Inappropriate Sinus Tachycardia Following Cardioneuroablation for Reflex Syncope: A Case Report and Review of the Literature Illustrating this Underappreciated Adverse Effect

Cardioneuroablation (CNA) is a promising tool for the treatment of reflex asystolic syncope.¹ The aim of the procedure is to reduce or abolish parasympathetic drive to the heart, thereby preventing reflex bradycardia or asystole. These effects are achieved using endocardial radiofrequency (RF) ablation of areas where ganglionated plexi (GP) are localised, usually around epicardial fat pads and neighbouring atrial myocardium. Nerve fibres, which are present in GP areas, consist of both parasympathetic and sympathetic endings. The neural bodies of the sympathetic system are localised more distal from the cardiac tissue than the post-ganglionic vagal nerve parasympathetic endings, which are usually located just over or inside the atrial myocardium.¹ In addition, the regeneration of the parasympathetic bodies following RF ablation, called parasympathetic reinnervation, is much slower and less complete than that of the adrenergic nerves. Therefore, the net effect of CNA is the complete elimination or significant attenuation of the vagal nerve effects on the sinus and atrio-ventricular (A-V) nodes, whereas the effects on the adrenergic part are less pronounced and transient. The CNA-induced imbalance in the cardiac autonomic nervous system may cause sinus rate acceleration.^1,2

Indeed, the most common adverse effect of CNA is inappropriate sinus tachycardia (IST), which – in the majority of patients – resolves by 3–12 months after the procedure because of partial parasympathetic reinnervation. However, in some subjects IST may become chronic and may be very symptomatic causing palpitations, fatigue or decreased exercise capacity. Possible long-term adverse effects of IST, such as development of tachycardiomyopathy or aggravation of pre-existing cardiac disorders, should also be taken into account.

In this case report, we present the most complicated patient from our cohort of more than 400 patients treated with CNA so far in our department. The case illustrates the problems that can arise when CNA is performed probably too vigorously in a patient with many co-morbidities associated per se with autonomic imbalance and an increased risk for various complications. However, it should be noted that post-CNA IST syndrome may also be encountered in otherwise completely healthy subjects undergoing this procedure. In our experience, this risk is 7%.²

Case Report

An 18-year-old female with frequent recurrent syncopal and presyncopal episodes, often occurring without prodromal symptoms and associated with injury, was referred for consultation for CNA. Despite optimal non-pharmacological treatment, she continued to suffer from frequent episodes of syncope. On physical examination she had a slow sinus rhythm of 45 BPM and low blood pressure of 95/70 mmHg. Her baseline 24-hour Holter ECG recorded on the day when she had no syncope revealed profound bradycardia with a mean sinus rate of 37 BPM (range 23–73), with the longest RR interval of 2,628 ms. Tilt testing was performed, which showed mixed type vasovagal response with sinus pause of 4 seconds and the lowest systolic blood pressure of 40 mmHg. Syncope was reproduced. Echocardiography was normal. Concomitant disorders included depression, Fanconi’s syndrome with preserved renal function, myasthenia gravis, Ehlers-Danlos syndrome, a positive human leukocyte antigen-B27 test and suspected lupus erythematosus. The patient underwent atropine testing, which showed sinus rhythm acceleration from 40 to 70 BPM (an increase of 75%) following intravenous injection of 2 mg of the drug. Symptomatic functional bradycardia and vasovagal syncope were diagnosed. At that time, the patient was reluctant to try heart rate-accelerating medication, such as theophylline or salbutamol. Other therapeutic options were discussed with the patient and she opted for CNA.

In February 2021, the patient underwent the first CNA under general anaesthesia and muscle relaxation. We used our standard bi-atrial approach with RF energy delivered under the guidance of a 3D electro-anatomical mapping system, intracardiac echocardiography and analysis of fragmented atrial potentials. The effectiveness of CNA was controlled using extracardiac vagal stimulation (ECVS) from the right and left internal jugular veins.² During the procedure, paraseptal GPs from both atria were targeted. The sinus rate accelerated from 30 to 60 BPM and ECVS showed full vagal denervation. Atropine given at the end of the procedure did not cause any acceleration of sinus rhythm confirming that full vagal denervation was achieved.

