So, I welcome you to the Cardioneuroablation for the Treatment of Reflex Syncope and Functional Bradyarrhythmias, what we have learned from ERA, HRS, LARS document. It's a joint session. I'm Jody Hurwitz. I was immediate past president yesterday, but today I'm past, past president. And my co-chair, Dr. Arsh Kochar from Cleveland Clinic. And our first speaker is Dr. Varsaghi, talking about anatomy and physiology of cardiac autonomic nervous system for cardioneuroablation from UCLA. Okay. Great. It's starting. Good afternoon, everyone. I just want to thank the organizers for the opportunity. And let's get started. Anatomy and Physiology of the Cardiac Autonomic Nervous System for Neuroablation. So, I think the first thing that I just want to briefly point out is that the autonomic nerves truly encase the heart. So, this is actually a cleared mouse heart, because we can't clear whole human heart tissue. But everything that you see here is a nerve fiber. And so, you have nerve fibers innervating the atria, the ventricles, as well as the coronary arteries and the blood vessels of the heart. And these nerves consist of both postganglionic parasympathetic fibers and sympathetic fibers, as well as afferent fibers that are taking information from the ventricles and the atria and the conduction system up to the central nervous system. Now, when it comes to cardioneuroablation, as you know, doing vagal nerve stimulation is a strategy that's been proposed to be able to look at your endpoints in terms of when to stop ablating the GPs. So, a word about the vagus nerve. First of all, 85% of vagal nerve fibers are afferent. That means that they're sensing what's happening in the viscera and transmitting that information to the brain. The preganglionic cardiomotor neurons that innervate the heart start in the nucleus ambiguous and the dorsal motor nucleus of the vagus. They go through the vagus and synapse on to the neurons that live in the gangliated plexi. And then these postganglionic parasympathetic neurons send innervation to the atria, the ventricles, and the conduction system. Now, you can actually stimulate the vagus nerve transvascularly. You can do it with these multi-electrode catheters that are either non-circular or circular. Personally, I like to use circular catheters because I think it finds it easier to be able to stimulate the vagus transvascularly. Nonetheless, you have to be pretty high up, kind of at the angle of the jaw or higher. And the vagus, if you look under ultrasound, is generally found between the great vessels, so the internal jugular vein and carotid artery. So this is where the vagus is. And you can bring your catheter to that area and stimulate at about 20 hertz, anywhere between 10 to 25 milliamps, and see a bradycardia response. And this is actually a non-EP study, but they used vagal nerve transvascular stimulation to look at responses to make sure the vagus was actually intact in this case. But it was a beautiful study because it showed that about 94% of the time, you will find the vagus in this number one position when you're trying to do transvascular stimulation. So if you're in the IJ, you want to point your catheter more medially, right, and kind of stimulate along and see if you can capture the vagus. And you'll see a very nice, rapid, dramatic bradycardia when you do. But the vagus is not the only nerve that innervates the heart. You also have postganglionic sympathetic innervation that starts in the sympathetic chain, the stele, T2, T3, and T4 ganglia. And they actually provide nerve fibers that come down to the heart. And by the time you get to the hilum of the heart, and this is one of the things that I think it's important just to understand, is that these nerve fibers are not mixed fibers. So they've actually joined with the vagal branches. And so any one of these nerves that are forming the plexus are a mixture of sympathetic, parasympathetic, and afferent fibers. But along these nerves, you will find these beautiful, almost like cities along a highway, you know, like grapes on a vine, ganglia. And there are many of them. Now, most of the nomenclature that we use today for cardioneuroablation that's found in the literature is actually based on Drew Armour's idea of where these kind of ganglia duplexi were predominantly located. And so he described ganglia duplexi that were located posteriorly along the SVC and kind of septally. And he called that the posterior right atrial GP. And then there's ganglia duplexi that are really kind of around the IVC and the coronary sinus, right? And those he described as the posterior descending GP, as well as the posterior medial left atrial GP. There's a very distinct ganglion or GP that's located kind of superior to the LSPV. And of course, there are the plexi that kind of lie along all the blood vessels, including the vena martial. So in total, he described seven ganglionic suplexi, or GPs, that's what we call them today, total 800 epicardial ganglia at the base, and 43,000 intrinsic cardiac neurons that innervate the heart. I've showed this picture because when you look at the literature, different people have slightly named these GPs differently. And so you may run across them, right? But they actually refer to the same anatomic area. So the right superior GP, which Armour described, can also be referred to as the ventral right atrial GP, right? And then you have, for example, the left superior GP, which can be described as ventral left atrial GP. So they have slightly different terminologies. Again, but really kind of an idea of the most important thing is knowing where they're located. So let's take a look at where they're located, right? So this is, I would say, in terms of the GPs that have been targeted for cardioneuroablation. The RSGP, the LSGP, and the posterior medial left GP are the most kind of ones that have been targeted the most, in a way. And the RSGP, this right superior GP, is the biggest GP of the heart in both pigs and canines and human beings. So it provides a lot of innervation to the atria and the ventricles. And it's located, again, on that posterior aspect, most remedial aspect of the SVC. There is a right inferior GP that is closer to the IVC. You see the IVC down here. And this is that posterior medial left GP, which is kind of along that left atrial septum, superior to the coronary sinus. And then finally, we have the left superior GP, which is kind of that distinct GP on the superior aspect of the LSPV. And the left inferior GP, sometimes referred to as the posterolateral GP, left posterolateral GP, that is located along the infralateral aspect of the left atrium. Now, Petrone and colleagues have basically kind of promoted this idea that if you're trying to target sinus node function for vasovagal syncope, you should spend most of your time on the RSGP and the LSGP. And that if you're going to target AV node function, then you should be really spending a lot of time on this posterior medial left GP, which