Ignite Creation Date:
2024-06-16 @ 11:51 AM
Last Modification Date:
2024-10-26 @ 3:32 PM
Study NCT ID:
NCT06458140
Status:
RECRUITING
Last Update Posted:
2024-06-13
First Post:
2024-06-09
Brief Title:
Cardioneuroablation and Ventricular Proarrhythmia
Sponsor:
Centre of Postgraduate Medical Education
Organization:
Centre of Postgraduate Medical Education
Study Overview
Official Title:
Acute electRophysiOlogical Changes of Ventricular Myocardium Following cArdioneuroablatioN for Asystolic Reflex Syncope
Status:
RECRUITING
Status Verified Date:
2024-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Roman4
Brief Summary:
Cardioneuroablation CNA is a promising tool to treat patients with asystolic reflex syncope CNA acts through complete or near complete abolition of vagal nerve chronotropic and dromotropic effects on the heart resulting in sinus node acceleration and improved atrio-ventricular conduction which in turn prevents vagally-mediated reflex asystole However lack of parasympathetic protection may potentially be proarrhythmic especially on the ventricular level Whether this is a real threat is not known Therefore the aim of our study is to assess acute effects of CNA-induced total vagal denervation measured by extracardiac vagal stimulation on ECG and electrophysiological parameters as well as vulnerability to ventricular arrhythmias The study group will consist of 50 consecutive patients undergoing CNA in our institution Cardioneuroablation will be performed in standard manner The following parameters will be assessed at baseline and after CNA directly after CNA after atropine injected after CNA and after isoproterenol bolus injected at the very end of the procedure QTc interval QT dispersion right ventricular action potential duration right ventricular effective refractory period and susceptibility to complex ventricular arrhythmias using programmed ventricular stimulation
Detailed Description:
Cardiac arrhythmias both atrial and ventricular can be modulated by changes in autonomic tone In ventricular arrhythmias sympathetic tone is thought to be pro-arrhythmic whereas increased parasympathetic tone exerts protective effects The main mechanisms responsible for parasympathetic protection involve direct effects on ventricular repolarisation maintaining electrical stability via preservation of gap junction communication between myocytes reducing heterogeneity of action potential duration and decreasing circulating catecholamines and inflammatory markers It has also been shown that enhanced parasympathetic activity increases ventricular fibrillation VF threshold Also termination of ventricular tachycardia VT by manoeuvres leading to augmentation of parasympathetic tone has been demonstrated Numerous experimental studies showed that vagal nerve stimulation may decrease susceptibility to ventricular arrhythmias
Cardioneuroablation CNA is a new promising method to treat reflex syncope which is due to vagally-induced functional sinus arrest or atrio-ventricular block AVB The goal of the procedure is to ablate post-ganglionic endings of parasympathetic part of autonomic nervous system ANS located in ganglionated plexi GP in the epicardial fat and in the myocardium Although both sympathetic and parasympathetic nerves are localised in GPs the latter ones only barely regenerate Therefore CNA-induced damage of the parasympathetic part of GP is greater and more durable than that of the sympathetic part of ANS Because increased vagal activity is one of the main mechanisms leading to reflex sinus arrest or atrio-ventricular AV block targeting this part of ANS by CNA may prevent recurrences of reflex syncope Indeed it has been shown that CNA may be effective in approximately 80-90 of very symptomatic subjects with reflex syncope
While the reduction of parasympathetic drive to the atrial GPs responsible for sinus node and AV conduction seems to be logical and effective way for treating hypervagotonic reflex syncope CNA-induced changes at the ventricular level may be theoretically harmful As mentioned above parasympathetic tone exerts protective effects on ventricular arrhythmias Recently the long-term safety of CNA has become an issue raised by some investigators They expressed concerns that CNA-induced chronic and long-lasting decrease in parasympathetic activity may be dangerous during the future life of usually young people undergoing CNA nowadays For instance if they develop coronary artery disease heart failure or other cardiac diseases which increase propensity of ventricular arrhythmias lack of parasympathetic protection may lead to the occurrence of complex or even life-threatening ventricular arrhythmias
