Cardioneuroablation for Reflex Syncope
Cardioneuroablation for Reflex Syncope
Aim. To assess the effects of cardioneuroablation (CNA) on cardiac autonomic regulation and
 syncope recurrences in patients with vasovagal syncope (VVS), and to compare this novel
 approach with standard non-pharmacological treatment.

 Measurements.

 1. Before CNA:

 1. Detailed history taking and assessment of eligibility

 2. Baseline 12-lead ECG for heart rate assessment, morphology and duration of the P
 wave and PR interval

 3. 24-hour Holter ECG for heart rhythm (mean, minimal, maximal, pauses) and heart rate
 variability (HRV) assessment

 4. Passive tilt test (70 degrees, 45 minutes) to fulfill inclusion criterion and to
 assess baseline autonomic parameters such as HRV and baroreflex sensitivity (BRS)
 using sequential method. These parameters will be calculated from 5 min recordings
 before and after orthostatic stress (tilt).

 5. Atropine test - positive response to intravenous atropine in a dose of 2 mg defined
 as at least 30% increase in sinus rate compared with baseline value

 6. Assessment of quality of life using the SF-36 questionnaire

 7. Implantable Loop Recorder (ILR) implantation 2-3 days before CNA

 2. During CNA:

 1. Heart rate before and immediately after CNA

 2. Episodes of bradycardia (sinus arrest or atrio-ventricular block) during
 application of RF to GP.

 3. Standard electrophysiological parameters (sinus node recovery time, corrected sinus
 recovery time, refractory atrio-ventricular node, atrio-ventricular conduction -
 Wenckebach point, A-H and H-V intervals) will be assessed before an immediately
 after CNA

 4. Atropine test (2 mg) will be repeated immediately after CNA.

 3. After CNA:

 1. 1-2 days after CNA standard ECG

 2. Follow-up: 3, 12 and 24 months after CNA assessment of symptoms, 12 lead standard
 ECG, control of ILR, 24-hour Holter ECG, tilt test and atropine test will be
 performed. Additionally, quality of life will be assessed using SF-36 questionnaire

 Anticipated results.

 1. CNA performed with technique used in the present study is effective in > 90% of
 patients.

 2. CNA-induced changes in analysed ECG and autonomic parameters predict CNA efficacy
Introduction.

 Reflex syncope due to vasovagal reaction is the most frequent cause of transient loss of
 consciousness (TLOC) in general population. [1-4] It markedly decreases quality of life and
 may lead to injury. [5, 6] The mechanism of vasovagal syncope (VVS) is complex. One of the
 most important mechanisms is enhanced parasympathetic activity triggered by abnormal
 mechanoreceptor reflex and other mechanisms. This leads to prolonged asystole and/or
 vasodilatation, resulting in syncope. [7] Treatment of VVS remains a challenge.
 Non-pharmacological treatment such as fluid and salt intake, avoiding situations triggering
 syncope or tilt training is not effective in a significant proportion of subjects with
 syncope. Pharmacotherapy is even less effective. Syncope recurs in 25-65% of patients.
 Alternative therapy, especially in patients with prolonged asystole, is pacemaker
 implantation, recommended by the guidelines in patients aged > 40 years with documented
 spontaneous cardioinhibitory VVS and severe symptoms. However, permanent pacing occurs
 ineffective in at least 25% of patients. In addition, VVS occurs predominantly in young
 persons in whom permanent pacing should be avoided as much as possible. [8-13] Thus, the need
 for new treatment options in VVS is clear.

 Ablation for atrial fibrillation (AF) has been successfully performed for almost two decades.
 Apart from pulmonary vein isolation which is a corner stone of AF ablation, autonomic control
 of the heart is modified by ablation of ganglionated plexi (GP). It has been well documented
 that in some patients GP ablation increases the success rate of ablation, especially in
 patients with vagally-mediated AF. Thus, the technique of GP ablation, mainly using the
 radio-frequency energy, is well established and safe.

