Reflex or neurally mediated syncope is the most common form of syncope in any setting and at all ages [1]. It is associated with an autonomic imbalance in which vagal hyperactivity predominates, resulting in vasodilation or bradycardia or both, thereby producing a fall in global cerebral perfusion. It is divided into three types: vasovagal, situational, and carotid sinus syndrome.

Reflex syncope occurs when the body inappropriately reacts to certain triggers such as emotional stress, a long period of standing, extreme heat, or intense pain. It is benign and usually occurs in healthy people; however, very frequent syncope or events without prodromal symptoms can lead to injuries and affect long-term quality of life. Nonpharmacological and medical therapies proven effective in randomized clinical trials are scarce [2]. In certain patients with frequent and burdensome cardioinhibitory reflex syncope, dual-chamber cardiac pacemakers seem to be beneficial [3, 4]. More recently, catheter-based cardiac autonomic modulation, or cardioneuroablation (CNA), has emerged as a novel therapy for reflex syncope, and positive results in small open-label cohort studies, and more recently in the first randomized study, have been reported [5, 6].

On one hand, the literature provides sufficient evidence that cardiac pacing should be considered in select patients affected by severe forms of reflex syncope. Current guidelines indicate that pacemaker therapy should be considered in patients aged more than 40 years with frequent recurrent reflex syncope when asystole has been documented, induced by either carotid sinus massage or the head-up tilt test or recorded via electrocardiography (≥ 3 s if syncope, ≥ 6 s if asymptomatic) [7].

On the other hand, cardiac autonomic system modulation by endocardial ablation targeting atrial ganglionated plexi (GPs), or CNA, has been recently proposed as a novel therapy for reflex syncope [5]. The rationale for CNA is based on the anatomy and physiology of the cardiac autonomic nervous system, which is divided into 3 major partitions: one afferent (the sensory division) and 2 efferent (the parasympathetic and sympathetic branches). Efferent fibers comprise essentially 2 primary cells—the preganglionic and the postganglionic neurons. The parasympathetic preganglionic body neuron is located in the bulbus, in the vagus motor nucleus. Its axon reaches the heart via the vagus nerves. The parasympathetic postganglionic fiber is remarkably short, and its cell body is located in the heart on the epicardial surfaces of the left and right atria. In contrast, the long sympathetic postganglionic neuron is located in the paravertebral sympathetic chain. The targets of CNA are these postganglionic neuronal bodies of the parasympathetic system (the GPs) located in the epicardial fat pads around both atria. Theoretically, if the GPs can be precisely located, radiofrequency can be applied to them, permanently damaging the postganglionic neuronal bodies of the parasympathetic system. The sympathetic and sensory systems are not permanently affected because they have only postganglionic nerve fibers in this region and can be repaired over the long term by an axonal regeneration process [8].

Cardioneuroablation was introduced by Pachon et al. [5] in 2005. In the initial study, 21 symptomatic patients with vasovagal syncope, functional high-degree atrio-ventricular block, and/or functional sinus node dysfunction were treated with CNA without complications. Follow-up for a mean of 9.2 months demonstrated symptom relief for all patients. Several small studies and case series subsequently confirmed the efficacy of this approach [9]. In a recent randomized prospective study, Piotrowski et al. [6] documented that not only could CNA significantly reduce recurrences of syncopal episodes in patients with vasovagal syncope, but it could also improve quality of life.

The primary strength of this therapeutic approach is that it avoids pacemaker implant, a procedure with a significant complication rate during long‐term follow-up in a population composed predominantly of young and otherwise healthy patients. Nonetheless, a potential limitation of CNA is reinnervation. Several recent studies have documented poor reinnervation in the first year and no additional reinnervation after the first year, but very-long-term studies are lacking [9].

In this issue of the Journal of Interventional Cardiac Electrophysiology, Gopinathannair et al. [10] compare the efficacy and safety of CNA vs. permanent cardiac pacing for recurrent vasovagal syncope. This study will have a large impact, given that it is the first to compare these two techniques in vasovagal syncope. Nevertheless, because it is a non-randomized study with a retrospective design, it offers some limitations.

Importantly, no differences in efficacy and safety were found between these two techniques. A slight trend in favor of CNA was observed; however, design limitations and a modest sample size cast uncertainty on this result. However, the way I see it, the study penalizes the pacing group in two ways:

(a)

Compared to the CNA group, the pacing group included a significantly greater proportion of patients with a mixed response, that is, with a combination of cardioinhibition and vasodepression. It is well known that pacing effectiveness is limited if hypotension is predominantly of vasodepressor origin or if bradycardia occurs only late during the development of the vasovagal event when hypotension is already severe. In fact, the American and ESC guidelines recommend only cardiac pacing in the cardioinhibitory type (especially type 2B). Therefore, the inclusion of patients with only reflex cardioinhibitory syncope but not a mixed response (or at least the absence of differences between groups) would have allowed a more accurate comparison.

(b)

Within the pacing group, various types of pacemakers and algorithms were used, specifically closed-loop pacing (CLS), rate drop response, and leadless pacing. This heterogeneity makes comparison difficult and probably penalizes the pacing group, where the implant of a dual-chamber CLS pacemaker seems to have an attractive benefit (see the SPAIN study or BioSync CLS study).

Second, although new information about the treatment of reflex syncope is welcome for all ages, studies about pacing in reflex syncope have greatly focused on people aged more than 40 years. For this reason, a comparison among only those in this age group would have been especially interesting. This study included patients with a mean age of 35.6 ± 10 years. For those younger than 40 years, the debate should focus on the long term (complications of pacemaker use, reinnervation following CNA, etc.) rather than on the short term.

Finally, it would have been especially interesting to know the impact on quality of life after performing each of the procedures, either directly, through a quality-of-life test, or indirectly, through the description of the rate of near-syncope. Reflex syncope is closely linked to a reduction in quality of life, so it seems to be an outcome that needs to be known.

This study concludes that in appropiately selected patients with recurrent cardioinhibitory vasovagal syncope, CNA, when compared to permanent cardiac pacing, has a similar effectiveness in preventing recurrent syncope and also a comparable safety profile.

Based on the results of this study, and the excellent results reproduced by many investigators worldwide, CNA should be considered in patients with reflex syncope, particularly those who display an important cardioinhibitory component of syncope. However, before a stronger recommendation can be given, a randomized clinical trial to assess the true benefit of CNA and to compare this technique with pacemaker implantation should be performed. Results could guide the physician to the best choice in this scenario.