is, again, kind of on that inferior septal aspect of the left atrium above the coronary sinus. But keeping in mind that many of these other GPs are still involved in the innervation of the atrium, the ventricle, and the conduction system. So as I mentioned, and this is a beautiful study by Paza, this is a network of ganglion nerves on the heart. So what does that mean? That means that when you do functional studies, you will see responses of one GP in multiple regions. So in this case, let's focus on the right superior GP, that big GP that everyone's targeting for sinus node function or dysfunction. So here, for example, when you do right atrial GP ablation in pigs, you will see a decrease in their heart rate. So it goes from about 100 beats per minute to about 95 beats a minute. And then when you do right cervical vagal nerve stimulation or left cervical vagus nerve stimulation, you no longer have the decrease in heart rate after right superior GP ablation. But you also affect the AH interval, so AV nodal function, when you ablate the RSGP. So that when you ablate the RSGP, you no longer have responses to left or right cervical vagal nerve stimulation with regards to on the AH interval. And similarly, the vagus is a powerful modulator of left ventricular inotropy and dromatropy. And so when you do RAGP ablation, you also mitigate the effects on the ventricles, even though really what you may be aiming at is just the heart rate and the sinus node. So I think that's kind of an important lesson. And when you do RSGP stimulation, you get a decrease in heart rate, but you also get AV block. So this one GP is actually innervating the HR of the ventricles, the AV node, and the SA node. There's no such thing as one GP, one location. And that was also really well shown by Hao and Sherlock and colleagues back in 2007 when we were studying this for AFib. And basically what they showed was that here's the superior left GP, the one that's located on the LSPV. And when you stimulate this GP, you will get a decrease in heart rate, which is greater at higher voltages. You will get a prolongation in the AH interval. And you get a decrease in the ventricular rate, which is, again, greater with greater levels of stimulation. But now if you go and you get rid of the ARGP, and ARGP is another terminology for RSGP, that big GP on the posterior superior SVC. You still will get a decline in heart rate, but it's just not as much as it used to be before you ablated a totally different GP. And you will still get a decline in the ventricular rate, but still a little less than what you used to get when ARGP was intact. So what does that mean? That means all these GPs are actually not only communicating with different parts of the heart, they're actually communicating with each other. And so this was a study actually out of Korea, a canine study, where they injected a tracer called CTB into various ganglia, and then looked to see what other ganglia lit up. And what they found is that when you, for example, inject into the ARGP, or RSGP is the other word, you will get a whole bunch of left-sided ganglia that are still lighting up. And when you inject into the superior left GP, look at how much of the RAGP neurons and ganglia lit up, right? So this is truly a network on the heart. And even though we think of certain GPs of having certain spheres of influence, they're all really connected. And getting rid of one doesn't necessarily mean that you're only affecting that part of the heart's function. I want to spend the last just few minutes talking about the fact that there is significant parasympathetic innervation of the ventricles, as well as the HGN, the conduction system. And this has now been shown in pigs, in guinea pigs, as well as humans. And multiple studies long before we were doing cardioneuroablation were showing that vagal activation or parasympathetic innervation is antiarrhythmic for the ventricles. And in fact, if you did a vagotomy or you gave muscarinic blockade, you would do things like COSVF, or increase the likelihood of having ventricular fibrillation. And this was actually shown by two studies. One came out of China and one out of UCLA, where they did GP ablation in China in the setting of a prior infarct. And they showed that the dogs that had GP ablation now had increased susceptibility to ventricular tachycardia and ventricular fibrillation. And then in our study, we basically did GP ablation. And six to eight weeks later, brought the pigs back and just did a simple LAD occlusion and looked to see which group of the pigs actually fibrillated. And what we found was that if you'd had a prior GP ablation six to eight weeks beforehand, and we basically targeted the same ones, RSGP, LSGP, the posterior medial left GP in these animals, you were actually much more likely to have a higher incidence of VF during scremia, to have more polymorphic VT, and to have a greater PVC burden. So I think, yes, I think that cardioneural ablation, and you can ablate certain GPs, you should keep in mind that these are all connected, and that there is also significant parasympathetic innervation, whose side effects and effects, long-term effects, we currently don't know about. And I'm going to stop there, and thank you for your attention. Do you want to stay in case there's a question or two? Please remember to put any questions that you have in the chat. I have a rather naive question, since this is all new to me. You insinuated that all these GPs talk to each other, and I think maybe you alluded to the fact that if you affect one, you can affect the other. Does the directionality, if you will, what you affect first, second, does that make a difference? Could that ultimately affect the induction of VTVF? So that's a really good question. By far the biggest GP on the heart, as I mentioned, is the RSGP. So it seems like if you take that one out, you will have a significant effect on atrium, AH, and as well as AV nodes. And that is kind of both good and bad. It could potentially be supportive of the clinical studies that maybe all you need to ablate is the right side of GPs, and that may be enough to treat vasovagal syncope, because there have been clinical studies that have suggested you don't need to go into the left atrium. But it also suggests that certainly you can still have effects between GPs. So it isn't bidirectional. If you stimulate the RSGP and you take out the LSGP, and I didn't show those studies, but they do exist, you can still affect, right? You will see changes in both AV nodal conduction and the sinus rate as well. So although there are definitely distinct GPs that we think are associated with different regions, there's bidirectionality in their communication, and affecting one definitely seems to affect at least partial function of the others. And I guess the only other question is durability. Do you have any? I mean, I don't think we have very good durability data other than the clinical data that has followed