CNA Conference - Dr. Dan Wichterle - The Effect of Pulsed Electric Field Energy on Cardiac Ganglionic Plexi evaluated by Extra Cardiac Vagal Stimulation

I'm gonna uh introduce uh Doctor Dan Witcherley. Uh, he's the associate professor with the Department of Cardiology, uh, the Institute for Clinical and Experimental Medicine at the first medical facility, uh, in Charles University of Prague, uh, Chechnya. Uh, Doctor Wicherley, uh, will be discussing the unique effects of pulse field, uh, of pulsed electric field energy on cardiac ganglionic plexi evaluated by extracardiac vagal stimulation. I would like to thank the organizers for inviting me to this conference. My task is to give a lecture on the effect of uh pulsed electric field energy on cardiac ganglionated plexi evaluated by extracardiac vagal stimulation. This is a very focused topic, because there is only one such study published by our group. And that's why I slightly extended the content of my talk, uh, which will cover the effect of past electric field energy on ganglion plexi irrespective of how this effect was investigated. This is uh my agenda today. I will start with how we investigated the impact of PF energy on cardiac ANS by means of extracardiac vagus nerve stimulation. Second, I will demonstrate the practical implications of our findings. Third, I will mention how others investigated the impact of PF energy on cardiac ALS. And finally, I will provide some information on currently ongoing trials on PF and modulation of cardiac autonomic nervous system. All right, what we did. We did a prospective non-randomized study. It was done in a population of patients undergoing pulmonary vein isolation for, for paroxysmal atrial fibrillation, and we investigated the impact of ablation on, on cardiac ANS. RFulation is nice uh model of unintentional but considerably strong modification of ganglionated plexide. And we hypothesized that PF energy, uh, uh, or PF ablation would have a much bigger impact. PVI was done in a point by point fashion. PF energy was uh delivered by lattice tip sphere 9 catheter from A Company at the time. And RF uh ablation as a comparator was done by Navistar Thermocool catheter. The procedure uh outcome measure, uh, was the response of the sinus and atrioventricular node uh to extracardiac vagus nerve stimulation by the dedicated neurostimulator, the method introduced by Dr. Passion. Stimulator settings are here, consisting of high amplitude, high frequency, and narrow impulses. In this particular study, we stimulated right vagus only, and here are examples of the response of sinus and atrioventricle node at baseline. And this examination was repeated during the procedure. What we observe. Uh, first, these graphs. Uh, are for a radio frequency energy ablation. Live ports display maximum sinus, um, pause or AV nodal pauses induced by, by extracardiac vagus nerve stimulation assessed at baseline here. After a left pulmonary vein isolation, and after a right PV isolation, and after 20 minutes of waiting time. Responsiveness of both nodes to vagal stimuli was specifically suppressed by right PV ablation. And, uh, and these graphs are for, um, uh, for past field energy ablation, and please note weaker effect compared to radio frequency ablation. And what is more, most important, uh, the, uh, clear, uh, although statistically non-significant uh non-significant recovery during the 1st 20 minutes post ablation. This figure summarizes the results in a kind of simplified categorical fashion when the extracariac vagus nerve stimulation induced pauses of less than 1.5 seconds during the final assessment, uh, uh, was considered complete or near to complete denervation. Radiofrequency energy PVI resulted in sinus node innervation in all patients, and AV nodal denervation in all but one patient. While after pasted electric field PVI in 2/3 of patients, both sinus and AV node uh remained non-valve denervated. It indicates that PF ablation, at least in the form that was developed for myocardial ablation, or specifically PVI, is not suitable for cardio ablation because a rapid intraprocedural partial recovery of ganglionated plexi suggests that in the couple of hours or a couple of days, the ganglionated plexi are likely to recover fully. Such observation has uh some practical implications, and I would like to show or demonstrate this on this uh in this case report. This was 60 year old man with both symptomatic paroxysmal AF and uh symptomatic uh paroxysmal sinoatrial block here. The bloc nicely responded to a drop in administration. Um, and, uh, if I consider this a couple of years ago when we did all PVI procedures by thermal, either radiofrequency or cryoablation, I would indicate PVI only in this patient because uh sinus nodal denervation and consequently elimination of dysfunctional sinoatrial block can be expected after such, such a procedure because of collateral parasympathetic derivation. However, however, now we are living in the era of past electric field ablation. And at our institution, we do all common uh AF procedures invariantly uh with uh uh past field energy. And therefore, um, uh, in this particular case, we decided to combine two ablation modalities, PF energy for durable pulmonary vein isolation, and RF energy for guardian neuroablation. We started with uh power field ablation, and here, um, there is a pentospine far wave catheter inside the left atrium at the ostream of left superior pulmonary pulmonary vein. And out of curiosity, we set up the catheters for extracardiac, uh, vagus nerve stimulation to guide the procedure. After