Comparative analysis of the outcomes of cardioneuroablation and pacemaker implantation in cardioinhibitory vasovagal syncope

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Epidemiology and Relevance of the Problem

Vasovagal syncope (VVS) is a common condition: by the age of 60, 42% of women and 32% of men have experienced at least one episode of syncope [1]. Although the outcome is usually favorable, VVS can lead to injuries and a reduced quality of life [2; 3]. The pathophysiology of VVS is caused by reflex hypotension and bradycardia due to excessive activation of the vagus nerve [4]. Traditional methods of treating VVS are often ineffective [5].

Cardio-neuroablation (CNA), used to treat functional bradyarrhythmias and VVS, suppresses excessive vagal activity and restores autonomic balance [7–9]. Data on CNA are encouraging, but issues of patient selection and protocol standardization limit the widespread use of this method [10–12].

Classification of Vasovagal Syncope

Depending on the type of cardiovascular system reactions, three types of VVS are distinguished [13; 14]:

• cardioinhibitory,
• vasodepressor,
• mixed.

A cardioinhibitory reaction is characterized by sinus node arrest, development of AV block, or prolonged bradycardia. A vasodepressor reaction manifests itself in pronounced blood pooling in the venous bed due to a decrease in peripheral venous tone. In vasodepressor reactions, arterial hypotension is usually the main symptom and is not always accompanied by bradycardia. Many people experience mixed reactions that include both cardioinhibitory and vasodepressor components.

Pathophysiology of Vasovagal Syncopes

Despite the ongoing development of new treatments for this condition, the pathogenesis of VVS remains a subject of debate. According to a widely accepted theory, VVS is caused by an abnormal vegetative baroreflex mediated by the autonomic nervous system, whose purpose is to maintain homeostasis. For example, when a person stands up, the volume of peripheral blood circulation increases by 500–800 ml, activating the sympathetic nerves to prevent hypotension [15]. However, during VVS, an abnormal reflex response leads to excessive blood accumulation in the periphery, causing excessive sympathetic outflow and increased ventricular contraction, which paradoxically increases blood flow to the central nervous system, resulting in a persistent increase in vagus nerve activity and bradycardia, which ultimately leads to loss of consciousness [14].

The principle of action of cardio-neuroablation. Parasympathetic hyperactivity is a key factor in bradyarrhythmias, making it a target for treatment [16]. Autonomic regulation of the heart is carried out through a complex neural network involving efferent and afferent neurons concentrated in the epicardial adipose tissue [17]. Ganglionic plexuses, consisting of pre- and postganglionic fibers, regulate cardiac activity. CNA consists of catheter ablation of these plexuses, which provides parasympathetic denervation and improves the condition of patients [8].

Location of ganglionated plexuses. The ganglionated plexuses (GP) of the heart include five atrial (3 in the left atrium (LA), 2 in the right atrium (RA)) and five ventricular, which do not affect the effectiveness of the CNA [18; 19]. The density and distribution of GPs vary among individuals [20], which explains the discrepancies in their anatomical classification [21]. In the RA, there are upper and lower plexuses. In the LA, there are five plexuses located around the pulmonary vein ostia and Marshall's ligament. Marshall's vein also contains parasympathetic fibers that innervate the LV structures and coronary sinus [22].

Methods for determining ganglionated plexuses. Three methods are used to localize GP in CNA: spectral analysis (SA), high-frequency stimulation (HFS), and electroanatomical mapping (EAM) [23]. A study by Aksu et al. (n = 20) showed that EAM reduces procedure and fluoroscopy time with comparable efficacy to the combined approach (SA + HFS) [24]. Xu et al. (n = 108) demonstrated comparable efficacy of VFS and EAC—83.7% of patients achieved cessation of syncope [25]. A meta-analysis by Vandenberk et al. confirmed no significant differences in efficacy between the methods [26].