them for a very short period of time, actually. Thank you very much. All right, so for our next speaker, we're going to transition a little more to the clinical side. We have Dr. Pichone from Sao Paulo University who will speak to us on the clinical evidence and a question that's on all of our minds. Is this ready for prime time? Thank you very much. It's a pleasure to be here with all of you. We are going to talk about cardioneuroblastion ready for prime time. What does the clinical evidence say? My answer is cardioneuroblastion is ready for prime time. However, it should be considered only if there is clinical treatment failure. It is absolutely fundamental. Let's tell something about the history. In the 90s, we described, we found and described the atrial fibrillation nests. The atrial fibrillation nests are the input, the entrance of the innervation in the atrial wall. We observed that the ablation of the atrial fibrillation nests caused a very important denervation, very important vagal denervation. Based on this, we created the name cardioneuroblastion. We patented this name here in the United States, and we created the procedure, cardioneuroblastion for treating functional bradyarrhythmias and atrial fibrillation. The rationale of the cardioneuroblastion is very objective, elimination of the visceral neuron of the vagus. The postganglionic neuron, it causes a relatively permanent denervation in order to treat the arrhythmias depending on the vagal hyperactivity. The first trial, we began in the 90s and published in 2005. In this trial, we observed, surprisingly, very good results in neurocardiogenic syncope, functional AV block, sinus node dysfunction, and atrial fibrillation. These are the indications of the cardioneuroablation. However, based on this observation, how to control the cardioneuroablation, it was a challenge. How to control? In that time, we used to control in an empirical way, empirical, by basically an indirect response. Sinus rate increase, the vancubus point increases, sinus node recovery time reduction, and atropine disappearance of the atropine response. However, it was not enough. Because of this, we developed the extracardiac vagal stimulation that is very easy to get, putting a lead inside of the internal jugular vein. And here, we have the most important issue that I would like to show you in this presentation. Here, the vagal stimulation causes an asystole, similar of the asystole of the TUT test. And after cardioneuroablation, the same vagal stimulation causes no more bradycardia. It is the end point of the cardioneuroablation. Based on this, we developed the cardioneuroablation controlled by vagal stimulation, by direct control of the sinus node, the AV node, the denervation, and atrial wall denervation. What the studies said about this, the cardioneuroablation controlled by vagal stimulation, not the high frequency vagal stimulation in the atrial wall, the vagal stimulation in the neck, presented in about four times better results than the empirical cardioneuroablation. So when we study any result about cardioneuroablation, it is important to know if this cardioneuroablation was performed with vagal stimulation or not. It is very important. And the vagal stimulation allows us to see three different domains, the sinus node domain, the AV node domain, and myocardial domain that are relatively independent. It makes possible to us to treat each patient depending on the clinical condition. So the cardioneuroablation may be different, dependent on the clinical indication. And in order to improve our method, we developed, we created the diffractionation mapping that makes possible to have a probability mapping of innervation. And here we can see these light areas are related to more probability of innervation. And there is an easy way to control cardioneuroablation. What is the best test for indication? Atropine. What is the best test to contraindicate cardioneuroablation? Also atropine. What is the best test to contraindicate for AV block? The Ajmalini test, the atropine test, and AP study. What is the best resource for procedure control? The extracardiac vagal stimulation. What is the best test for clinical follow-up? We have a lot. Heart rate variability, Holter, adaptivity testing, and so on. So cardioneuroablation is currently a comprehensive and safe procedure because it has robust and clear indication tools. It has well-established approach based on the atrophibulation ablation, for example. It can be guided by objective and rationality points, for example, the extracardiac vagal stimulation. It has reliable outcome prediction. It may be predicted by the atropine testing. And it has a straightforward and reliable follow-up, for example, by heart rate variability. So it is a very comprehensive procedure, and the literature is showing us that the clinical measures presents a poor result in neurocardiogenic syncope. The pacemaker presents moderate results, and the cardioneuroablation is showing good results for treating neurocardiogenic syncope. The first study, meta-analysis about cardioneuroablation, was published 12 years after our initial publication, 12 years by Dr. Axel, was the first study in a form of meta-analysis. And here, the study of cases showing a good result in that time. Nowadays, we have randomized trials, the Roman I and Roman II were randomized, very well randomized trials, showing very good results in reduction of syncope and good results about the B-atrial ablation. So the cardioneuroablation that is performed in B-atrial approach is better than that cardioneuroablation in one atria. And we have in about 12 trials that are ongoing, like the Gentle Pacey, Cardiocyte, CanePain, Panacea, all of them are ongoing. So I think in next, probably, months or years, we will have good results about these trials. There is a recently published meta-analysis showing good results in about 20, 80 studies showing good results of cardioneuroablation. However, we have to take into account that the good result may be better because all of these trials, all of these studies, were performed without real extracardiac vagal stimulation. So it's very important to be criticized in order to see if the procedure was well controlled. It's very, very important. Here, meta-analysis that we are finishing, and we found 32 studies. And only two studies, the study of Josa and the study of Barrio Lopes, showed poor results, but very studies without control. So I think it is very, very important to see how the cardioneuroablation was controlled. Here, the results of our service in the dot red line, the results in neurocardiogenic syncope, the results are better than pacemaker, but the most important, the results were the same if the patient has more than 40 years or less than 40 years. So for us, the age is not a limitation for indicating the cardioneuroablation. The atropine test is the main player to see if there is indication or contraindication of the cardioneuroablation. So at