isolation of all veins, the responsiveness of the sinus nodes to extra cardiac vagus nerve stimulation was, as expected, suppressed only temporarily, and returned to baseline within 20 minutes. Uh, we, uh, constructed the left atrium voltage map, uh, with, uh, PVs isolated here, as shown, and, uh, and complemented with the right atrium anatomy here. And subsequently we switched to RF Energy and created our standard cardio neuroablation lesion set as visualized here, here and here. Um, Subsequently, we switched, yes, uh, and Subsequently, we verified that after such an RF ablation, the heart was no longer responding to extracardioovvagus nerve stimulation, with the primary interest in the sinus node degeneration, of course, because the sinoatrial block was the clinical problem. This is a summary of, of this case report. Uh, the patient is free from AF and sinoatrial block during the long-term follow-up. Uh, the concomitant use of both PF and RF energy enabled effective treatment of the disorder consisting of symptomatic tachyarrhythmia and bradyarrhythmia. Ablation systems uh that offer switching between PF and RF energy like AFEA, now, uh, from Medtronic, or Centauri, Galaxy Medical, will be the optimum tools to treat such complex cases requiring the ablation of both myocardium and cardiac neural tissue. There are only a few other studies that investigated the impact of PF energy on cardiac ANS. The study by Musikantov demonstrated that PVI by pulsed electric field energy did not affect heart rate, while single-shot thermal PVI irrespective of whether it was RF or cryoballoon, was overall associated with acceleration of sinus rate by 10 beats per minute at the 3 months post ablation. The study by Guo investigated the effects of pulsed field energy on both biochemical markers of neural lesion, a total of 4 proteins were analyzed and indices of heart rate variability. They didn't find, find a single statistically significant change post ablation. The study by Tohoku, who compared the effect of PVI by pulsed electric field versus cryo, and only cryoenergy ablation was associated with a significant elevation of protein S100 as a marker of neural damage. Finally, this was a, uh, there was a surgical study in which epicardial ganglionated plexi is showing this figure, uh, vari ablated by pulsed electric field energy as a concomitant procedure to cabbage. And perhaps because of uh direct contact, the ablation had some effect on cardiac autonomic nerves, but this was uh rather modest. They reported the prolongation of atrial refractory period by 40 milliseconds, but the median change um as shown in this figure was only 10 milliseconds. And also the mean heart rate change at one month's visit was not as high as after the thermal endocardial PVI. In the final part of my lecture, I will briefly mention the currently ongoing multi-center trial we are taking part in. This is the B Poxa trial, which is sponsored by the University of Bordeaux, France and funded by the European Union. It is, it is an open label randomized controlled trial comparing clinical outcomes after ablation for AF in the two parallel groups. In which PVI will be performed either by PF energy delivered by pentas line farawave catheter or RF energy delivered by conventional smart touch catheter in point by point fashion. What is, however, important in my perspective is that BparoxIF trial has a substudy that is designed to investigate the impact of ablation on the function of intrinsic cardiac autonomic nervous system. The sub-study will investigate the acute as well as the long-term uh alteration of cardiac ANS after PVI performed either using PF or RF energy. This will be, of course, done in randomized session in the line with the randomization scheme in the main study. But on the top of it, the patients will also be sub-randomized to different order of PVI, either left or right PVI first. Patients uh will be investigated during the procedure using a simple EP EP study, and importantly, by extracardiac vagus nerve stimulation. Long-term effects will be assessed during the one-year follow-up period, utilizing serial halters and atropin testing. 2 of 9 centers are enrolling patients into this substudy, and approximately 100 patients will be recruited by the end of December this year. This is a detailed view of examinations as part of ANS substudy. Once again, a long-term follow-up is scheduled using the Holter atropin testing up to the uh one year uh uh after the ablation, and rigorous examination, um, by extracardiac vagus nerve stimulation, uh, will be done not only at the baseline, at, uh, uh, at the, at the end of the, um, ablation procedure, but also in the middle. And it, it'll be used to assess the differential impact of left or right PV's isolation on cardiac autonomic regulation. My feeling is that the study will bring unprecedented and very detailed insight into the mechanism uh of how different ablation energies and uh different ablation sites impact the functioning of the intrinsic cardiac nervous system. Here are my take home messages. The effects of pulsed electric field energy on cardiac autonomic nervous system are weak and temporary. Extracardiac vagus nerve stimulation is an excellent tool how to investigate the fleeting denervation phenomena due to PF ablation. The concomitant use of both PF and RF energy enables effective treatment of the disorder consisting of symptomatic tachyarrhythmia and bradyarrhythmia. And finally, selective myocardial effects of PF energy may allow to design trials that would help to establish the role