Comparison Between Cardioneuroablation and Pacemaker Therapy in Patients with Functional Bradycardia

The epicardial autonomic ganglia of the heart regulate cardiac physiological function. The ganglionated plexi are associated with large numbers of intrinsic cardiac neurons.¹ An increase in parasympathetic overactivity may negatively affect the myocardium and cause vagal bradycardia.

Patients with functional bradycardia generally have a normal cardiac structure and function but may present with subtle symptoms of fatigue, recurrent syncope and presyncope.² Patients with symptomatic functional bradycardia are at risk of injury and poor quality of life (QoL) if left untreated.

Since 1985, cardiac pacing has been one method for treating bradycardia. However, no clear guidelines have been proposed for symptomatic functional bradycardia. Due to the long-term effects of pacemaker (PM) therapy, choosing cardiac pacing for younger patients with symptomatic functional bradycardia is of major concern. Further, up to 27% of patients with cardioinhibitory syncope continue to experience recurrent syncope despite having PM therapy.³ Therefore, in the younger population with functional bradycardia, an alternative to PM therapy is cardioneuroablation (CNA).

During CNA, the neuromyocardial interface on the endocardium and the ganglionated plexi (GP), which are intrinsic structures located in the epicardial atrial fat pads, are ablated. Excessive excitation of vagal activity can be inhibited by CNA and the autonomic nervous system is rebalanced.⁴ The ROMAN study showed that CNA can reduce syncope recurrence and improve QoL in patients with vasovagal syncope (VVS).⁵ Despite the efficacy and safety of CNA in treating functional bradycardia, there have been concerns about the long-term efficacy and the effects of parasympathetic withdrawal on the heart as vagal nerve activity reduces.

Both PM and CNA are effective treatments for functional bradycardia. This study is the first to examine the efficacy and safety of CNA versus PM in patients with functional bradycardia.

Methods

Study Setting and Population

We conducted a retrospective study on patients with functional bradycardia who underwent CNA or PM between 2019 and 2024 at the Sarawak Heart Centre, Sarawak, Malaysia. Functional bradycardia was defined as a positive atropine test or cardioinhibitory VVS from the tilt table test (TTT). We administered IV atropine sulphate 0.04 mg/kg (maximum 2 g) to our patients under continuous ECG recording for 30 minutes. A positive response was defined as an increase of ≥25% in the sinus rate in the first 15 minutes after atropine infusion or resolution of atrioventricular (AV) block (AVB), which excludes intrinsic disease of the sinus node or the AV node.⁶ The inclusion criteria were: patients with symptomatic functional bradycardia such as fatigue, presyncope or syncope. Exclusion criteria were: syncope due to neurogenic causes; MI and heart failure; an underlying psychiatric disorder; patients with sinus bradycardia due to other medical causes or AV node dysfunction; and incomplete follow-up or loss to follow-up at 1 year.

Patients’ baseline demographic and clinical features, as well as data from the baseline ECG, telemetry or Holter monitoring, were obtained from hospital records along with the clinical outcomes of the therapies.

Cardioneuroablation – Procedural Details

CNA was carried out as described in the literature.⁷ In brief, a pre-procedure atropine response was done in all cases at least 48 hours before ablation and after 4 hours of fasting. The procedure was performed under conscious sedation with IV midazolam. Mapping was done during sinus rhythm with Advisor HD Grid mapping catheter using EnSite Precision cardiac mapping system (both Abbott Cardiovascular). Electrograms (EGMs) demonstrating ≥2 deflections in regions anatomically consistent with GP sites were tagged as ablation targets (Figures 1A and 1B). After all GP targets had been identified in the left atrium, radiofrequency ablation was delivered in the following order: the left superior GP (LSGP); the left inferior GP (LIGP); the Marshall tract GP; the right anterior GP (RAGP); and the right inferior GP (RIGP). If the sinus rate after left atrial GP ablation reached the pre-ablation atropine response test, no additional ablation in the right atrium was performed. Otherwise, additional ablation was performed at the posteromedial GP, superior vena cava (SVC)-aortic GP and septal GP region. The posteromedial left atrial GP was ablated in patients with AVB. Radiofrequency ablation was done with an energy of 40 W and 45 °C using the TactiCath Quartz Contact Force ablation catheter (Abbott) with a minimum of 30 seconds at each point or after elimination of the vagal response. Contact force was maintained at >10 g.

The endpoint of the procedure was achieving 75% of the sinus rate detected during the pre-ablation atropine test in patients with sinoatrial (SA) block or cardioinhibitory VVS. In patients with functional AVB, the endpoint of the procedure was the achievement of 1:1 AV conduction or a reduction of the PR interval >25%.

Pacemaker Therapy – Procedural Details

Patients had a single-chamber PM or dual-chamber PM implanted based on the standard of practice. In patients with PM after 2021, Closed Loop Stimulation (CLS; Biotronik) was preferred. The standard PM programming for dual-chamber PM was the DDDR rate-modulated mode with a base rate of 50–60 BPM, and for the single-chamber PM it was the VVIR mode with a base rate of 50 BPM.