the end, I would like to comment why to perform cardioneuroablation. Because it is a curative approach. It treats the reflex, the cardioinhibition, rather than merely pacing over pauses. It has high efficacy, more than 8% of good results in at least one year. It is a device free because it does not need insertion of pacemaker. It has excellent safety profile. It presented in a trial that was published by Professor Kulakowski. It presents an increased quality of life. It is very important. And at the end, it is the momentum to include cardioneuroablation in the guidelines. Thank you very much. Do you want to stay for a question, too? Do you have a question? Yeah, go ahead. Dr. Pichon, first of all, congratulations on really pioneering this technique. And I had the privilege of working with Dr. Santangeli on a few of these cases. And he takes a little bit of a different approach to the way you do it. And I think one of the challenges is the heterogeneity of endpoints. Your extracardiac vagal stimulation is a great acute endpoint. Can you comment a little bit on doing an anatomical approach of mapping ganglia versus high-frequency stimulation versus EGM approach? Is there any data that one is better than the other? Thank you for your question. The high-frequency stimulation is the stimulation of the ganglia in the endocardium of the atria. It has a problem that is the induction of atrial fibrillation that is easy to induce because the high-frequency stimulation in the atrial wall. Another problem is when you do the high-frequency stimulation in the atrial wall, you are stimulating the branches of the tree, not the stem of the tree. In the extracardiac vagal stimulation, we use it to stimulate all the vagal fibers, not only branches of the vagus. So it is easy, very easy, very easy to get the control by stimulating the vagus. You see the rest of the sinus node, the whole induction of every block, and after this, disappears completely. So in our service, we use it since the beginning, the extracardiac vagal stimulation. That is very easy to get. And relating to the anatomical approach, the anatomical approach is easy. However, there is high variability between patients about the position of the ganglia. You just saw that there are many ganglias in the heart, and we have to eliminate a portion of these ganglias. So for us, we use the anatomical approach at the beginning, and we use the vagal stimulation. The vagal stimulation shows this appearance of the vagal effect. The procedure is stopped. But if there is a vagal response, it is necessary to enlarge the anatomical approach. And obviously, if necessary, the fractionation mapping can help us to see several areas that must be ablated. Thank you very much. That was great. Sorry. As you know, there was a late-breaking clinical trial earlier today, and they talked a little bit about this, and someone had mentioned doing pulmonary vein isolation in association with this. So I'd love to know your opinion about that. Obviously, one of the big things, and I'm sure you're a proponent of this, if you really, since most of us are using pulse field ablation, and it really does not appear to affect these ganglion plexi, where do we go? What do we do? And maybe catheters that deliver both RF and PFA will be the future, but this raises a lot more questions than it answers. It is a crucial question, because the PFA, the proposal of PFA is avoid lesion of the neural system. But obviously, nowadays, we know that it is very important to get vagal denervation to treat atrial fibrillation. There are several evidences about it. So I think it will be very interesting to change a little bit the energy of PFA in order to get the fibers of the vagus. It will be very interesting. The first trial that studied this situation, they used our stimulator in PFA, and it was Professor Kostner in Prague. They found that there is less denervation with PFA compared to RF. There is less denervation. So obviously, we have to follow the patients to get conclusions. But obviously, in my opinion, it will be very interesting to have a little bit change of the PFA in order to get more consistent denervation. It will be very interesting. Do you do pulmonary vein isolation with all of these? Yes. Yes. If the patient needs only cardioneuroblastion, we advance it to pulmonary veins depending on the vagal response. Many times, treating the interatrial septum and the ganglia one, it's enough to treat the case. But if there is no elimination of the vagal response, it's necessary to advance it to pulmonary vein. Obviously, the great benefit of the pulmonary vein isolation for atrial fibrillation ablation is also the denervation because there is an important denervation that in many cases after PVA, maybe the vagal response disappeared in many cases. But obviously, in other patients, the vagal response remains the same at the beginning of the procedure. So I think this question of the denervation, it will be probably one step more after the PFA. Thank you very much. Thank you. The next talk is titled Approach to Cardioneuroblastion for Functional AV Block. This is a recorded case. This is from the Libin Cardiovascular Institute. And Dr. Agaduelo will be the one delivering. Unfortunately, Dr. Morillo had to go home. So welcome. Good afternoon, ladies and gentlemen. Thank you very much for the opportunity. Thank you. First of all, thanks for the opportunity to the chairman to present this lecture. I'm Juan Agudelo from Medellin, Colombia, and I'm going to share with you our approach to cardio-neuroablation for functional AV block. The proof of concept has been widely explained by the father of the cardio-neuroablation that I have the honor to share in the main table with Professor Pachon. In this slide, I would like to show the summary of the concept of the influence of autonomous system in the heart. Thanks to the decisive research contributors for Professor Pachon and colleagues, we now know about these two types of myocardial cells in the atria, compact myocardium and fibular myocardium. In the compact myocardium, the polarization is very smooth, meanwhile, in the fibular myocardium, the polarization is very heterogeneous. This fact is demonstrated in the morphology in the endocardial potential. If a Fourier transform, that is a mathematical treatment of the electricity, is applied, a wide frequency can be found, and it's evident in the fibular myocardium. Ganglionary plexus, then, are specifically located in the atria. This concept is critical because it's important to locate it in very, very specific, as I will show you later. And the other important thing that we have as a main tool to demonstrate the effect is the extracardiac vagal stimulation, because this extracardiac vagal stimulation generates an abnormal response in the heart, consisting in deep bradycardia, sinus pulses, or even EV block. The concept of the three domains allow to understand the influence of the autonomous nervous system into the