The heart has a dense innervation that permanently regulates its activity, composed by the autonomic visceral nervous system. However, unlike skeletal muscle, the cardiac nervous system has the sympathetic partition that stimulates and the parasympathetic one that inhibits cardiac functions.
Also, different from the skeletal muscle, between the central nervous system and the heart, there is a ganglion, located in the vertebral column (in the paravertebral sympathetic chain), in the sympathetic branch, or in the heart (in the cardiac ganglionated plexuses and inside the myocardium), in the case of parasympathetic.1 This anatomical arrangement determines that the sympathetic ganglionic neuron is long (neural body far from the heart) and the parasympathetic postganglionic one is very short (neural body in the cardiac wall or on the epicardium) (Figure 1).2-4 The sensory neuron also presents the neural body far away from the heart. This peculiar arrangement allows endocardial ablation to eliminate the parasympathetic postganglionic neuron (see ** in Figure 1), and preserves the sympathetic and sensory systems (see * in Figure 1).5
In the normal heart, the vagal tonus predominates at rest. Thus, when the cardiac innervation is canceled by pharmacological or surgical methods, the resulting spontaneous sinus rate is significantly higher than the preceding basal one. This is called intrinsic heart rate (IHR) and can be estimated by the following regression equation: IHR=118.1-(0.57x age).6 The cardiac neural tone is only modulator, different from that one of the skeletal muscles in which the neural tone is trophic. Thus, by denervation, the heart increases spontaneous sinus rate and continues its normal function, whereas denervation of skeletal muscle causes hypotony, total loss of function, and progressive atrophy. Therefore, in addition to abolishing the cardioinhibitory response, denervation causes an increase in basal heart rate, which is extremely beneficial in all clinical conditions that present symptomatic functional bradycardia.7 (Figure 2)
The Problem of Vagal Hypertonia
Many patients suffer from symptoms such as dizziness or syncope due to excessive reflex, or permanent vagal action.8-10 (Table 1)
This happens, for example, in cardioinhibitory or mixed vagal syncope,11,12 in which fainting occurs due to the intense reflex vagal action that causes transitory cardiac arrest or severe bradycardia, known as “cardioinhibitory syncope” (Figure 3).13 Otherwise, in permanent vagal hypertonia, the patient has persistent bradycardia. These conditions, when very symptomatic, can be treated with a pacemaker according to current guidelines.13,14
Pacemaker: A Questionable Solution
Most of these patients are young, and generally, both the patient and their family demonstrate great rejection to the pacemaker. Furthermore, since the pacemaker causes ventricular dyssynchrony and does not prevent the vagal reflex, it has a low resolution and is a questionable IIb indication. In a recent systematic review, published by Varosy et al, the authors concluded that the evidence does not support the use of pacing for reflex-mediated syncope beyond patients with recurrent vasovagal syncope and asystole documented by implantable loop recorder.15
Treating Cardioinhibition by Ablation Without a Pacemaker
In the 1990s, we identified areas in the atrial walls with poorly connected myocardium, referred to as an "Atrial Fibrillation Nest" (or “AF Nest”).16,17AF Nest ablation made the heart unresponsive to atropine due to vagal denervation.16-18 Based on this, we developed and proposed ablation as a method of vagal denervation for treating neurocardiogenic syncope and functional bradycardia without a pacemaker, a technique known as cardioneuroablation (CNA).19,20 (Video 1)
CNA is performed in a procedure similar to AF ablation, with ablations focusing on the ganglionated plexus (GP) regions21 (Figure 4), guided by spectral mapping,19,20 conventional mapping,22 through anatomic orientation,22-25 by high-frequency stimulation in the atrial walls,26-28 or by fractionation mapping with the EnSite Velocity Cardiac Mapping System (Abbott). Transseptal puncture allows extensive ablation of the “P Point”19,20,22 (Figure 4) area of the interatrial septum between the right pulmonary veins (PV) insertion, atrial ceiling, and fossa ovalis. In addition, the right PV insertions and the areas of GPs 1 and 3 are widely ablated. In some cases, when there is unsatisfactory denervation, it is necessary to proceed with additional GP 4 and Waterston’s groove ablation. (Video 2)
Control of Cardioneuroablation
For a successful CNA, it is necessary to have confirmation that the radiofrequency is being applied at the correct points to effectively achieve denervation. With this aim, we developed extracardiac vagal stimulation (ECVS).29 This method allows to test the cardiac vagal innervation, control the progression of vagal denervation, and determine the right moment and best endpoint to complete the CNA.
Extracardiac Vagal Stimulation (Video 1)
Vagal nerves leave the brain along the internal jugular veins through the jugular foramina (Figure 5C). During CNA, we can easily advance a quadripolar catheter through the superior vena cava and internal jugular veins up to the right and left jugular foramina (Figure 5B). At this point, we can stimulate the vagus remotely, from the venous lumen.29
The result is an immediate asystole and/or atrioventricular block (AVB) that recovers seconds after stimulus cessation (Figure 6A). This demonstrates that vagal innervation is intact and allows accurate denervation control. Vagal stimulation without direct vagus contact, from the interior of the internal jugular vein, is performed by electric field and depends on stimuli with special features of amplitude, current, pulse width, frequency, duty cycle, and impedance output in order to prevent vascular and vagus nerve lesions.29 (Figure 5A)
Verifying Electrophysiological Success in CNA
At the end of the procedure, several maneuvers allow us to validate the success of vagal denervation. Electrophysiological parameters typically present a clear modification with increased sinus rate, reduced sinus node recovery time, and Wenckebach’s point increase.