Data in literature on possible proarrhythmic effects of CNA are limited and not uniform From the anatomical and physiological point it has been shown many years ago that destruction of cardiac innervation at the atrial level may also damage ventricular innervation downstream Although CNA targets GP localised mainly around the left and right atria responsible for sinus and AV nodes innervation ventricular GPs may be also affected indirectly by alterations in interaction with atrial GPs or even by direct ablation of some of ventricular GPs According to Pauza et al there are several ventricular GPs which are located in the epicardial fat surrounding the aortic root close to right and left coronary artery ostia at the area of the proximal posterior descending coronary artery close the proximal right acute marginal coronary artery and at the origin of the left obtuse marginal coronary artery However the number of ventricular GPs is much lower than that of the atrial ones 20 of atrial GPs and their density is also lower Thus it is very likely that during ablation of some atrial GPs like postero-medial left GP PMLGP or within the coronary sinus CS also ventricular GPs integrity and function may be altered
Specific data in literature on possible pro-arrhythmic effects of CNA on ventricular myocardium are scarce A few experimental studies suggested that decreasing the parasympathetic drive to the heart by ablating epicardial GPs increases susceptibility to ventricular arrhythmias both in normal and ischaemic animal hearts Also one recent study showed that acute ischaemia occurring 6 weeks after CNA was associated with significantly higher incidence of VF than in control untreated swine As far as human data is concerned a few cases of possible proarrhythmia - polymorphic VT induction after pulmonary vein isolation with concomitant parasympathetic denervation or after pure CNA have been described
Susceptibility to complex ventricular arrhythmias before and after institution of pharmacological treatment or performing a procedure can be assessed invasively by measuring drug- or procedure-induced changes in the ventricular effective refractory period VERP ventricular action potential duration VAPD and directly by using programmed ventricular stimulation PVS However these data in subjects undergoing CNA are lacking
Apart from invasive measurements changes in the duration and dispersion of ventricular repolarisation may be indirectly assessed on surface ECG by measuring the corrected QT QTc interval and QT dispersion QTd Data on the CNA-induced changes on QT are scarce and conflicting While Aksu et al showed that CNA caused significant shortening of QT interval duration which may be in some situations such as long QT syndrome anti-arrhythmic others showed that PVI with CNA does not change QT interval or that CNA causes prolongation of QT interval which may in fact have proarrhythmic effects It has also been shown that QTd increases after PVI which is almost always combined with some GPs ablation or after pure CNA The preliminary results from one excellent CNA centre showed that QTc was significantly prolonged by 25-30 ms immediately after the procedure only by 5-10 ms one day after CNA returned to the baseline values 3 months later and was slightly shorter than at baseline one year after the procedure
In summary it is little known about possible proarrhythmic effects of CNA at the ventricular level This study was set out to explore these effects
Aim To assess acute effects of CNA-induced total vagal denervation measured by extracardiac vagal stimulation ECVS on ventricular refractoriness and vulnerability to ventricular arrhythmias in patients undergoing this procedure due to reflex asystolic syncope
Hypothesis Acutely CNA prolongs ventricular effective refractory period ventricular action potential duration and QT interval without increasing susceptibility to stimulation-induced sustained ventricular arrhythmias The effects on QTd are difficult to predict