heart. In general terms, the right vagal stimulates mainly sinus node domain. The left vagal stimulates mainly the left atrial, the left vagal stimulate the AV node domain. Thus, depending on the clinical scenario, one or more domains are the target of ablation. To test each domain, extracardiac vagal stimulation should be performed. For each site, a vagal stimulation is performed to see if a sinus pulse is produced. Next, another vagal stimulation should be performed, but during atrial stimulation. This is very important, because if a sinus node is imposed, it's not possible to test or to see if there is change in the conduction of the AV node. Depending on the affected domain and the clinical information of the patient, a target to be ablated is chosen. Depending on clinical scenario and response to extracardiac vagal stimulation, different areas should be ablated. As was shown in the previous slides, for functional AV block, the GP2, the GP2 areas, the GP4 and marshal veins area are the main target in the case of functional AV block. Nowadays, exist three complementary tools to localize GP and evaluate the response to ablation. Every tool, this is very important, every tool is complementary to each other. From the practical point of view, in our approach, the first step during CNA is perform electro-atomical mapping with the specific parameters to localize each ganglionary plexus. The parameters are still not clear and depend on the navigation system that you use. Then the next step that we follow is an extracardiac vagal stimulation performed on each site. First, without atrial stimulation to see if a sinus pulse is generated and then anatomies performed on their general, on their atrial stimulation to see if an AV block is produced. If the clinical picture is an AV block, it's very important to stimulate both sites and finally some cases can even perform it without a clear software localization of the pulmonary ganglion. The usual locations are explored to see if response during ablation is produced. You can see the advantage in the extracardiac vagal stimulation. One of the most important advantages is to allow a targeted ablation because it's possible to identify the vagal pathways and enhance procedural efficacy. And it's possible, and it's another critical advantage of this method, to monitorize the real time of the results of the procedure. As a disadvantage, it's important to say that the complexity of this procedure at the beginning should be important. At the end of the time, as I will show you later, it's not very difficult to get an extracardiac vagal stimulation. The other technique is to perform it just guided by fractionated electrogram analysis. It's more precise and reduce the procedural time, but it's a technique that depends on the type of the mapping system. Unfortunately, until now, there is not precise parameters to program and to show what is the location of the fractionation. So by this reason, the variability is too wide. Finally, the anatomical approach is the simpler way, but it's impossible to not have individualization and could be not precise and the response is impossible to evaluate. This is the possibilities of extracardiac vagal stimulation. Of course, the most important way to do that was the device designed and built by Professor Pachon and colleague to trigger the vagal response in the heart. However, this device is not still widely available. For this reason, an alternative is to use a nervous stimulator connected to a quadripolar catheter in a standard way. A 50 hertz during five second stim is administrated. In our experience, this device allows to evocate the vagal response in a safe and reproducible manner. At the beginning of our experience, a stimulation with a Clarisse polygraph was attempt. However, the main problem with this approach does the maximum permitted output is 20 milliamperes. For this reason, with this device, this maneuver was not reproducible. This is the biggest report of use of CNA in functional AV block. The acute procedural success is almost 96%. CNA may reduce recurrences for syncopal episode and second or higher degree AV block in patient with functional AV block. Avoiding is important to say that this approach could be avoid the necessity of pacemaker. Neither the use in this registry, neither the use of extracardiac vagal stimulation, not the experience, the operator have a significant role in the ablation results. For this registry, many of the PGE were located by electroanatomical mapping. This approach simplifies the procedure and allow to be performed by inexperienced operators. However, comparing to other indication of CNA, AV block has an inferior success rate. But if an alternative pacemaker is considered, an ablation procedure is justified. This is our clinical case. It's a 24-year-old lady, a medical student, with four year of episodes of recurrent syncope without prodroms, including fascial and ankle trauma, and without any other medical relevant condition. Her heart is completely normal and this is, you can show in the whole episodes, complete AV block without escape were observed, generating pulses up to six seconds, coinciding clearly with the syncope episode. As I told you before, her heart is structurally normal. The options were discussed at length and it was agreed to attempt a CNA procedure. Our standard approach to CNA include a single transeptal puncture guided by intracardiac echo, initially mapping the left atrium with established parameter of software of fractionation. At the moment, we are testing different configuration for such software in ongoing research. The next step is to perform extracardiac vagal stimulation to focus on the problematic or responsible areas. Then we perform the extracardiac stimulation on each of the side. As you can see here in the right side, an eight seconds pause is initially generated and ends in AV block. You can see the pause and you can see the P waves without any QRS. For the next step for us is to stimulate the left vagus. In this case, under basal condition, there is a complete AV block and by this reason, it's not necessary to stimulate in the atrium. You can demonstrate the AV block at the top of the slide. You can see the pause of the atrium during, through the intracardial echo. In ablation, GP4 area, a pause was observed. Then we applied to all the surrounding points in such way, in such way that we don't notice any other pause and did decide to apply to ablation to GP2 and area P, and P area. Interestingly, in this area, we also appreciate pauses in each application. The area was then consolidated applying radiofrequency to everything around it until no response was observed, either from pauses or AV block. This is the most important because considering the excellent response obtained during ablation, we decided to perform an extracardial stimulation to test on both sides. As you can see, we didn't get any pauses or any AV blocks after three attempts on each side. Since