After initial improvement and no syncope recurrences during the first 6 months after the procedure, the patient again started to experience syncopal and presyncopal episodes. Holter ECG performed at that time showed a mean sinus rate of 80 BPM (range 41–130). However, very long periods of symptomatic sinus bradycardia of 40 BPM, also during the daytime, were recorded. On physical examination, severe bradycardia of 30 BPM was present. Theophylline and salbutamol were tried but without success. It was felt that the result of CNA was suboptimal due to parasympathetic reinnervation. After a thorough discussion with the patient, a shared decision was made to proceed with another CNA.

The second CNA was performed in January 2022. At baseline, the sinus rate was 27 BPM and ECVS documented pacing-induced complete A-V block. The paraseptal GPs as well as GPs located close to the left pulmonary veins and aorta–superior vena cava were effectively targeted and subsequent ECVS showed complete vagal denervation. Immediately after the CNA, sinus bradycardia was still present, atropine did not increase the sinus rate and the patient was re-started on salbutamol and theophylline. However, this remained ineffective and had to be stopped because of allergy a few weeks later.

After the second CNA there were no syncope recurrences; however, the patient developed new symptoms: palpitations and chronic fatigue. On physical examination her heart rate was 120–140 BPM at rest and the systolic blood pressure was <100 mmHg. Post-CNA IST syndrome was suspected, which was confirmed on 24-hour Holter ECG monitoring; mean sinus rate was 107 BPM (range 95–148). She underwent ineffective treatment with ivabradine, propranolol and both agents in combination. Verapamil was also ineffective and caused profound hypotension and bradycardia, leading to emergency hospitalisation. Thus, pharmacological attempts to treat IST were ineffective.

Because the patient had permanent IST and remained severely symptomatic, the decision was made to perform sinus node modification to slow down the sinus rate. The procedure was performed in November 2022. Multiple RF applications were delivered; however, there was a very wide area of phrenic nerve capture precluding applications at the optimal site. Despite this, slowing of sinus rhythm from 140 to 100 BPM was achieved with visible transient change in the P wave morphology in leads I, II and III, from positive to flat or slightly negative.

There was a transient moderate improvement in clinical symptoms. Nevertheless, IST-related symptoms reappeared after 3 months, and a repeated ablation or modification of the sinus node was thought to be necessary. The procedure was performed in May 2023. This time an inflatable balloon was introduced to the pericardial space and the phrenic nerve was moved away from the sinus node area. The procedure was acutely effective, with the sinus rate slowing from 140 to 90 BPM. The patient’s condition improved immediately. Holter ECG performed 2 days after ablation showed mean heart rate of 65 BPM (range 50–116). The patient continued to feel well, without syncope, palpitations or fatigue. The next Holter performed 1 month after ablation showed mean heart rate of 102 BPM (range 74–156) with SD of NN intervals of 99 ms, leading to concerns that the beneficial effects of sinus node modification might have disappeared; however, the patient continued to feel well.

When 6 months had elapsed from the second sinus node modification procedure, the patient started to experience syncope recurrences. On examination she had bradycardia of 52 BPM and Holter ECG showed a mean heart rate of 45 BPM (range 38–54). Atropine only minimally accelerated sinus rhythm from 52 to 58 BPM (12%), which suggested that sinus bradycardia was this time not due to parasympathetic overactivity but due to post-ablation sinus node injury. The decision to implant a pacemaker was made and a dual-chamber pacing with closed loop stimulation (DDD-CLS) pacemaker was implanted in November 2023.

After implantation, the patient immediately improved and syncopal episodes were no longer present. In the meantime, she underwent surgery for thymoma and corrective surgery for flexible jaw joints (Ehlers-Danlos). Surgery for thymoma was complicated by delayed healing of the wound at the chest area where laparoscopic instruments were introduced during the procedure.

Unfortunately, 5 months later the patient developed local complications at the pacemaker pocket area. The skin was reddened and scaled, without signs of infection. Allergy testing revealed allergy to titanium and the decision was made to remove the DDD-CLS pacer and to implant a gold pacemaker. The procedure was performed in March 2025.