of GP ablation in patients with atrial fibrillation. Thank you. Thank you, Doctor Richley and welcome. Hello, can you hear us? Yeah, I can hear you. Hi, thank you. Thank you very much for your presentation. Uh, a couple of questions that we had. Um, actually, one of the first questions I, I had, uh, was your PF, uh, your PFA voltages, frequencies, and pulse widths. Uh, were you able to do an analysis of any that are better over another, um, and then if they do have any sort of effects or changes on the GPS. No, no, this was not investigated because I, uh, we solely, uh, use the uh Doctor Passion neurostimulator, so we had no chance to uh investigate any other. Of course, we tried the, like low pro uh low power, uh, stimulators, but they are not useful because if you don't, uh, if you use the output like, uh, let's say, Uh, 20 or 30 mills, it is not to, uh, it is not enough to induce the reasonable response of vagal nerves. So we have a question uh in the chat from Doctor Abdullah Masri. Uh, his question is any potential for CNA and tachy-Brady arrhythmia syndrome as opposed to the pacemaker? Yeah, definitely, definitely. It's, uh, especially in young patients because there are, uh, if you, if you consider the guidelines, uh, at least ESC guidelines, uh, there are no, there is no evidence that, um, Or there is no evidence that the, the pacemaker should be used in, in patients less than 40 years because all these studies uh uh uh that investigated the, the treatment of uh reflex, the treatment of reflex syncope was done in patients uh 40+ and the mean age was about 60. Of course, nobody argued that. The, uh, definitely the pacemaker should be, uh, effective also in the young, younger patients, but the long-term um safety was not investigated. I, uh, and I wouldn't implant, uh, the pacemaker in such young patients because of this long-term issues. Uh, Doctor Peron, you had a question. Uh, thank you very much for participating in this meeting. It's an honor for us, your participation, and, uh, uh, congratulations for your achievements in cardio neuroablation. And uh do you have the, the, uh, have the, the, the opportunity to test the uh different frequency for PFA in order to get more lesion of the neural system? Because, uh, even in atrial fibrillation, I think it's necessary to eliminate the venom. uh myocardial, uh, interface and also it's important to eliminate the neural myocardial interfaces. So I think if you, it would be possible to change the frequency of PFA probably we, you have an alternative to get more derivation. Yeah, uh, but, uh, I, yeah, maybe you are true, uh, but I'm not an expert, and, uh, of, of that there is no single PFA, uh, ablation, but usually this is, uh, information which, uh, companies don't share with investigators and don't, don't share with, uh, EP, uh, EP, and, uh, operators, uh, so. In fact, we are do some sort of blinded ablation. Uh definitely, the parameters of PFA may, may be uh adapt adjusted and uh. Uh, and, but if they will be more tar, uh, more, uh, more targeted to, uh, to like also cardiac nerves, they may increase the, uh, let's say a risk of collateral damage, uh, either for phrenic nerve or, uh, um, so, uh, it's questionable. Now, it is, now the, uh, PF energy is set to damage primarily myocardium and it is what we want to have, uh, if we do PV isolation only. But, uh, nobody knows if the collateral uh neural degeneration is important for PF, uh, for, uh, for, for patients. At least the, the outcome of RF and PF is comparable at least by the RBEN trial which was presented on HRS or ESC Congress, uh, this year. And, uh, I think, um, The only chance how to, how to investigate the, uh, the benefit from neurodegeneration uh to treat uh AF ablation is to compose the randomized trial in, uh in which uh the, all patients will be treated by PF, uh, so PV isolation will be done by PF. Uh, and subsequently, uh, uh, half of them will be, uh, denervated by RF. It would, it would be the design that will give the final answer on whether the neural denervation is important for, uh, elimination of AF or not. Thank, thank you, thank you, Dan. Please send regards to Tim. Doctor Wicherley, I have 11 other question. Do you see the possibility of PFA being the sham procedure that everybody has been asking for in CNA, uh, because if you'd have to find a group of AF patients who also have vasovagal syncope, but, um, I think it, there could be an Ethical allowance in that case where you're in there doing the AF ablation with PF and yes or no, you take out the vagal inputs at the same time. Yes, it could be, but I think uh that we will have the result of SEM uh controlled study earlier than any other study will be designed because currently, uh, there is one such study, uh, uh, already ongoing in Belgium in 3 centers. And I had the opportunity to speak to one guy of, of one of these centers recently, and he told me, of course, I can't, he didn't tell me any details, but simply The study is going very well, and in, uh, in active arm, in the cardio neuroablation arm, there uh there were only, uh, only a few cases of syncope, about 10%. And uh all patients in SHEM uh arm already had uh uh uh recurrent syncope. So the study is not yet finished and they, they, uh, they want to uh finalize the full follow-up, um, but probably within one year, we will, we will have the results of this study, and the, the, uh, difference between both treatment AR, ARM active and the SHEM group is highly significant already just now. Great. Thank you very much and thank you for joining us. Thank you, Doctor Richard.