we had achieved the goal of abolishing initial vagal response, we believe that additional ablation is not necessary. Therefore, we decided not to do any more RF application and proceed to a final electrophysiological study. The final test demonstrated normal AV conduction and the atropine test showed no significant increase in the heart rate. In conclusion, ladies and gentlemen, the CNA is a promising technique safe in the short term and may constitute an alternative management for young patients with functional AV block. Clinical evidence for this technique is still evolving. Therefore, it should not be considered as the first line for patient management and in any case should be discussed extensively with each patient. Robust clinical trials and solid registries are required prior to becoming part of the conventional therapeutic toolbox. Thank you very much. Do you have any questions? Thank you very much. That was great. This is all very interesting. It looks like the follow-up is about two years. These are pretty young patients. Any longer-term follow-up? I guess one of the other key questions is whether there is any increase in stimulation going forward, whether there's any risk. Thank you for the question. The critical point for this technique is the follow-up because as I showed you during the pre-regnal registry, the acute success as in this case was almost 96%. But if you see one year of follow-up, the successful rate is 70-something percent. So there is a 30% of patients that still will need a pacemaker. In our case, this case was performed in the past February. Until now, there is not syncope episodes and we are performing follow-up twice or three years, three times a year, each one with halter and stress test. Until now, we have no recurrence. But of course, the concern is the recurrence particularly in the AV block. In our experience, we have not a lot of patients with AV block, but we feel, it's my feeling, that it's not the best response and I'm still afraid of the still episodes of AV block. For now, the evolution is quite satisfactory. I'm going to just ask a little bit of a follow-up question on that. In terms of long-term endpoints, you mentioned halters and that's kind of how you've been monitoring. I know there's some data for selection of patients with this metric of deceleration capacity, which is an offshoot of heart rate variability, but maybe a little more specific for if it's high, there's higher vagal tone. Is that a metric that is being looked at for long-term recurrence rates? Of course, but it's true. For us, the most important thing is the clinical follow-up because not for the cases of AV block, but the cases of bradycardia, even for syncope, the final output should not be zero syncope, but increase the quality of life, decrease the number of syncopes a year. If you have a patient with syncopes every morning or two or three times a week, if you improve to one syncope amount, you are improving quality of life. It's true that we don't have elements to say what will happen in the future, but in my opinion, as the previous trial was published, a compassionate approach is very important in this kind of patient. Thank you very much. All right, so for our final speaker, we have Dr. Wick-Terle from the Institute of Clinical and Experimental Medicine, and he will be discussing known and possible risks of cardio neural ablation. Dear Chairman, dear colleagues, as you've seen I have no disclosure and first of all I would like to thank organizers for inviting me, it's a great opportunity for me. My task today is to talk about and discuss about the known and possible risk of cardioneuroblastion. According to European Heart Association survey, cardioneuroblastion can be performed safely and as you see here, 71% of responders reported the complication rate less than 1%, 22% of responders reported the complication rates between 1 and 5%. Of course this was not monitored study, this was not even registry, so in such a case underreporting is likely, but at least some information. And in addition there was no information provided about the types of complications, but fortunately no fatality was reported, as mentioned by Rod Tank one hour ago in his presentation concerning the U.S. experience, but it was probably not related to CNA itself. Of course CNA has common risk of catheter ablation and after performing more than 350 cases I have seen most of them, fortunately rate of major complication was around 1.5% in our center and fortunately all without long-term sequelae. I haven't seen dose, damage to AV node, large-wave stenosis, thromboembolic events, but it's probably a matter of time or a matter of chance. I hopefully will not ever see the esophageal damage because we don't blade at posterior LA wall at all and I don't suggest doing this because effective CNA can be done without getting the LA posterior wall, it's radiofrequency energy. There are specific risks of cardio-neuroablation. I am not sure if I have ever seen a sinoatrial artery damage which was described, but of course inappropriate sinus tachycardia is relatively common, but this may not be specific for CNA because, for example, if you do AF ablation for long-standing persistent atrial fibrillation and if you heavily blade at anterior wall and suddenly you terminate the atrial fibrillation, you end up with very slow sinus rhythm or even junctional rhythm. It may be because of underlying or concealed sinus nodal disease or it may be also because of sinus nodal artery damage. In terms of sinus nodal acceleration, sinus rate acceleration, it is also common after thermal cryo or RF ablation of atrial fibrillation, even if it is a little bit less intensity compared to CNA. It's well known that after CNA, there is huge acceleration of sinus rate, but fortunately, there is a small decline in time during the first year. I don't know if it is fortunately because, on the other hand, it interferes with the efficacy of the procedure, but if there are some strong symptoms in initial days, weeks, and months, it may alleviate during the first year. And there are a little bit limited data on inappropriate sinus tachycardia reported in all CNA trials and recently, we tried to put it together and did kind of small meta-analysis and we were able to identify a lot of studies that reported the sinus rate at 12 months either by EKG, more than 100 beats per minute, or by Holter, more than 90 beats per minute. And we calculated weighted data in more than 500 cases and there was acceleration of sinus plus 11, 12 beats per minute. And because of most studies reported also standard deviation of the sinus rate, we were able to estimate the proportion or rate of inappropriate sinus tachycardia, which was between 6% and 7% in all these studies. We did also some investigation in our own cohort, we looked if there are any predictors of inappropriate sinus tachycardia at 3-month visit. And we identified two factors. First one is, two independent