A graphical summary of all procedures performed on this patient, results of serial Holter ECG monitoring and clinical status are summarised in Figure 1. This case report shows how difficult treatment of functional (at least, in part) bradycardia can be, how CNA can cause even further deterioration in patient’s condition due to intractable IST and how the patient can return to unwanted basal state with profound sinus node ablation-induced symptomatic bradycardia. Perhaps a less vigorous approach to CNA by avoiding the second CNA or performing a procedure confined to the right atrium only would be more appropriate. However, it seems that the right-sided CNA causes similar sinus rate increases as the bi-atrial procedure, although no head-to-head comparison has been performed.³ Denervation of the A-V node is much more easily achieved using a bi-atrial approach.^1,2 Furthermore, less extensive sinus node modification by ablation and more vigilant assessment of a patient with so many generalised disorders, associated with autonomic abnormalities, might likely have resulted in better treatment. Specifically, the tendency for orthostatic hypotension and poor wound healing because of the patient’s Ehlers-Danlos syndrome should have been considered more thoroughly when making therapeutic decisions. Twenty-four-hour ambulatory blood pressure monitoring would also have been helpful and should have been done according to the current literature.⁴ However, the patient strictly followed all the rules of non-pharmacological methods advocated for syncope prevention and frequent home recordings of blood pressure did not reveal any significant hypotension. So, the final question is, what can one offer an 18-year-old female with recurrent syncope due to permanent severe functional bradycardia? CNA still seems to be the most promising initial treatment; however, in our patient, this was not the case.

Discussion

Although nearly 150 articles on the use of CNA for the treatment of reflex syncope have been published up to December 2024 (data from PubMed), the true incidence of IST is difficult to establish. The results of some studies reporting this adverse effect are summarised in Table 1.^1,2,5–17 According to these reports, the incidence of post-CNA IST varies from 0–23%, with a mean value of 7%. Female sex predominates. However, these numbers should be taken with caution for several reasons.

Firstly, this complication is probably under-reported in the literature. An increased sinus rate after CNA is common and may be very symptomatic and long-lasting in some patients, yet the majority of published studies did not mention this adverse effect. Of approximately 150 papers in PubMed describing CNA, only 15 (10%) reported post-CNA IST.

Second, in the reports in which post-CNA IST was mentioned, terminology and definitions varied broadly. Some authors used the term “sinus tachycardia”, some used “symptomatic sinus tachycardia” and others used “inappropriate sinus tachycardia”. In addition, no strict definition of sinus tachycardia or IST was used in these reports. The standard definition for IST states that this is a clinical syndrome, defined as fast sinus rate >100 BPM at rest or mean heart rate >90 BPM over 24-hour ECG ambulatory monitoring.^18,19 Nevertheless, even in papers strictly devoted to IST, definitions vary and most publications did not offer a specific measurement of time or duration at or over which heart rate should be measured.²⁰

Third, the question arises whether the definition of post-CNA IST should be the same as in other conditions associated with IST. CNA-induced sinus tachycardia is an expected phenomenon because attenuation of parasympathetic effects on the heart is the mechanism by which the procedure prevents reflex syncope recurrences. In addition, post-CNA IST is a transient phenomenon in the majority of patients and disappears after 3–12 months due to partial parasympathetic reinnervation.^1,2,5–17 Thus, the definition of post-CNA IST should probably include the timing after the procedure. To summarise, a possible definition could be as follows: “mean sinus rate >90 BPM on 24-hour ECG monitoring associated with symptoms and lasting >1 year from CNA”. The time limit of 1 year is rather arbitrary since there are no data in literature on the long-term course of IST after CNA. However, more data are available on the heart rate and heart rate variability (HRV) changes after CNA, which may be of some relevance to symptoms associated with IST. All studies showed that there is a prompt increase in sinus rate and prompt decrease in the HRV indices after the procedure, with gradual – albeit not complete – return towards baseline values by 1 year of follow-up.^{1,5,6,9,12,21,22} Interestingly, one study showed no further significant reinnervation beyond 1 year.²² Thus, 1 year may be regarded as the cut-off point between the IST being just a transient adverse effect of CNA to the IST being a more durable complication of CNA.