Follow-up for Cardioneuroablation

Patients were followed up at 1, 6 and 12 months in the clinic with ECG, 24-hour Holter monitoring and repeat TTT. All instances of presyncope and syncope were documented, along with any pauses, tachyarrhythmias and bradycardias, whether or not they correlated. Intra- and post-procedural complications were recorded, including vascular site complications, pericardial effusion/tamponade, stroke/transient ischaemic attack, heart block, pericarditis and oesophageal fistula. We also looked for the presence of inappropriate sinus tachycardia during follow-up.

Follow-up for Pacemaker Therapy

For the PM group, patients were also seen at 1, 6 and 12 months. All presyncope and syncope were recorded. Intra- and post-procedural complications were collected, including pocket-related complications, pericardial effusion and lead-related complications during follow-up.

Study Outcomes

The primary efficacy endpoint was time to first syncope recurrence, switching from CNA to PM or from PM to CNA. The safety endpoints were complications related to CNA (procedural-related complications and unresolved inappropriate sinus tachycardia) and complications related to PM, such as lead-related complications, infections and haematoma.

Statistical Analysis

All statistical tests were performed with SPSS software, version 22 (IBM). Continuous data are shown as median (interquartile range [IQR]) when appropriate. Categorical variables were presented as frequencies and percentages. The cumulative risk of the study outcomes over time was estimated using the Kaplan-Meier method and p<0.05 was considered significant.

Results

Study Population

A total of 14 patients with functional bradycardia were recorded from 2019–2024. Six patients underwent PM and eight patients underwent CNA (Figure 2). They were followed up at 1, 6 and 12 months with 12-lead ECG and 24-hour Holter monitoring. There were two crossovers: one patient in the PM group crossed over to the CNA group and one patient in the CNA group crossed over to the PM group.

Patient Baseline Clinical Characteristics

The baseline clinical characteristics are summarised in Table 1. The median age of the CNA group was 46.5 years (24.3–64.8) and the median age of the PM group was 37.5 years (20.5–45.8). There were 37.5% (n=3) in the CNA group and 83.3% (n=5) in the PM group (p=0.09). The median length of stay for each procedure was 1 day. The indication for CNA was sinus bradycardia in two patients, VVS in five patients and AVB in one patient. The indication for PM was sinus bradycardia in three patients, VVS in three patients and AVB in one patient. The median number of syncope episodes pre-CNA was 2.2 (0–3.8), whereby five of the eight patients sustained a traumatic fall. The median number of syncope episodes pre-PM was 2.5 (1.0–3.5), whereby five of six patients sustained a traumatic fall. Although procedural time for CNA was significantly longer than for PM (230 versus 85 minutes, p=0.003), there were no significant differences in fluoroscopy time or radiation dose between the groups.

Procedural Results

In the CNA group, the median baseline heart rate was 56.5 (50.3–62.8) BPM and increased to 90.5 (69.8–103.8) BPM after CNA (p=0.002). All patients had an acceleration of sinus rate ≥25% higher than baseline values following GP ablation. All patients had left atrial GPs ablated. Nine patients had a saphenous vein graft to the aorta, and five patients had PM-GP ablation.

In the PM group, three patients had dual-chamber PMs and one patient had a single-chamber pacemaker. Two patients had CLS PMs, and 16.7% of patients had pacing <20%, whereas 66.7% had pacing more than 20%.

Clinical Outcomes

At 1 year, the primary efficacy endpoint was met in one patient in the CNA group and one patient in the PM group (p=0.88) (Figure 3A). One patient in the PM group had recurrent syncope syncope, whereas none of the patients in the CNA group did (p=0.25; Figure 3B). One patient crossed over from the CNA group to PM at 8 months. He had symptomatic sinus bradycardia 3 months after CNA and his symptoms resolved after the implantation of a dual-chamber PM. For the PM group, one patient had a syncope event and crossed over to the CNA group at 12 months (Figures 3A and 3B). He underwent CNA 1 week after the syncope event and had no more syncope after the CNA.

The safety endpoint occurred in one patient in the PM group and in none of the patients in the CNA group (p=0.25) (Figure 3C). No intra-procedural complications were noted in the CNA group. One patient experienced transient symptomatic inappropriate sinus tachycardia, which resolved at the 3-month follow-up. However, in the PM group, one patient had an atrial lead fracture where the atrial lead was stuck to the generator during the box change.

Discussion

Efficacy of Cardioneuroablation and Pacemaker Therapy

Functional bradycardia is common among younger populations. The 2021 European Society of Cardiology guidelines and the 2018 American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines include class 1 recommendations to consider PM implantation in patients aged 40 years or older who experience syncope due to vagally mediated bradycardia.

