionic nerve fibers) and adrenergic (sympathetic postganglionic nerve fibers) fibers, the former cause negative chronotropic and dromotropic effects through releasing acetylcholine (ACh), while the latter enhance cardiac contractility and accelerate myocardial electrical conduction by releasing norepinephrine (Shivkumar et al., 2016; Manolis et al., 2021). The cardiac autonomic nervous imbalance is one of the etiologies for the genesis of arrhythmia, such as bradycardia (Manolis et al., 2021).

SND is linked to impaired pacemaker function in the sinus nodes with various presentations, including sinus bradycardia (sinus rate <50 beats per minute), sinus pause (depolarization ceases >3 s) or arrest, sinoatrial exit block, ectopic atrial bradycardia, alternating periods of atrial tachyarrhythmias and bradyarrhythmias (tachycardia-bradycardia syndrome), inappropriate variation in heart rate during stress or exercise (chronotropic incompetence), and isorhythmic dissociation (Kusumoto et al., 2019). Patients usually have accompanying symptoms (dizziness, amaurosis, fatigue, and palpitation), and syncope; even sudden death has been noted in severe cases (Kusumoto et al., 2019). Syncope is a common complaint in patients with SND and has been reported in 50% of patients undergoing pacing therapy (Nielsen et al., 2011). These symptoms may occur at rest, during or after exercise, and in a pathological pause at the end of an episode of atrial tachyarrhythmia (Dobrzynski et al., 2007).

The mechanism underlying SND development is not fully understood; however, evidence suggests that it may be caused by changes in the sinus node itself (degenerative diseases, myocardial ischemia or infarction, inflammation, and endocrine abnormalities) or extrinsic factors such as autonomic imbalance (Kusumoto et al., 2019). According to the European Society of Cardiology (ESC) guidelines on cardiac pacing, hypervagotonia is a potentially reversible or treatable cause of SND (Glikson et al., 2021). The neurophysiological mechanisms underlying vagal overactivity include the recruitment of vagal neurons, more efficient transmission at the level of the ganglia, and/or just increased excitability of vagal neurons, although this apparent plasticity of the nervous system remains unknown. The basic pathophysiological mechanism of functional SND (Figure 1) is that the ACh released from excited vagal nerve endings, which bind to M2 muscarinic ACh receptors (mAChRs) on the cell membrane, increase potassium permeability and facilitate the efflux of potassium ions (K+). Besides that, the inhibition of K⁺ uptake may occur through stimulation of the nicotinic ACh receptors (nAChRs) on the sinus node cells (Bibevski and Dunlap, 2004). Owing to hyperpolarization of the sinus node cell membrane, and the inward current of the phase 4 depolarization of the action potential is inhibited, the automatic depolarization rate decreases, ultimately resulting in changes in auto-rhythmicity and chronotropism of the sinus node (Doyen et al., 2019). There is evidence that, nAChRs mediate a large part of ganglionic transmission in canine intracardiac neurons, suggesting that active nAChRs may promote the activity of the vagus nerve (Bibevski et al., 2000). In hence, the M2 mAChRs mainly mediate cardiac myocyte signaling, whereas nAChRs maybe mediate both signaling at the postganglionic neuron and cardiac myocyte.

An animal study has demonstrated that surgical dissection of the fat pad overlying the junction between the right pulmonary and left atrial veins can interrupt the vagal inputs to the sinoatrial node region (Randall et al., 1987). In humans, a preliminary attempt at selected ablation of the parasympathetic nerves surrounding the sinus node (cardiac ganglia would not be damaged) for treating bradyarrhythmia patients achieved good results (Lu et al., 2020). Also, we have previously reported specific parasympathetic plexus fibers that significantly affected the heart rate (Hu et al., 2019). Therefore, theoretically, in functional SND patients who select the treatment, modification of cardiac vagal ganglia would help to improve the symptoms resulting from bradyarrhythmias.

In the current guidelines, symptomatic SND associated with bradyarrhythmias is an indication for permanent pacing therapy (Class of Recommendation I, Level of Evidence B) (Glikson et al., 2021). To date, there has been no clear recommendations proposed for symptomatic sinus bradycardia or sinus pauses that are secondary to elevated vagal tone (Kusumoto et al., 2019; Glikson et al., 2021). For younger patients with major symptoms, without organic sinus node damage, and ineffective drug therapy, choosing cardiac pacing as a therapeutic strategy would be concerning due to long-term effects.