Another question – whether IST is only relevant when symptomatic or if asymptomatic patients should also be defined – is difficult to answer because the long-term prognosis in CNA-induced IST is not known. Post-CNA IST is a new entity that may differ in the course, need for treatment and prognosis from the classical idiopathic IST. Regarding nomenclature, it may be suggested to use the term “post-CNA IST” as 24-hour sinus rate >90 BPM in all patients who fulfil this criterion and the term “post-CNA IST syndrome” in those who fulfil this criterion and have symptoms due to elevated heart rate.

Fourth, differences in post-CNA IST incidence may be due to different follow-up protocols. Currently, there is no optimal follow-up scheme recommended²⁰ and the role of repeated ambulatory ECG, implantable loop recorders or tilt testing has not been fully established. Obviously, less rigorous follow-up, consisting only of telephone calls and sporadic clinic visits, conducted by primary care physicians and not by CNA specialists, would probably result in under detection of post-CNA IST and undertreatment of these patients.

The treatment of post-CNA IST seems the same as that of other forms of IST. The mainstay is elimination of secondary causes of IST, exercise training and pharmacotherapy with ivabradine.²³ β-blockers and calcium channel blockers may also be used; however, the main problem with these agents is their hypotensive effect. This often precludes administration of these drugs in many patients with reflex syncope who already have low baseline blood pressure and susceptibility to hypotension. Of β-blockers, non-selective agents seem to be preferable, including propranolol with a low starting dose of 10–20 mg/day and the possibility to increase the dose if well tolerated.²

If lifestyle modifications, exercise training and pharmacotherapy are ineffective, invasive treatment may be an option. However, sinus node modification or ablation is currently not recommended by the guidelines because of poor efficacy, risk of phrenic nerve injury and a high risk (up to 50%) of creating very symptomatic sinus bradycardia or even complete lack of sinus rhythm, requiring pacemaker implantation.²³

Another very important yet unresolved issue is the identification of patients with reflex syncope who are at increased risk of developing post-CNA IST. Data in the literature are lacking. It may be speculated that those who already have fast sinus rate before the procedure (for example, mean sinus rate >80 BPM on ambulatory ECG monitoring) may be more prone to the development of post-CNA IST because the procedure-induced vagal denervation may result in resting or mean heart rate >100 BPM, which may be very symptomatic. In addition, the prognostic value of the pre-procedural atropine test is unknown. Again, it may be speculated that those with a marked acceleration of sinus rhythm following atropine injection (for example, sinus rate increase >100%) may be at higher risk of developing post-CNA IST since one may expect similar heart rate after CNA-induced full vagal denervation.

Lastly, techniques and procedural parameters may be important in creating post-CNA IST. Such issues as the number of RF applications, extensive versus limited areas of GP ablation and intra-procedural usage of extra-cardiac vagal stimulation versus standard electrophysiology parameters to assess acute CNA efficacy and to guide decisions to end the procedure, have not been yet addressed.

The long-term adverse effects of persistent post-CNA IST are not known. The possible risk of tachycardiomyopathy should be taken into account. However, CNA is not the only ablation procedure that may cause IST. Heart rate acceleration has also been described in patients undergoing ablation for A-V nodal re-entrant tachycardia (AVNRT). Local parasympathetic denervation at the area of slow pathway may cause IST in 4.7% of patients or postural orthostatic tachycardia syndrome. ^24,25 A similar, albeit much more frequent phenomenon, is observed after thermal ablation for AF.^26,27 It is not surprising because several areas where energy is delivered during pulmonary vein isolation are the same as those ablated during CNA, especially at the anterior ridge of the right pulmonary vein. It has been shown that the extent of parasympathetic denervation after AF ablation is similar to that occurring after CNA and there are several reports suggesting the increase in sinus rate to be a good predictor of AF ablation efficacy.^28,29 Nonetheless, no increase in the rate of complications associated with faster heart rate nor elevated risk of death following ablation for AVNRT or AF have been reported so far, which is encouraging when the risk of IST after CNA is evaluated.

Conclusion

Post-CNA IST happens and may be devastating. In the majority of patients, the sinus rate slows down up to 1 year after CNA due to partial vagal reinnervation; however, in some the syndrome becomes chronic. The incidence, risk factors, optimal treatment and long-term outcome of post-CNA IST have not yet been established. We believe that post-CNA IST is an underappreciated adverse effect of CNA and should be studied and reported more carefully in future literature than it has been thus far.