Methods Patients The study group will consist of consecutive patients undergoing CNA in our institution Patients are offered CNA if they have severe recurrent symptoms due to reflex syncope with ECG documented asystole 3 seconds especially if associated with injury or recurrent presyncope with persistent reflex bradycardia The patients have to have a history of ineffective prior non-pharmacological treatment and positive baseline atropine test sinus rate acceleration 30 and no AV block following 2 mg of intravenous atropine All patients gave informed written consent to undergo CNA and to participate in the study Ethics Committee approval 332024 Cardioneuroablation The procedure is performed under general anaesthesia with muscle relaxation using a 35 mm irrigated tip catheter Navistar ThermoCool SmartTouch with contact force module and electroanatomical system Carto 3 Biosense Webster US The ablation index is set at 500 except coronary sinus CS where the target value is 350 Intracardiac echocardiography ICE Acuson SC2000 Siemens Germany AcuNav Ultrasound Catheter Biosense Webster US is also used throughout the whole procedure and serves for guiding ablation including identification of presumed GP areas The extra cardiac vagal stimulation ECVS is performed using two diagnostic catheters positioned in the right and left jugular veins utilizing neurostimulator designed by Dr Pachon Sao Paulo Brazil pulse amplitude of 1 Vkg body weight up to 70 V 50 ms width 50 Hz frequency delivered over 5 sec Complete bilateral vagal denervation of both sinus and AV nodes no sinus arrest slowing of sinus rate no more than 10 compared with baseline and no AV block with PR interval no longer than at baseline documented on ECVS is the end-point of CNA
Ablation is usually started in the left atrium LA at the anterior antrum of the right pulmonary vein where the superior paraseptal GP SPSGP is located followed by ablation of the inferior paraseptal GP IPSGP at the floor of LA Next these GPs are ablated from the right atrium RA If the intraprocedural endpoints of CNA are not achieved by ablation of paraseptal GPs additional applications in the LA at the sites of superior and postero-lateral LA GPs are performed followed by applications in CS
At the end of the procedure atropine test is performed in order to assess the residual if present vagal nerve activity The value of 10 of increase in sinus rate following atropine injection 2 mg iv will be taken as successful vagal denervation
Surface ECG The QT interval is measured in lead II and corrected for heart rate QTc using the Bazett and Fridericia formulas The QT dispersion QTd - the difference between the shortest and the longest QT interval in 12-lead ECG is also measured All measurements are performed at baseline and after CNA using electronic callipers Bard EPLab system at a speed of 100 mmsec The QTc interval is also measured from 12 lead standard ECG at a speed of 25 mmsec performed one day before and one day after CNA
Invasive electrophysiology VAPD will be measured during the procedure before and after CNA from the right ventricle RV using unfiltered unipolar recording with contact force CF 10 g using the same CF value before and after CNA in a given patient Baseline measurement will be taken just before first RF application at the time when a patient will already be given a full dose of anaesthetic drugs to ensure that all VAPD recordings will be performed under unchanged sedation and muscle relaxation drug regimen The measurements will be performed during sinus rhythm and during constant atrial pacing at a cycle length of 400 ms and at a speed of 200 mmsec
The VERP at baseline and after CNA will be measured during sinus rhythm and after eight-beat drives at cycle length CL of 400 ms delivered from the RV The same protocol will be simultaneously used to perform PVS in order to assess vulnerability to non-sustained VT or sustained VT lasting 30 sec or causing haemodynamic compromise polymorphic VT and or VF
The VAPD VERP and PVS will be repeated after atropine injection 2 mg and finally after isoprenaline bolus of 20 mcg at the end of the procedure
Cardioneuroablation CNA is a new promising method to treat reflex syncope which is due to vagally-induced functional sinus arrest or atrio-ventricular block AVB The goal of the procedure is to ablate post-ganglionic endings of parasympathetic part of autonomic nervous system ANS located in ganglionated plexi GP in the epicardial fat and in the myocardium Although both sympathetic and parasympathetic nerves are localised in GPs the latter ones only barely regenerate Therefore CNA-induced damage of the parasympathetic part of GP is greater and more durable than that of the sympathetic part of ANS Because increased vagal activity is one of the main mechanisms leading to reflex sinus arrest or atrio-ventricular AV block targeting this part of ANS by CNA may prevent recurrences of reflex syncope Indeed it has been shown that CNA may be effective in approximately 80-90 of very symptomatic subjects with reflex syncope