Before, During, and After CNA
At the beginning of the CNA, ECVS is performed to settle the intense vagal action characterized by severe bradycardia, asystole, and/or AVB. (Figure 6A, Video 1)
During the procedure, ECVS is repeated until the complete disappearance of the vagal effect, after which the CNA can be finished (Figure 6B). Whenever possible, it is very important to stimulate both vagi. The right vagus inhibits predominantly the sinus node, causing sinus arrest, and the left one acts more on the AV node, causing AVB. At the end of the CNA, it is important to confirm the total absence of response of both vagi, considering that when eliminating the action on the sinus node, some patients may have symptoms due to AV block occurrence.
Atropine causes muscarinic receptors blockade, abolishing the cardiac vagal response and reproducing the vagal denervation.22 It is an important test before the CNA to predict the possible response of the patient. It can also be used at the end of the CNA, and if there is any atropine response, it means that the CNA was incomplete. However, in most patients, we have found no atropine response at the end of the CNA. In a study of 43 patients, we observed significant reduction in the atropine effect in acute and long-term phases. The pre-CNA atropine test was normal (positive) in all patients. The percentage of heart rate increase (Δ%HR) before CNA had a mean of 79.4 ± 31% (30.8-158.6%). An increase of >25% was considered positive. At the end of the CNA, there was a very small rate increase with atropine: ΔΔ%HR = 4% ± 8% (0-42.6%). The long-term atropine test (21.7 ± 11 months post-CNA) was negative in 33 patients (76.7%, P<0.01), partially positive in 7 (16.3%), and normal in only 3 patients (6.9%).22
Head-Up Tilt Table Test
In a controlled way, the head-up tilt table (HUTT) test may be valuable for evaluating the cardioinhibitory syncope treatment result.30 In a study of 26 patients with HUTT pre-and post-CNA, all cases presented with syncope pre-CNA. After the CNA (mean follow-up of 28 months), the control HUTT did not show cardioinhibition except in one case that had syncope with high-grade transient AV block.22 In this early case, the pre-CNA HUTT showed asystole and the CNA was performed without ECVS control. This finding suggests that it is suitable to always seek the sinus and AV node denervation to avoid that the patient remains at risk of syncope with a different mechanism (Figure 7).
This parameter always presents very significant changes with CNA. In the immediate post-CNA phase, there is a drastic SDNN reduction denoting almost complete elimination of vagal tone. In the chronic phase, the SDNN increases in a variable way in different patients, but remains reduced, demonstrating a significant long-term vagal denervation, which is fundamental for ensuring cardioinhibitory reflex attenuation and good clinical response.22 (Figure 8) Measurement of SDNN in the chronic phase is very important because it may be used as an indirect marker of vagal reinnervation.
Although the AV node has wide innervation from the two vagi, there is a predominance of the right vagus on sinus node and of the left vagus on the AV node. Reflex cardioinhibitory syncope may occur due to sinus arrest, high-grade AV block, or the association of these two mechanisms. When sinus arrest occurs during HUTT or during vagal stimulation, the AV conduction evaluation is lost because of the temporary absence of the sinus stimuli. By performing sinus node denervation only, the patient could still have cardioinhibitory syncope due to transient high-grade AV block. Thus, the CNA endpoint should be the complete abolishment of sinus node depression, aside from the elimination of the AV block induced by ECVS, during atrial pacing. An ideal procedure should have sinus inhibition and transient AV block eliminated, both confirmed by right and left ECVS. (Figure 9, Video 2)
Potential Cardioneuroablation Indications
CNA has a well-defined indication for malignant cardioinhibitory syncope.19,22,31 However, since 2005, there has been evidence of good results in several clinical conditions related to vagal hypertonia. One of them in which CNA has been extremely useful is in the treatment of vagal atrial fibrillation (Video 3). Although there has not yet been time and learning curve for randomized studies, the technique has been applied by a large number of authors worldwide, and there are currently numerous publications showing reproducible results in several clinical settings.32-38 This vast material allows us to recommend CNA in conditions in which there is permanent or reflex vagal hypertonia.39 It is fundamental to avoid patients with significant structural heart disease. An atropine test before the procedure is of great value because it anticipates the possible results of the procedure.20,22 Therefore, if there is no atropine response, the CNA is contraindicated. Table 2 provides a list of potential indications.
Results of Cardioneuroablation
According to current guidelines, the treatment of vasovagal cardioinhibitory syncope has been performed through clinical options,40-42 or in refractory cases, with pacemaker implantation.13,14,43 Figure 10 shows CNA results compared to clinical treatment and pacemaker implantation.
The results observed so far (Figure 10D) are superior to those obtained with clinical treatment (Figures 10A and B),44-46 and even with pacemaker implantation46 (Figure 10C). It is important to consider that the ISSUE-3 study46 was the one that presented the best pacemaker result and the most rigorous selection for patients’ inclusion. However, the pacemaker does not prevent the cardioinhibitory reflex47 since it acts only after the vagal reaction has started and, at this moment, the stimulation causes ventricular dyssynchrony resulting in hemodynamic impairment (unless implanted in the His). On the other hand, besides eliminating the efferent arm of the reflex interrupting the cardioinhibition, the CNA also eliminates a great part of the ganglion cells and can attenuate the action of the mechanoreceptors. This fact still needs to be studied in a specific way, since we have observed that even cases of vasopressor syncope can have significant improvement with the CNA.
Disclosures: The authors have no conflicts of interest to report regarding the content herein. Outside the submitted work, Carlos Thiene C. Pachón, MD reports patents pending for ECANS and MEDSA; José Carlos Pachón-M., MD, PhD, CCDS and Enrique I. Pachón-M., MD, PhD also report that the AF-Nest patent is licensed to St. Jude Medical.
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