Different approaches to conducting CNA. There are three types of CNA: right atrial (RA-CNA), left atrial (LA-CNA), and biatrial (BA-CNA). Debruyne et al. [27] demonstrated a 95% efficacy of RA-CNA after 12 months. Mesquita et al. [28] confirmed the efficacy of isolated right atrial ablation. Aksu et al. [29] developed a stepwise approach with a success rate of 96.7%. Debruyne et al. [30] proposed a less invasive technique of partial RA ablation. Studies by Scanavacca [31] and Yao [7] demonstrate the effectiveness of HFS-controlled CNA and LA ablation as alternatives to the bariatric approach [8]. All techniques show comparable effectivenes.

CNA in Patients with Sinus Node Dysfunction

Zhao et al. [45] studied the efficacy and safety of CNA in patients with symptomatic sinus bradycardia (SB).

The study included eleven patients (mean age 45.9 ± 10.9 years; 8 males) with long-standing SB (106.2 ± 43.7 months). Five ganglion plexuses (GP) identified by anatomical mapping and high-frequency stimulation were ablated. The ultimate goal of the procedure was to eliminate vagus nerve responses at the ablation sites. SB symptom and Holter ECG monitoring were performed after 3 days, 6 months, and 12months, and then for 18 months. The subjects were divided into two groups according to age: 6 patients were younger than 50 years (group I) and 5 were between 50 and 60 years old (group II). During 18.4 ± 6.2 months of observation, all patients reported a significant improvement in symptoms, and their heart rate increased significantly. At the same time, compared to patients in group II, a greater increase in heart rate was observed in group I.

Qin et al. [46] studied the effectiveness of electroanatomical mapping for GP ablation with the aim of increasing heart rate and improving quality of life in patients with symptomatic SB.

The study included 62 patients with symptomatic SB: group A included patients under 50years of age (n = 40); group B included patients aged ≥ 50 years (n = 22). All patients underwent cardiac neuroablation, and during one year of follow-up, 24-hour Holter monitoring and quality of life assessment using the Medical Outcomes Study Short-Form 36 Health Survey questionnaire were performed. Although HR significantly increased in all patients after CNA, this increase was significantly greater in patients under 50 years of age than in those over 50 years of age (19.3 ± 9.9 vs. 10.8 ± 5.4 bpm; р = 0.001). HR values remained elevated for 12 months only in patients in group A. The authors concluded that anatomical ablation of atrial GP effectively increased HR and improved quality of life in patients under 50 years of age.

Song et al. [47] compared two approaches to ablation: total (complete) ablation of all GP (n = 46) and simplified ablation of only the lower (posterior) and upper (anterior) RA-GP (n = 27) in 73 patients with symptomatic bradycardia. As a result, no significant differences in HR increase were found between the two groups: 19.5 ± 6.8 bpm with total ablation and 20.5 ± 5.9 bpm with simplified ablation (p = 0.485). In addition, this study found a negative correlation between patient age and HR increase after ablation.

Chen et al. [48] published data on six patients with symptomatic vagus-induced sinus node dysfunction who underwent biatrial cardio-neuroablation using extracardiac vagus nerve stimulation between December 2020 and March 2022 (ECNS). The results showed that ablation of the upper RA-GP led to a significant increase in heart rate and elimination of sinus arrest caused by ECNS. After the procedure, the heart rate increased to 64–86% of the maximum heart rate during atropine testing at initial state. The median heart rate during Holter monitoring increased from 52.8 ± 2.1 beats/min at baseline to 73.0 ± 10.4 beats/min after the procedure (p = 0.012) and to 71.3 ± 10.1 beats/min after 6 months of follow-up (р = 0.011). Symptoms associated with bradycardia disappeared in all patients within 6 months of observation. This series of cases demonstrates the feasibility of using the CNA method with ECNS.

CNA in Patients with Atrioventricular Block

Aksu et al. [49] published their experience treating patients with vagally induced atrioventricular block (VI-AVB) using CNA. In their study of a group of 241 patients with symptomatic AVB, 12.9% (n = 31) had a functional form, of which 59% suffered from a permanent form of the disease. These patients (n = 31) underwent 3D electroanatomical mapping, during which areas corresponding to the electrograms of the ganglionic plexuses were identified. The aim of the procedure was to eliminate the positive vagal response during radiofrequency ablation. Twenty-four patients underwent bilateral CNA, four underwent LA-CNA, and three underwent RA-CNA. An immediate positive effect of the procedure was observed in 96.7% of patients. During the 19.5 ± 15 months after CNA, none of the patients experienced recurrent syncope attacks.