While the reduction of parasympathetic drive to the atrial GPs responsible for sinus node and AV conduction seems to be logical and effective way for treating hypervagotonic reflex syncope CNA-induced changes at the ventricular level may be theoretically harmful As mentioned above parasympathetic tone exerts protective effects on ventricular arrhythmias Recently the long-term safety of CNA has become an issue raised by some investigators They expressed concerns that CNA-induced chronic and long-lasting decrease in parasympathetic activity may be dangerous during the future life of usually young people undergoing CNA nowadays For instance if they develop coronary artery disease heart failure or other cardiac diseases which increase propensity of ventricular arrhythmias lack of parasympathetic protection may lead to the occurrence of complex or even life-threatening ventricular arrhythmias
Data in literature on possible proarrhythmic effects of CNA are limited and not uniform From the anatomical and physiological point it has been shown many years ago that destruction of cardiac innervation at the atrial level may also damage ventricular innervation downstream Although CNA targets GP localised mainly around the left and right atria responsible for sinus and AV nodes innervation ventricular GPs may be also affected indirectly by alterations in interaction with atrial GPs or even by direct ablation of some of ventricular GPs According to Pauza et al there are several ventricular GPs which are located in the epicardial fat surrounding the aortic root close to right and left coronary artery ostia at the area of the proximal posterior descending coronary artery close the proximal right acute marginal coronary artery and at the origin of the left obtuse marginal coronary artery However the number of ventricular GPs is much lower than that of the atrial ones 20 of atrial GPs and their density is also lower Thus it is very likely that during ablation of some atrial GPs like postero-medial left GP PMLGP or within the coronary sinus CS also ventricular GPs integrity and function may be altered
Specific data in literature on possible pro-arrhythmic effects of CNA on ventricular myocardium are scarce A few experimental studies suggested that decreasing the parasympathetic drive to the heart by ablating epicardial GPs increases susceptibility to ventricular arrhythmias both in normal and ischaemic animal hearts Also one recent study showed that acute ischaemia occurring 6 weeks after CNA was associated with significantly higher incidence of VF than in control untreated swine As far as human data is concerned a few cases of possible proarrhythmia - polymorphic VT induction after pulmonary vein isolation with concomitant parasympathetic denervation or after pure CNA have been described
Susceptibility to complex ventricular arrhythmias before and after institution of pharmacological treatment or performing a procedure can be assessed invasively by measuring drug- or procedure-induced changes in the ventricular effective refractory period VERP ventricular action potential duration VAPD and directly by using programmed ventricular stimulation PVS However these data in subjects undergoing CNA are lacking
Apart from invasive measurements changes in the duration and dispersion of ventricular repolarisation may be indirectly assessed on surface ECG by measuring the corrected QT QTc interval and QT dispersion QTd Data on the CNA-induced changes on QT are scarce and conflicting While Aksu et al showed that CNA caused significant shortening of QT interval duration which may be in some situations such as long QT syndrome anti-arrhythmic others showed that PVI with CNA does not change QT interval or that CNA causes prolongation of QT interval which may in fact have proarrhythmic effects It has also been shown that QTd increases after PVI which is almost always combined with some GPs ablation or after pure CNA The preliminary results from one excellent CNA centre showed that QTc was significantly prolonged by 25-30 ms immediately after the procedure only by 5-10 ms one day after CNA returned to the baseline values 3 months later and was slightly shorter than at baseline one year after the procedure
In summary it is little known about possible proarrhythmic effects of CNA at the ventricular level This study was set out to explore these effects
Aim To assess acute effects of CNA-induced total vagal denervation measured by extracardiac vagal stimulation ECVS on ventricular refractoriness and vulnerability to ventricular arrhythmias in patients undergoing this procedure due to reflex asystolic syncope