 Based on data coming from GP ablation during AF procedures, this method has been recently
 proposed for patients with VVS. The postulated beneficial mechanisms of GP ablation in VVS
 are attenuation of parasympathetic activity, leading to elimination or reduction reflex
 asystole and bradycardia. To date, a few case series consisting of up to 70 patients
 demonstrated very promising results. [15-18]. However, this experience is limited to a few
 centers. Also, the optimal methodology of the procedure, called cardioneuroablation (CNA) or
 cardioneuromodulation, is not known. There is no consensus yet as to how many GP's, in both
 atria or only in the right atrium, in which order and to what extent should be ablated.
 Moreover, mechanisms responsible for beneficial effects of CNA as well as methods assessing
 it's efficacy are not clear.

 Aim. To assess the effects of CNA on cardiac autonomic regulation and syncope recurrences in
 patients with VVS, and to compare this novel approach with standard non-pharmacological
 treatment.

 Hypothesis. CNA using GP ablation causes significant changes in autonomic control of the
 heart, predominantly parasympathetic withdrawal, which is associated with long-term efficacy
 of the procedure, and is significantly more effective than standard non-pharmacological
 therapy.

 Methods. This is an open-label, randomized, controlled, prospective study.

 Study group. Forty consecutive patients with recurrent cardioinhibitory or mixed VVS will be
 included between August 2018 and July 2021.

 The patients will be randomized into 2 groups:

 1. Treatment arm (n=20): CNA

 2. Control arm (n=20): standard non-pharmacological treatment The patients from the control
 arm will be allowed to cross over to the CNA group if syncopal episode occurs despite
 adherence to the non-pharmacological recommendations.

 The number of 40 patients will be enough to demonstrate superiority of CNA over standard
 approach, assuming that the effectiveness of CNA will be over 90%, and the effectiveness of
 the standard non-pharmacological treatment will be 50%.

 Inclusion criteria:

 1. At least one documented spontaneous VVS during preceding 12 months or one syncope in
 history leading to injury and minimum 2 presyncopal events during preceding 12 months,
 refractory to all recommended types of standard treatment.

 2. In case of lack of ECG documentation during spontaneous syncope and history suggesting
 reflex syncope, at least 3 seconds of asystole due to sinus arrest or atrio-ventricular
 block with syncope or bradycardia <40 beats per minute with syncope or presyncope during
 baseline tilt test

 3. Sinus rhythm during ECG and tilt test

 4. Significantly decreased quality of life due to syncope

 5. Positive response to atropine test

 6. Obtained written informed consent.

 Exclusion criteria:

 1. Other possible and treatable causes of syncope such as significant cardiac disease,
 cardiac arrhythmia or abnormalities of vertebro-basiliar arteries

 2. History of stroke or TIA

 3. History of cardiac surgery

 4. Contraindications to ablation in the right or left atrium

 Cardioneuroablation The procedure is performed under mild sedation (midazolam and fentanyl)
 using a 3.5 mm irrigated tip catheter (Navistar ThermoCool SmartTouch; Biosense Webster,
 Diamond Bar, California, USA) with contact force module and electroanatomical system Carto 3
 (Biosense Webster, Diamond Bar, California, USA). After gaining transseptal access, an
 electroanatomical map of the right (RA) and left (LA) atrium is created and
 anatomically-based ablation of GP is performed. Ablation in the RA is started from the
 supero-posterior area (superior right atrial GP), to the middle-posterior area (posterior
 right atrial GP). In the LA, ablation is started at the site of the anterior right GP and is
 continued downwards along the anterior part of a common vestibulum of the right pulmonary
 veins (PV), opposite to the right-sided ablation lesions. Finally, area of right inferior GP,
 close to the RIPV is ablated under intracardiac echocardiography control. Using this
 technique, GP's located close to the left PV are not ablated. We use a pure anatomic approach
 without identification of GP by high-frequency stimulation or other imaging techniques.

 Measurements.