A large-scale study by PIRECNA [50] aimed to investigate the main procedural characteristics and medium-term results of electroanatomically guided cardio-neuroablation in patients with VI-AVB. The international multicenter retrospective registry included data collected from 20 centers. The study included patients with symptomatic paroxysmal or persistent VI-AVB. All patients underwent CNA (n = 130). The success of the procedure was determined by rapid relief of atrioventricular block and complete cessation of the response to atropine. The primary endpoint was the occurrence of syncope and AVB-II or AVB-III. Immediate procedural success was achieved in 96.2% of cases. During the observation period, which lasted an average of 300 days (150; 496), the primary endpoint was reached in 17 of 125 (14%) cases with successful emergency interventions. A history of atrial fibrillation, hypertension, and coronary heart disease was associated with a higher incidence of primary endpoints. Only 4 patients with primary endpoints during follow-up required pacemaker implantation.

Long-term effect of CNA. Despite the relative novelty of the method, studies demonstrate a sustained effect of CNA. Pachon et al. report a weakening of the vagal reflex over a period of 45 months [10]. Although some studies indicate the possibility of reinnervation in the first 6 months after ablation [51; 52], Pachon et al. did not find it after 2 years [53]. Long-term results require further study, especially given the possibility of reinnervation even after heart transplantation [54].

CNA safety. CNA is considered a relatively safe procedure. Scana-vacca et al. [55] described rare cases of sinus node artery occlusion and suggested preventive measures. The procedure carries the standard risks of invasive interventions: vascular complications, cardiac tamponade, thrombotic events.

A study by Aksu et al. [56] (n = 47) demonstrated that even beginner operators can successfully perform CNA, although experienced surgeons achieved a higher number of vagal responses (90.3 vs. 62.5%; p = 0.022) and shorter procedure times (83.4 ± 21 vs. 118.0 ± 21 min; p < 0.001). At the same time, there were no recurrences of syncope in either group during 8 ± 3 months of follow-up.

The effect of age on CNA effectiveness. The multicenter study by ELEGANCE Francia et al. [62] (n = 60) showed that CNA is effective in patients of all age groups (18–40; 41–60 years, > 60 years). The overall success rate of the procedure was 93% with no significant differences between groups (p = 0.42). After CNA, a negative orthostatic test was recorded in 53% of patients, with no age differences (p = 0.59). After 8months of follow-up, 88% of patients were asymptomatic. The prognostic value of a negative orthostatic test reached 91.7%. The authors concluded that CNA is effective for the treatment of reflex syncope regardless of age.

International Recommendations on CNA

In August 2024, joint recommendations for cardio-neuroablation were published by four leading international arrhythmology associations [64]. This document contains detailed information on the cardioneuroablation procedure, including anatomical and pathophysiological rationale, patient selection strategy, preoperative examination algorithm, the actual technique of the procedure, potential risks, and anticoagulant therapy regimen. The authors of the recommendations note that the evidence base is currently insufficient and that the community is awaiting studies of long-term outcomes.

Other Indications for CNA

In addition to VVS, WI-SND, and VI-AVB, which have become “classic” indications for CNA over the past two decades, there is evidence of the use of this procedure in other nosologies.

The favorable results of CNA have recently been confirmed in long QT syndrome [65].

In addition to functional bradyarrhythmias, CNA can also be used as adjunctive therapy for SF [66–68].

Neto et al. demonstrated that CNA may be an alternative treatment for bradyarrhythmia caused by overtraining [69].

Similarly, the use of CNA may be considered for carotid sinus hypersensitivity syndrome [70]. However, the specific mechanisms and long-term outcomes need to be clarified in future studies.

