Differential effects of ganglionic plexi ablation in a patient with neurally mediated syncope and intermittent atrioventricular block: a commentary

This editorial refers to ‘Differential effect of ganglionic plexi ablation in a patient with neurally mediated syncope and intermittent atrioventricular block’ by M. Fukunaga et al., on pages 119–126.

The treatment of functional bradyarrhythmias by means of endocardial radiofrequency (RF) catheter ablation of the autonomic nervous system began with the original publication in EP-Europace in 2005 and it is known as ‘cardioneuroablation’ (CNA).^1,2 The reproducibility and good long-term results have largely been observed justifying its rapid worldwide expansion having deserved a specific section at Heart Rhythm Society Annual Sessions in 2015 and 2016. The main goal of CNA is the parasympathetic denervation of the heart to allow the treatment of bradyarrhythmias symptomatic reflex (neurocardiogenic syncope) and/or functional (sinus node dysfunction and functional atrioventricular (AV) block). Currently, it has been observed very good results in same types of functional brady-tachy syndrome. It is essentially based on a very specific cardiac neural distribution.

In this issue of EP-Europace, in their very interesting article, Fukunaga et al.³ present a quite remarkable case report of a 35-year-old, apparently healthy woman, suffering from recurrent syncope (twice a month) for 20 years related to reflex high-degree AV block, caused by severe AV nodal cardioinhibition. She had an implantable loop recorder that was extremely important to clarify the outcome. After 2 months asymptomatic, there was a new syncope; however, no more episodes of bradycardia were recorded by the implantable loop recorder. It was related to vasodepression successfully treated with midodrine. No more symptoms or AV block occurred in the next 7 months of follow-up.

Scientific and practical aspects of this report

In this very interesting case-report, several aspects deserve to be commented.

The main objective

The aim of CNA is to attenuate or even to eliminate the cardioinhibition. The best indication is the pure cardioinhibitory syncope. In these cases, the highly positive tilt-test, typically becomes completely negative after ablation.

Late vasodepression response may be observed even with successful cardioneuroablation

After ablation, when control tilt-test is prolonged and sensitized, some patients may present with progressive hypotension accompanied by dizziness and even syncope related to advanced vasodepression that is significantly delayed and blunted compared with pre-ablation. Therefore, these patients usually have no more spontaneous symptoms, because the threshold for dizziness or syncope becomes clearly high. Somehow, it seems to make the patient much more resistant to triggering factors. This may similarly occur in cases treated with pacemaker in which, despite the prevention of asystole, may have vasodepressor syncope. In CNA, this highly desirable effect, by increasing the threshold of symptoms, can achieve clinical cure, even in the presence of a residual vasodepressor response disclosed in excessively rigid research conditions.

The exception

As the author explains, this case is an exception of the vasovagal syncope, because it shows almost exclusively a massive AV node inhibition without depression of the sinus function. It is well known that it is far unusual in spontaneous form of neurocardiogenic syncope; nevertheless, we have observed this behaviour associated with acquired factors like in post surgeries constraining the visceral nervous system, for example following bariatric surgery.⁴

Pharmacological indication criteria

The author appropriately reports that the atropine test before CNA showed normal sinus node and AV node response. However, regardless of suggesting a good AV node dromotropic reserve, it does not exclude an AV nodal subclinical disease despite 1:1 AV conduction up to 114 bpm. It would be necessary to perform, under the atropine effect, a programmed and progressive atrial stimulation in order to exclude residual AV nodal disease. Nevertheless, in case of mild AV node lesion, probably it would not change the results. Our current recommendation is that only the patients with normal response to atropine must be considered for CNA.

The main question

It is remarkable that, despite the good result, ablations were empirically performed without spectral mapping or vagal stimulation. That is the central question. Despite the promising results, our main concern lies on the fact of how the CNA must be performed, controlled, and confirmed during the procedure. Many factors can distort the results and may give origin to partial denervation with non-responders increase due to incomplete ablation or early reinnervation. Thus, it is important to keep in mind a few following thoughts.