 1. Before CNA:

 1. Detailed history taking and assessment of eligibility

 2. Baseline 12-lead ECG for heart rate assessment, morphology and duration of the P
 wave and PR interval

 3. 24-hour Holter ECG for heart rhythm (mean, minimal, maximal, pauses) and heart rate
 variability (HRV) assessment

 4. Passive tilt test (70 degrees, 45 minutes) to fulfill inclusion criterion and to
 assess baseline autonomic parameters such as HRV and baroreflex sensitivity (BRS)
 using sequential method. These parameters will be calculated from 5 min recordings
 before and after orthostatic stress (tilt).

 5. Atropine test - positive response to intravenous atropine in a dose of 2 mg defined
 as at least 30% increase in sinus rate compared with baseline value

 6. Assessment of quality of life using the SF-36 questionnaire

 7. Implantable Loop Recorder (ILR) implantation 2-3 days before CNA

 2. During CNA:

 1. Heart rate before and immediately after CNA

 2. Episodes of bradycardia (sinus arrest or atrio-ventrocular block) during
 application of RF to GP.

 3. Standard electrophysiological parameters (sinus node recovery time, corrected sinus
 recovery time, refractory atrio-ventricular node, atrio-ventricular conduction -
 Wenckebach point, A-H and H-V intervals) will be assessed before an immediately
 after CNA

 4. Atropine test (2 mg) will be repeated immediately after CNA.

 3. After CNA:

 1. 1-2 days after CNA standard ECG

 2. Follow-up: 3, 12 and 24 months after CNA assessment of symptoms, 12 lead standard
 ECG, control ILR, 24-hour Holter ECG, tilt test and atropine test will be
 performed. Additionally, quality of life will be assessed using SF-36 questionnaire

 Definitions used for CNA efficacy assessment:

 -  Complete efficacy - no syncope or presyncope during two years of follow-up

 -  Partial efficacy - reduction of the number of syncopal (or presyncopal)
 episodes or change from syncopal to presyncopal episodes

 Primary endpoint

 - Time to first syncope recurrence

 Secondary endpoints

 -  Syncope burden (number of syncopal episodes during two years)

 -  Presyncope burden (number of presyncopal episodes during two years)

 -  ILR: assessed heart rate and atrio-ventricular conduction if syncope occurs

 -  CNA-induced changes in autonomic parameters

 -  Prognostic value of autonomic parameters.

 -  Safety of CNA: tamponade, stroke, phrenic nerve injury, permanent sinus
 arrest, local bleeding or vascular complications related to vascular access
 (hematoma / arteriovenous fistula)

 Statistical analysis Results will be presented as mean ± SD or numbers and
 percentages. Also CNA-induced changes(∆) in analysed parameters will be calculated.
 The ECG, electrophysiological and autonomic parameters obtained before and after
 CNA will be compared using student t-test or Mann-Whitney test where appropriate.
 The values of analysed parameters in predicting CNA efficacy will be assessed by
 computing sensitivity, specificity, positive and negative predictive value. The ROC
 curves will be drawn in order to establish optimal cut-off points of analysed
 parameters in predicting CNA efficacy.

 Anticipated results.

 1. CNA performed with technique used in the present study is effective in > 90% of
 patients.

 2. CNA-induced changes in analysed ECG and autonomic parameters predict CNA efficacy
Inclusion Criteria:

 -  At least one documented spontaneous VVS during preceding 12 months or one syncope in
 history leading to injury and minimum 2 presyncopal events during preceding 12 months,
 refractory to all recommended types of standard treatment.

 -  In case of lack of ECG documentation during spontaneous syncope and history suggesting
 reflex syncope, at least 3 seconds of asystole due to sinus arrest or
 atrio-ventricular block with syncope or bradycardia <40 beats per minute with syncope
 or presyncope during baseline tilt test

 -  Sinus rhythm during ECG and tilt test

 -  Significantly decreased quality of life due to syncope

 -  Positive response to atropine test

 -  Obtained written informed consent.

 Exclusion Criteria:

 -  Other possible and treatable causes of syncope such as significant cardiac disease,
 cardiac arrhythmia or abnormalities of vertebro-basiliar arteries

 -  History of stroke or TIA

 -  History of cardiac surgery

 -  Contraindications to ablation in the right or left atrium