Cardiac autonomic modification by an interventional method with minimal invasion is a new treatment idea; most previous curative effective studies have focused on VVS patients (Pachon et al., 2005; Pachon et al., 2011; Yao et al., 2012; Aksu et al., 2016; Debruyne et al., 2018; Hu et al., 2019; Aksu et al., 2020; Pachon et al., 2020; Aksu et al., 2021; Debruyne et al., 2021; Tu et al., 2022) and shown high efficacy and safety. GP ablation can restore the balance between sympathetic and parasympathetic components and change their effects on diverse physiological functions of the heart. Thus, the modulatory effect of CNA on the vagal nerves indicates CNA may also be effective in patients with functional SND. Previous studies involving patients with SND who underwent CNA comprised several mixed cohort studies that included patients with VVS, SND, or FAVB (Table 1) (Pachon et al., 2005; Pachon et al., 2011; Yao et al., 2012; Zhao et al., 2015; Aksu et al., 2016; Qin et al., 2017; Debruyne et al., 2018; Hu et al., 2019; Aksu et al., 2020; Pachon et al., 2020; Aksu et al., 2021; Debruyne et al., 2021; Tu et al., 2022). Application of CNA to overcome the deleterious effects of enhanced vagal tone in bradyarrhythmia-related cases was originally reported by Pachon et al. (Pachon et al., 2005). None of the patients with SND had syncope recurrence in the 9.2 ± 4 months following GP ablation. Subsequently, two single cohort studies have investigated the efficacy of CNA for treating symptomatic sinus bradycardia in non-elderly patients (Zhao et al., 2015; Qin et al., 2017). In one study, during a follow-up of 18.4 ± 6 months, all patients reported significant symptom improvement (Zhao et al., 2015); similar results were repeated by Qin et al. (Qin et al., 2017). With partial ablation of the cardiac ganglionated plexus, Debruyne et al. demonstrated good efficacy by using more restricted selection criteria before the procedure and through a computed tomographic-guided procedure in patients with SND (Debruyne et al., 2018).

Four cardiac vagal GPs on the surface of the atrium are the major ablation sites (Manolis et al., 2021), generally located at junctions of the left atrium and four pulmonary veins: left superior GP (LSGP), left inferior GP (LIGP), right anterior GP (RAGP), and right inferior GP (RIGP) (Figure 2). It has been reported that sinus nodes are mainly innervated by nerve fibers from the RAGP, and electrically stimulating the RAGP can decrease the sinus rate and shorten the effective refractory period of peripheral atrial cells but does not affect atrioventricular nodal conduction (Hou et al., 2007). Consistent with this study, we have previously reported that ablation of the RAGP could immediately increase heart rate and maintain stability for a long period (Hu et al., 2019). The other target GP that can significantly increase heart rate is located within the fat pad between the superior vena cava and the aortic root (SVC-Ao); the SVC-Ao fat pad is the “head station”, which connects the extrinsic with the intrinsic cardiac autonomic nervous system (Qin et al., 2017). Most efferent cardiac vagal fibers to the atrium, sinus node, and atrioventricular node pass through this area and then project onto the RAGP (Armour et al., 1997; Chiou et al., 1997). A recent study confirmed that the ablation of SVC-Ao GP significantly increased the heart rate, while elimination of vagal response evoked by extracardiac vagal stimulation (Chen et al., 2022). The RAGP and SVC-Ao GP were considered more valuable candidate targets to modulate sinus node function in symptomatic SND patients when compared with other GPs. Notably, the ablation of SVC-Ao GP may change the electrophysiological function of the heart, such as prolonging the effective refractory period acutely, while shortening regional ERPs, which increase atrial fibrillation or tachycardia burden chronically (Lo et al., 2013). Exploration of the anatomical principles of the innervation of the heart is ongoing, which will improve the scheme for modern therapies to directly target cardiac autonomic nervous function.

CNA remains an emerging modality that did not eliminate vagal innervation of the whole heart, rather modified the degree of innervation of the overactive vagus nerve fibers, especially in SND patients conducted sinus node-related regional GP ablation protocols. Although increased heart rate is consistent with the expected effect of CNA, inappropriate sinus tachycardia is a common short-term adverse event in VVS patients (Vandenberk et al., 2022). However, only a minority of SND patients experience palpitations without recording arrhythmia events, which may be related to the patient’s short-term maladjustment to the significantly increased heart rate (Zhao et al., 2015; Qin et al., 2017).

Based on the above evidence, the following selection criteria will help to decide potential candidates: symptom-related daytime sinus bradycardia (<50 beats per minute) or arrest (>3 s); age <60 years; no structural and hereditary heart disease; positive AT (increment of heart rate ≥25% or heart rate ≥90 beats per minute) and/or abnormal electrophysiological study; intact chronotropic competence in exercise test; raised vagal activity (Figure 3).

Due to the absence of a gold standard for diagnosing functional SND and a lack of large sample size studies, the sets of criteria described above are based on previous reports and still need further improvement. Screening indicators have pros and cons and should therefore be selected and combined according to the specific situation (Table 3). In exclusive functional SND, electrophysiological means should only be used as an exclusionary diagnostic tool. But even with rapid atrial stimulation and autonomic blockade means, negative results can be observed in intrinsic SND. HRV can be applied to initially assess the overall balance of the autonomic nervous system, and further measurement of vagal tone using DC analysis is a better option. Examinations that reflect vagal activity should be supplemented in future research. Notably, the diagnostic value of DC has been proven only in patients with VVS aged approximately 40 years (Zheng et al., 2020).

As a feasible therapy, the moderation effect of vagal nerve by CNA increases heart rate and eliminates bradyarrhythmia-related symptoms in younger patients with functional SND. In this review, we summarized a set of selection criteria for the identification of the best candidates to enhance the success rate of CNA. However, the diagnostic accuracy of the truly “vagally mediated SND” is challenging because most of the studies have small sample size and lack quantification of vagal overactivity, resulting in evidence of limited value. Future comprehensive, large sample studies are warranted to remedy this situation.