Hypothesis Acutely CNA prolongs ventricular effective refractory period ventricular action potential duration and QT interval without increasing susceptibility to stimulation-induced sustained ventricular arrhythmias The effects on QTd are difficult to predict
Methods Patients The study group will consist of consecutive patients undergoing CNA in our institution Patients are offered CNA if they have severe recurrent symptoms due to reflex syncope with ECG documented asystole 3 seconds especially if associated with injury or recurrent presyncope with persistent reflex bradycardia The patients have to have a history of ineffective prior non-pharmacological treatment and positive baseline atropine test sinus rate acceleration 30 and no AV block following 2 mg of intravenous atropine All patients gave informed written consent to undergo CNA and to participate in the study Ethics Committee approval 332024 Cardioneuroablation The procedure is performed under general anaesthesia with muscle relaxation using a 35 mm irrigated tip catheter Navistar ThermoCool SmartTouch with contact force module and electroanatomical system Carto 3 Biosense Webster US The ablation index is set at 500 except coronary sinus CS where the target value is 350 Intracardiac echocardiography ICE Acuson SC2000 Siemens Germany AcuNav Ultrasound Catheter Biosense Webster US is also used throughout the whole procedure and serves for guiding ablation including identification of presumed GP areas The extra cardiac vagal stimulation ECVS is performed using two diagnostic catheters positioned in the right and left jugular veins utilizing neurostimulator designed by Dr Pachon Sao Paulo Brazil pulse amplitude of 1 Vkg body weight up to 70 V 50 ms width 50 Hz frequency delivered over 5 sec Complete bilateral vagal denervation of both sinus and AV nodes no sinus arrest slowing of sinus rate no more than 10 compared with baseline and no AV block with PR interval no longer than at baseline documented on ECVS is the end-point of CNA
Ablation is usually started in the left atrium LA at the anterior antrum of the right pulmonary vein where the superior paraseptal GP SPSGP is located followed by ablation of the inferior paraseptal GP IPSGP at the floor of LA Next these GPs are ablated from the right atrium RA If the intraprocedural endpoints of CNA are not achieved by ablation of paraseptal GPs additional applications in the LA at the sites of superior and postero-lateral LA GPs are performed followed by applications in CS
At the end of the procedure atropine test is performed in order to assess the residual if present vagal nerve activity The value of 10 of increase in sinus rate following atropine injection 2 mg iv will be taken as successful vagal denervation
Surface ECG The QT interval is measured in lead II and corrected for heart rate QTc using the Bazett and Fridericia formulas The QT dispersion QTd - the difference between the shortest and the longest QT interval in 12-lead ECG is also measured All measurements are performed at baseline and after CNA using electronic callipers Bard EPLab system at a speed of 100 mmsec The QTc interval is also measured from 12 lead standard ECG at a speed of 25 mmsec performed one day before and one day after CNA
Invasive electrophysiology VAPD will be measured during the procedure before and after CNA from the right ventricle RV using unfiltered unipolar recording with contact force CF 10 g using the same CF value before and after CNA in a given patient Baseline measurement will be taken just before first RF application at the time when a patient will already be given a full dose of anaesthetic drugs to ensure that all VAPD recordings will be performed under unchanged sedation and muscle relaxation drug regimen The measurements will be performed during sinus rhythm and during constant atrial pacing at a cycle length of 400 ms and at a speed of 200 mmsec
The VERP at baseline and after CNA will be measured during sinus rhythm and after eight-beat drives at cycle length CL of 400 ms delivered from the RV The same protocol will be simultaneously used to perform PVS in order to assess vulnerability to non-sustained VT or sustained VT lasting 30 sec or causing haemodynamic compromise polymorphic VT and or VF
The VAPD VERP and PVS will be repeated after atropine injection 2 mg and finally after isoprenaline bolus of 20 mcg at the end of the procedure
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None