Cardiac autonomic nervous system distribution

It is worth to consider the cardiac vagal nervous system organization^5,6 that spreads almost for practically entire extent of atrial wall with regions of high or low AF-nest density. In a simplified way, we can realize that it is composed of at least three neurons: (i) the one located in the atrial wall (the postganglionic whose clusters give rise to the type I AF-Nests,^1,7 related to the vagal AF and cardioinhibition), (ii) the second lies in GPs,^5,6 and (iii) the third is located in the central nervous system (in the dorsal nucleus of the vagus). The CNA can easily eliminate the first neuron, located by spectral mapping^1,7–10 or by AF-nests fragmented potentials.^1,8,9 The second one may be presumably eliminated by deep transmural heating on GPs areas that are not directly mapped, but can be anatomically assumed or by searching for AF-Nests high density that usually occur in GP-overlapping areas.^1,7 Since the neuronal cell bodies of the sensory and sympathetic neurons are located away from the heart, they are not affected by CNA as its fibres usually recover in few weeks.

The problem of reinnervation

Depending on the CNA extension, reinnervation usually occurs in a varying degree. The axons’ fibres recover almost completely; however, the neuronal bodies do not have or have a very low recovery. Thus, the CNA result is a significant and persistent long-term reduction almost exclusively of the parasympathetic tonus. As a consequence, in long term there is also a reflex reduction of the sympathetic drive in response to the reduction of the vagal tone. However, the chronotropic response is completely recovered. Although good results with empirical ablation may be observed as in this report, it is highly desirable to have a method for CNA guidance. This can be performed by spectral mapping or fragmented mapping of AF-nests¹ and/or detection of the electrical potential of the vagal efferent endings. However, whatever the method used, it is essential that it be guided by vagal denervation tests finishing the ablation only after eliminating any vagal response.

Vagal denervation test

In CNA, it seems fundamental and almost indispensable to demonstrate the vagal action at the beginning as well as its complete disappearance after successful ablation. This can be done in a very simple way by bilateral vagal nerve stimulation by forwarding one endocardial lead within the internal jugular vein up to the jugular foramen where the anatomical proximity usually allows easy vagal stimulation by electric field, even without direct contact with the nerve.¹¹ In this case report, it would have been very important, before and during CNA, the stimulation of the left vagus studying the distinct responses of the sinus and AV node, because it is well known that the AV node innervation, despite bilateral origin, presents a certain left vagus predominance. The advantage of this method is to accurately and objectively demonstrate the progressive vagal denervation inasmuch as the procedure progresses. The immediate success criterion is, and must be, the total disappearance of the bilateral vagal response. In this case, it would be the complete disappearance of AV block during atrial pacing at 100 ppm during left and right vagal stimulation.

Atropine test

As described in the original¹ and long- term^3,8,12 CNA publications, atropine test must be used as a selection criterion as patients with negative response are not CNA candidates. Furthermore, it can be used at the end of the procedure seeking for the absence of vagal response. However, after CNA, the atropine response may be affected in part by elimination of the sympathetic fibres that can lead to atropine response attenuation. Additionally, it has undesirable prolonged and sustained effect interfering on new ablations, case necessary. In the present study, a mild response to atropine showed that, despite wide, the vagal denervation was not complete. This should be pointed out because, in spite of the bright result, it suggests that the denervation could have been higher. That is important to prevent significant reinnervation. Reinnervation may potentially be the cause of relapses. It is not rare to have significant vagal effect even after a presumed wide CNA requiring a more extended ablation. In consequence, we basically consider that there is no way to make a wide, safe, and reliable CNA without the serial tests of vagal stimulation during the stepwise procedure. Furthermore, any CNA trial should use the vagal stimulation to normalize the results.

Final considerations

As presented in the 2015 HRS Congress, the rationale for CNA indication and contraindication are:

1. Indications

   All patients with severe symptomatic conditions, refractory to clinical treatment, and positive response to atropine:

   • — cardioinhibitory syncope

   • — mixed neurocardiogenic syncope with important cardioinhibition

   • — functional sinus node bradycardia and/or AV block

   • — young patient with Brady–Tachy syndrome without structural cardiopathy

2. Contraindications

   • — significant cardiopathy

   • — exclusive or predominant vasodepressor syncope

   • — absence or blunted atropine response

   • — syncope without significant cardioinhibition

   • — anatomical restrictions.

Conflict of interest: none declared.

Author notes

The opinions expressed in this article are not necessarily those of the Editors of Europace or of the European Society of Cardiology.