In our study, the median age of patients was 43.0 years (range = 21.5–52.0) and 25% of the patients were aged 60 or older in the CNA group. We observed that older patients with functional bradycardia did not respond well to CNA. The only patient who met the primary efficacy endpoint in the CNA group was a 69-year-old man with symptomatic sinus bradycardia. His sinus rate increased from a baseline of 30 to 50 BPM after CNA (>75% of the maximum sinus rate response in the atropine test and over a 25% increase from baseline). Nonetheless, the absolute sinus rate did not meet his functional needs and his symptoms improved with DDD pacing at 60 BPM. This underscores the importance of individualised pre-procedural selection of patients who might be suitable for CNA based on absolute heart rate during the atropine test.

Our study demonstrated that both treatment groups achieved their efficacy outcomes. There was no difference between the two groups regarding primary and secondary efficacy endpoints. Most of our patients’ cohort had cardioinhibitory or mixed VVS. The average number of syncope events before the procedure was similar between the CNA and PM groups.

At 1-year follow-up, there were no syncope events in patients receiving CNA. Conversely, two patients with a CLS pacemaker experienced recurrent syncope and pre-syncope. The patient who had syncope had no further episodes after receiving CNA. Our findings align with a meta-analysis published in 2022, which included small observational cohorts that reported a 92% overall freedom from syncope after CNA across 15 studies.

Safety Outcomes

Regarding safety outcomes, post-CNA complications such as inappropriate sinus tachycardia are usually temporary. In our study, inappropriate sinus tachycardia resolved within 3 months. Conversely, PM complications tend to increase over time.⁸ Most late complications after PM implantation are related to infection, pocket erosion and lead-related issues. Additionally, lead extraction carries different risk profiles.^9,10 Injury to the myocardium or venous vasculature during lead extraction can lead to fatal complications.⁹

Young patients with PMs are at risk of long-term complications because they may require several PM box changes throughout their lives. This was also highlighted in our study, where lead fracture occurred in a young patient during the first box change. Naturally, CNA might address these issues and serve as a suitable alternative for younger patients with functional bradycardia. One of our patients in the PM group, who later underwent CNA, was counselled regarding the possible discontinuation and removal of the PM. There is limited literature on managing patients who have discontinued PM therapy following CNA, which underlines the importance of shared decision-making.

Cardioneuroablation Procedure

We used fractional mapping to identify highly fractionated atrial EGMs characteristics of distal endocardial inputs of GP, in contrast to the surrounding atrial myocardium that has less fractionated or non-fractionated atrial electrograms.⁷ We identified GP sites with EGMs demonstrating more than three deflections.

Lellouche et al. also described the use of fragmented EGMs to localise GPs during sinus rhythm.¹¹ It was found that the best single predictor of vagal response during radiofrequency ablation was EGM fragmentation.

A fragmented EGM-based strategy was used in our study because it can be performed under sedation, requires shorter procedure and fluoroscopy times and achieves similar success rates in preventing vagal-related prodromal symptoms. Aksu et al. used low and high-fractionated EGMs for GP mapping at filter settings between 200 and 500 Hz. The authors demonstrated acute procedural success in all cases without any major adverse events.¹² The EGM-guided approach demonstrated similar clinical success compared to the ablation strategy based on spectral mapping and high-frequency stimulation.¹³ Similar to our study’s findings, none of the patients suffered from recurrent syncope during follow-up.¹³

For the ablation sequence, we started with left-sided GP.^14,15 We ablated the left-sided GP first because there will be a significant modification of vagal response during the ablation of the right superior GP in terms of changes in blood pressure and heart rate.¹⁶ Therefore, ablating the right superior GP first makes the evaluation of subsequent ganglia denervation difficult. We did not use vagal hyperstimulation as it requires general anaesthesia and can result in excessive vagal denervation. The long-term prognosis of total parasympathetic withdrawal was unknown. The patient’s symptoms, functionality and long-term prognosis could be affected by the uninhibited sympathetic response after CNA. The efficacy of CNA appeared limited in older patients. Ageing leads to degenerative changes at the structural level (the intrinsic component) and also in the autonomic nervous system (the extrinsic component). This results in a decrease in the intrinsic heart rate.¹⁷ Further, with advancing age, spontaneous remission of syncope is possible based on the natural history of reflex syncope. Therefore, complete and permanent parasympathetic denervation might not be needed for functional bradycardia. Studies with long-term follow-up will provide an answer to these issues.^18,19

Limitations

Our study has some limitations. First, it was conducted at a single centre with a small sample size. Therefore, the study may lack sufficient power to detect significant differences in efficacy and safety. However, this is the first study to compare the outcomes of CNA versus pacemaker therapy in functional bradycardia. Second, due to its retrospective nature, some patients might have failed to report pre-syncopal or syncopal episodes. Nonetheless, during each follow-up visit, the recurrence of syncope was thoroughly examined.

Conclusion

In our real-world experience, cardioneuroablation and pacemaker therapy appear to be safe and effective treatment options for patients with functional bradycardia. Larger multicentre studies with longer follow-up are required to confirm these findings.