factors, first one is baseline sinus rate and second one is post-atropine sinus rate. And both these factors are usually present in young females and in such a case, the CNA should be done relatively gently just to avoid the excessive sinus nodal acceleration. Despite this sinus nodal acceleration problems, which may be felt by patients like persistent or transient palpitations or decreased exercise capacity or dyspnea, as shown by Piotr Kulakowski group, the patient generally perceived CNA efficacy as very high, with general nice feeling and they usually conclude that the undergoing of CNA was good step in their lives. On top of these clear objective risks, there are speculative risks of cardioannulation. First, even if the acceleration of sinus rate is not fulfilling the criteria of inappropriate sinus tachycardia or if it is asymptomatic, it may be considered dangerous or harmful. It is also associated with attenuation of heart rate variability and on top of it, there might be loss of vagal protection resulting in proarrhythmia at the ventricular level. And let's look at it in detail. Is there a risk of elevated heart rate? Is this simply marker of underlying disease or is it independent risk factor? It was investigated and it seems that at least in patients with structural heart disease or some comorbidities, it may be the case because at least there were some interventions in heart failure patients and it appeared that reducing heart rate improved outcomes and it is in favor of causal association between elevated heart rate and clinical outcomes. On the other hand, we have no such evidence in a normal population and subsequently, we may speculate that analogically, that intervention that increases the heart rate in otherwise healthy subjects like in those undergoing CNA for reflux syncope may not be associated with adverse prognosis. What about heart rate variability? After CNA, you see this huge change in phenotype, whatever you use, if it is SDNN or some other marker of heart rate variability or index of heart rate variability and it resembles that one we have seen in patients with advanced heart failure or in patients with cardiovascular autonomic neuropathy because of diabetes. But remember that here in post-CNA, it is because of specific intervention. This is not because of primary underlying disease. So it may not be associated or it is not likely that it is associated with poor or adverse outcome. And you have already seen this experimental animal study was shown by Marmar. It was CNA was done in the first stage in animals. It was like very intensive CNA and subsequently, in patients, LAD was ligated to create a huge acute anterior MI and in control groups, the ligation was done in animals not undergoing this prior CNA. And what was seen that there was like in post-CNA animals, there was like higher incidence of ventricular fibrillation. There was shorter time to the NSVT or VF. There was higher burden of NSVT episodes and the episodes were more polymorphic than compared to animals without CNA. But this is animal model. It's difficult to project into the patient's population that are relatively young that are otherwise healthy. So it doesn't persuade me that this is an issue after CNA. In the recent 25 years, we did millions of AF ablations, it was thermal AF ablations, not caring about cardiac denervation, which is significant. And we didn't observe any increase in, not we, but in clinical trials, there was no excess of ventricular arrhythmias, not even sudden cardiac deaths. So probably it is not the case. It is not the problem. There are some reports shortly after AF ablation, and it may be the same shortly after CNA, that reported torsades, malignant torsades, which may be associated or caused due to QT prolongation. And indeed, we investigated this in small our cohort. And after CNA, there was prolongation of QTC by 30 to 40 milliseconds on average. But this is pure artifact due to the incorrect correction by BASET formula, which tends to overestimate the QT in the setting of higher heart rate. When we did the same experiment during the constant atrial pacing, 100 beats per minute prior to ablation and after ablation, there was absolutely no change in QT. So in terms of QT interval, I'm pretty happy, and there is no risk. This is one of my final slides. As in many EP procedures, that is always important, the balance between efficacy and safety. And when the procedure, if the procedure is extremely safe, it's usually not enough efficacious and vice versa. So a very efficacious procedure may not be nicely safe. To conclude, risk of cardiac ablation should be put into the perspective of first the risk of implanted pacemaker, the risk of injuries during syncope spells, and the risk of poor quality of life. And the really last slide, cardio-neuroblastion should not be withheld in suitable candidates, in my opinion, because of the risk of inappropriate sinus tachycardia, because of speculative long-term risk due to the loss of cardiac vagal modulation. Tailored cardio-neuroblastion should be our goal. Thank you. Thank you, that was a great talk. You know, just on your last slide, you mentioned that balance between efficacy and safety, and particularly taking into account the risk of pacemaker implant, and generally with younger patients. Do you think that the push to leadless pacemakers and, you know, single-chamber AAI pacemakers changes that threshold and balance at all in your clinical decision-making? I don't think that the leadless pacemaker or a single-chamber pacemaker is a good option for syncope patients, because it may, in fact, increase the burden of syncope. This, like, single-side ventricular pacing, there's no this. This is not like CLS biotronic pacemaker. Do you think that alkalization of the vein of Marshall is appropriate in the setting of CNA ablation, or do you have to, because it's more or less the whole region which is abolished, or do you need to go for additional endocardial ablation if you do this? If you do simply alcohol ablation of vein of Marshall without targeting any other areas, you don't eliminate the vagal responses of sinus node. You may significantly attenuate the responsiveness of AV node to extracardiac vagus nerve stimulation. So like a standalone procedure, it is useless. It may be, it could be used, like, on top of RF lesion, but usually only a couple of RF lesions at the anterior ridge of left superior or left inferior vein, because this is the localization of Marshall tract GP. It is usually enough. So I think this is the, like, alkalization of Marshall tract is unnecessary huge intervention for, to help to denervate the AV node. Okay, another question is the stimulator for the high-frequency neurostimulation. So is there a special recommendation, because I made a lot of research and it was not possible for me to find an adequate stimulator for making the vagal stimulation. Of course, all these devices are of label use, but you can, it can be, it is