Comparison of CNA with Permanent Electrocardio-Stimulation

Gopinathannair et al. [71] were the first to compare the efficacy and safety of cardio-neuroablation and permanent electrocardiostimulation in recurrent cardioinhibitory vasovagal syncope. This multicenter study included 162 patients (CNA = 61 and ECS = 101) aged 36 + 11 years with a syncope frequency of 6.7 ± 3.9 per year. In the CNA group, electroanatomical mapping was used to identify and remove ganglionic plexuses. ECS were implanted using standard techniques: dual-chamber pacemakers with rate-dependent reduction (RDR) or closed-loop stimulation (CLS). The primary endpoint of the study was freedom from recurrence of syncope. As a result, during one year of follow-up, 97% of patients in the CNA group and 89% of patients in the ECS group reached the primary endpoint (adjusted OR = 0.27; 95%CI 0.06–1.24; p = 0.09). There were no significant differences in the incidence of adverse events between the groups. No significant association was found between age (OR = 1.01; 95% CI 0.96–1.06; p = 0.655), gender (OR = 1.15; 95% CI 0.38–3.51; p = 0.809), and frequency of fainting episodes in the past year (OR = 1.10; 95% CI 0.97–1.25; p = 0.122).

At the time of this analysis, the study by Gopinathannair et al. [71] comparing CNA and ECS was the only one of its kind, which highlights the novelty and relevance of the current scientific work.

Discontinuation of Permanent Electrocardio-Stimulation after CNA

Safe discontinuation of permanent electrical pacing in vagus-mediated bradycardia is a dilemma. Stec et al. [72] conducted a study to present the results of a proposed diagnostic and therapeutic protocol aimed at discontinuing permanent pacemaker therapy in patients with vagally mediated bradycardia.

After initial clinical and electrophysiological examination, 17 patients with implanted pacemakers were deemed suitable for CNA. During the follow-up period after initial CNA, all 17 patients were asymptomatic. It was decided not to reimplant pacemakers in any patients after CNA. The authors concluded that permanent pacemaker therapy in patients with vagus-mediated bradycardia can be safely discontinued after cardiac neuroablation.

Funding. The research was conducted with financial support from the Ministry of Science and Higher Education of the Russian Federation (project No. FSNM-2024-0009).

Conflict of interest. The authors declare no conflict of interest.

Author contributions:

Asanbayev Ch.Z., Orekhova E.N. – defining the concept.

Asanbayev Ch.Z., Khuziahmetov R.D. – conducting research, working with data.

Asanbayev Ch.Z., Kdralieva N.V. – writing the draft text of the article.

Orekhova E.N., Kuchumov A.G., Kadyraliev V.K. – manuscript review and editing.

All authors approved the manuscript (version for publication) and agreed to be accountable for all aspects of this work, ensuring proper consideration and resolution of issues related to the accuracy and integrity of any part of it.

About the authors

B. K. Kadyraliev

FCCS named after S.G. Sukhanov

Email: nurslu.kdralieva@mail.ru
ORCID iD: 0000-0002-4007-7665

DSc (Medicine), Cardiovascular Surgeon

Russian Federation, Perm

R. D. Huziahmetov

FCCS named after S.G. Sukhanov

Email: nurslu.kdralieva@mail.ru
ORCID iD: 0009-0001-2835-9571

Cardiovascular Surgeon

Russian Federation, Perm

N. V. Kdralieva

FCCS named after S.G. Sukhanov; Perm National Research Polytechnic University

Author for correspondence.
Email: nurslu.kdralieva@mail.ru
ORCID iD: 0009-0005-7617-2305

Cardiovascular Surgeon

Russian Federation, Perm; Perm

A. G. Kuchumov

Perm National Research Polytechnic University

Email: nurslu.kdralieva@mail.ru
ORCID iD: 0000-0002-0466-175X

DSc (Physics and Mathematics), Professor of the Department of Computational Mathematics, Mechanics and Biomechanics, Head of Biofluids Laboratory

Russian Federation, Perm

Ch. Z. Asanbayev

Cardio Asia Plus Medical Center

Email: nurslu.kdralieva@mail.ru

Interventional Cardiologist

Kyrgyzstan, Osh

E. N. Orehova

Ye.A. Vagner Perm State Medical University

Email: nurslu.kdralieva@mail.ru
ORCID iD: 0000-0002-7097-8771

DSc (Medicine), Associate Professor of the Department of Hospital Therapy and Cardiology

Russian Federation, Perm

References

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