Regarding ‘Clinical controversy: methodology and indications of cardioneuroablation for reflex syncope’

This Letter to the Editor refers to the article ‘Clinical controversy: methodology and indications of cardioneuroablation for reflex syncope’, by Brignole et al., https://doi.org/10.1093/europace/euad033. ‘Response to the letter to the editor EUPC-D-23-00318 of Jesús Daniel Martínez-Alday’, by M Brignole, https://doi.org/10.1093/europace/euad178.

We have read with great interest the recent review by Brignole et al.¹ This review is very necessary for an emerging technique that requires clarification. As operators who have collectively performed ∼50 procedures, we would like to offer some comments for your consideration:

1. Under the generic title of reflex syncope, the two main forms are not clearly distinguished, at least the classic vasovagal syncope (VVS) and bradyarrhythmias due to parasympathetic hypertonia (BPH). Although we acknowledge that clinical differentiation is complex, we do believe that this distinction is essential based on the different ablation strategies and techniques needed in each setting. As such, for BPH, ablation of the superior and inferior para-septal ganglia (unification of terminology is very welcoming), biatrial or even from the right atrium, may be sufficient. For this group, we might even wonder whether ablation of the aorta-caval sub-plexus, the central station of entry for most atrial innervation (not taken into account in the mentioned review), could be sufficient. Nonetheless, ablation must be more extensive for the classic VVS. The left superior sub-plexus (from our point of view, the term sub-plexus is more appropriate than plexus) in relation to the left superior pulmonary vein is where the most vagal reactions occur during ablation.² Given the extensive connections of the sub-plexuses, its ablation is necessary for more complete denervation. Moreover, cardiac asystole contributes to syncope in 2/3 of patients.³ If we accept the current clinical results (>90% success rate), then there must be some other mechanisms of improvement not solely based on the absence of cardioinhibition. There are several arguments that could support a positive effect of cardioneuroablation (CNA) on vasodepression: (i) animal studies have shown that epicardial CNA decreases the Bezold–Jarisch reflex;⁴ (ii) atrial parasympathetic fibres jump over the coronary sinus innervating the ventricle, so hypothetically, this reflex could be modulated/inhibited by atrial ablation;⁵ (iii) left atrial ablation could also inhibit the inverse Bainbridge reflex mediated by vagal mechanoreceptors (bradycardia secondary to hypotension); and (iv) small clinical studies have observed a positive effect of CNA in vasodepressor forms.⁶ Consequently, the effects of CNA cannot solely be compared with those of a pacemaker due to its earlier onset of action, which may also have a beneficial effect on vasodepression.

2. We also would like to underline that extracardiac vagal stimulation (ECVS) is essential both for an adequate denervation evaluation and for limiting the extent of ablation. We access three sub-plexuses in the following order: left superior, superior, and inferior para-septal (from both atria). For each, ECVS is performed, and if the response is negative, we conclude the procedure with the atropine test.

3. Finally, although an ideal randomized study with a sham arm would be desirable, we consider it unfeasible. Apart from the reasons discussed in the article, most patients would be aware of their group allocation due to the manifestation of reflex sinus tachycardia, which would fail to prevent the placebo effect.