manufactured, for example, by Digitimer company, UK-based company. They develop the full range of devices that are used by neurologists for external nerve stimulation for this kind of neurological studies, and it can be, of course, of label use for this extracardiac vagus nerve stimulation, and quite recently we investigated the standard EP stimulator, Micropace EPS320, and when we adjusted the setting, because it is, the output is not enough, because maximum output is 25 milliamps. This is not enough for producing the vagal responses, but it can be, this inability, it can be compensated by increasing the pulse width, and when you set the pulse width to 10 milliseconds instead of very tiny impulse duration, you can reproduce almost the same, same responses like when you are using the stimulator. Okay, thank you. I would like to comment on an aspect that was presented by Dr. Dunn. Dr. Dunn, with Charlie, was probably one of the first enthusiasts about cardioneuroblastion, and we thank you very much for your cooperation in this area. There is a trial that was recently published about the shunk that showed that after an animal model, there was probably an increase of ventricular fibrillation after cardioneuroblastion and after myocardial infarction. So it is very important to see the following. These animal model is not appropriate for this study. Why? Because why the vagus causes atrial fibrillation? Because in atria, there is a channel that is the K3.1. This channel causes atrial fibrillation, but the nature in human, thank God, removed this channel. So we, in our ventricles, we have no K3.1 channel. So the nature did the cardioneuroblastion in human ventricle. Thank God. So in this trial that was published by Chang, it's very interesting. However, the model is not appropriate because in pigs, there is 3.1 channel in ventricle. It is, all of investigators know that the pig is terrible for ventricle fibrillation. It presents ventricle fibrillation very easy during studies, during preparations in laboratory. So it is very important to keep this in mind. The cardioneuroblastion, as also atrial fibrillation ablation, causes no increase in mortality, reduces the arrhythmias, the atrial and ventricular arrhythmias. Thank you. Thank you. We recommend. Piotr Kulakowski, Poland. Just a short add to these complications. We have now almost 500 cases and a few months ago, I encountered two patients with insomnia. This was something new for me, but it happened. So it was absolutely associated with the procedure, I mean timing. So I don't know why. Is it because of sinus rate and increased and such a feeling during the night? But obviously, as Dan tell us, two young ladies. These are the patients or the subjects who are most prone to such side effects of cardioneuroblastion. But insomnia was something new for me, but they are two cases. I have no such experience. On the other hand, in some patients with sleep apnea and pauses due to the sleep apnea, even without treatment of sleep apnea, they after CNA, they report like improvement in their sleep because of elimination of these heart rhythm disturbances. In patients with redo-AFib, especially when our pulse field is very affected, taking care of the veins and they're still having AFib, do you think going after the ganglion with other modality will be helpful? Of course, if now we, in our center, we do all the AFib ablation procedures with Farah Pulse technology and it's not possible to toggle between pulse field and RF. For example, with Afera technology, it would be much better because you may do the posterior part of veins, isolate this pulse field and target the anterior part with RF to denervate the sinus node and AV node in case of need. And of course, because of, not only because of denervation of sinus node and AV node, but because of innervation of atrial muscle, which is important for triggering of atrial fibrillation. You get the last question. Go ahead. I just had a question about patient selection now that we're coming out of the trial realm and into the sort of real-world aspect. We know the patients with vasovagal syncope obviously have clustering effects, so what about choosing patients? You know, the meta-analysis, I think, from a couple of years ago, or from last year rather, most of the trials have a median 12-month rate of about two to five. I think in the real world, if you saw someone with two episodes of syncope, is that enough for referring them for cardio-neuroablation? Is there a cut-off? Should we have one? Yeah, and the corollary to that is both of you, you alluded to a 17% recurrence rate, you alluded to a higher recurrence rate. Are there specific patients that you think this is going to happen to? Who do you choose? It's difficult to say. Any patient should be assessed individually, and it depends also how these things look like. If there are few of them but very sudden with less prodromes or rapid prodromes and injuries, I have a much lower threshold for indicating of CNA and vice versa. If it is like preventable syncope spells, it can be, you may use virtual waiting. Yes, I agree, it's a difficult point, but it's important to take, to be convinced of the functional nature of the problem. By this reason, it's critical to have a stress test to be convinced of the function and the correct functioning of the sinus node. And other aspect is that the patient has to be convinced of the necessity and the other measures, the non-pharmacological measures, as completely follow-up. If the patient is still having syncope, it's a good candidate, but as the doctors show us, the complication exists. By this reason, it's very important to follow the patient in terms of clinical before to offer the procedure. It's our approach, just for patient is still with symptoms after a completely follow-up of the instruction for non-pharmacological management. Thank you. Syncope is a delicate symptom, even one. I have to take care because many patients presenting a probable neurocardiogenic syncope are young ladies. We have to take care in this group with long QT syndrome. It's very important to evaluate very well the case. We must take care with the enthusiasm about cardioneuroblastion. It's necessary to evaluate very well the origin of the syncope. Obviously, if we are thinking about a dysfunction of sinus node, hypervagotony is necessary also, if we have some doubt, to do, for example, the atropine test. That is very, very easy to do in order to have an anticipation of the results of the probable cardioneuroblastion. About the indication, we agree with my colleagues about the comments they did. Thank you. Thank you very much. It's 2 o'clock. Thank you. Hope you all had a great meeting and see you next year. Thank you.

Cardioneuroablation

Reflex Syncope

Functional Bradyarrhythmias

Cardiac Autonomic Nervous System

Vagus Nerve

Ganglionic Plexi

Clinical Evidence

Extracardiac Vagal Stimulation

Functional AV Block

Pacemaker Alternative

Heart Rate Variability