Welcome to this webinar at the Heart Rhythm Society. It's recorded in San Diego of one of the sessions that has just completed. This is the session titled, The Autonomic Nervous System, The Next Ablation Frontier. And we have in this session a number of speakers, which included Dr. Kalyanam Shivkumar, Dr. Carlos Murillo, Dr. Pashon, and Dr. Stavros Stavrakis. We're going to include in this session a discussion on a panel discussion about this session as part of the webinar. And I'm gonna hand over to my co-chair, Dr. Michael Lloyd, who's gonna introduce the panelists. Thanks, Parash. Yesterday's session, I believe as they put it, was a set of rock stars in the autonomic space. And we have our own little mini set, some of whom were there at the session yesterday. We're honored to have Dr. Ching-Hsiu Du, Dr. Keshe Gopinathaner, and Dr. Eric Mullen. If I ruined your name pronunciation, I apologize. Welcome, panelists. So, I wanted to kick this off by highlighting some of the important aspects that this session featured. The first speaker was Dr. Shivkumar. And one of the things that stood out to most of me was this aspect of the brain of the heart and that there is no such thing as a denervated heart. Rakesh, can you talk about this idea that there's no such thing as a truly denervated heart, maybe just a decentralized heart? Yeah, that was an interesting concept. You know, traditionally we think of transplanted heart as a denervated heart, although it is somewhat denervated, but what Shiv was mentioning was that they were not totally denervated, in the sense that they still have innervation, especially through the epicardial fat pads, where, through which they can, you know, the autonomic connections are still there, not to the same extent. Where they lack some autonomic connections is through the afferent impulses that go from the heart directly to the brain. So, they are less prone to develop these sympathetic overactivity and parasympathetic withdrawal that's sometimes associated with heart failure exacerbation, or, you know, in stressful situations, creation of malignant ventricular arrhythmias through the autonomic system. So, that is much less common in the transplanted heart. That's due to partial denervation, but what Dr. Shiv Kumar said was that it's not completely denervated, and that's actually a helpful thing in that. And then over time, almost all the new hearts have some degree of re-enervation as well, and that's why we tend to see, as the age of the transplant goes longer, you start to see more arrhythmias in there that could be autonomically mediated. What is the brain of the heart? Dr. Ju, this intrinsic cardiac nervous system. Can you explain that? It's primarily where the nodal points for neural connections to get to the heart, the ganglionic plexi being one. There are also a lot of mechanoreceptors in the heart, especially in the posterior wall and sometimes in the anterior wall that also contribute to the sort of dialogue between the brain and the heart, and they also play a role, especially the mechanoreceptors in the so-called basal gyrus reflex that creates vasovagal syncope. And the neuronal, like for example, the parasympathetic ganglionic plexi are epicardial and closer to the heart, whereas the sympathetic ganglia are not closer. They are more in the neuronal bodies, and so these aspects of the autonomic nervous system are collectively called the intrinsic cardiac network. So the second talk was given by Dr. Carlos Murillo with a very provocative title of talking at the vagal nerve and how it extends well beyond. Dr. Xu, can I ask your comments on this? Because we're targeting the vagal nerve. What else are we affecting? What are your thoughts on that in terms of AF and vasovagal syncope? I think it's an interesting concept of vagal neuromodulation that we tend to, because the autonomic nervous system of the heart is so complicated, we tend to oversimplify it into a sympathetic input, adrenergic nerves that express enzymes to create the neurotransmitter norepinephrine, and then the parasympathetic component of which the primary neurotransmitter is acetylcholine. And so the concept of vagal neuromodulation focuses on, I suppose we'd make the assumption that it's purely a cholinergic stimulation of the heart. And the fact is that's simply not true. We know from high-resolution imaging studies that there are adrenergic fibers, fibers that express enzymes that create norepinephrine in the vagus that run along that vagus nerve. So when you actually perform vagal nerve stimulation, there's no way to guarantee that what the neurotransmitters you're releasing onto the heart are purely cholinergic. So I do think that there's a lot more research that needs to be done in this area before we can fully understand how, what we're doing, how the stimulations that we're doing and the neuromodulations that we're doing is affecting myocardial electrophysiology. Then this topic was extended by Dr. Pachon in his presentation. He's been working now for a number of years of modulating the autonomic nervous system. I found his talk quite provocative. What are your thoughts, Dr. Zhu, on this one? It's kind of an extension of the previous question. I'm sorry, could you clarify the question? So Dr. Pachon was advocating for cardioneural ablation for management of atrial fibrillation and for altering the autonomics in that form. Right. I think until we see more convincing data for the effects of cardioneural ablation, we need a much larger sample size than what we have on vasovagal syncope, on atrial fibrillation. It's going to be difficult to tease out what we're actually doing with the cardioneural ablations. I'd like to get the opinion of the other panelists as well. Rakesh, I'm interested in your thoughts. I think what Dr. Pachon is advocating is that there are two types of responses. Like for example, after you do a PVI and he contends that if you can induce atrial fibrillation with vagal nerve stimulation, they use a special stimulator near the carotid body and use kind of a grass stimulator kind of thing to stimulate the vagus nerve. If you can induce AF post-PVI, his take is that that is due to parasympathetically mediated atrial fibrillation and that requires cardioneural ablation where you ablate the vagal response, especially that's the left superior GPN, left inferior GPN, the Marshall tract, which is in the carina region. And they also ablate the right superior that will increase your heart rate. And so to get the as parasympathetically denervate that atrium as you can to prevent recurrence of atrial fibrillation. His single center data shows excellent results, but again, that needs to be replaced. The reason I think it's a good thought is that there have been studies that sort of combined autonomic modulation along with atrial fibrillation, but they have been kind of mixed results. I think part of it could be that they may not have been able to accurately identify what patient has vagal mediated AFib versus not. So that's where I thought it was interesting. So that this might be, potentially could be expanded to understand this better. And that could, we are kind of stuck in terms of success rate for AF ablations, persistent or proximal, even with PFA. And so this could be a mechanistic way that we could, if it's successful, could be good to benefit certain patients, more younger patients. That's it. No, I was going to pass it over to you in order to ask the same question. Look, I'd like to highlight a few key points that Professor Shipjumar made. And I think it really highlights the role that CNA plays currently in the literature today. And the first thing is that there is a lot of hierarchy in the autonomic nervous system. And there are layers of control that reside only within the heart, then between the heart and the spinal cord, and then between the heart and the brain. And so when you cut one thing out, you may find that there is an overactive section in the other end. So going with the cardio neuro ablation, what happens is that you are ablating nerves within the heart. And these nerves could be either parasympathetic or sympathetic, or at least another neurotransmitter, what Dr. Zhu was alluding to earlier. There are intracardiac neurons, which are very important network, and they do their own thing. We need a lot of data to try and understand exactly what these things do. Now, when we target these procedures, target these with procedures, such as CNA, it's a little bit like a sledgehammer. And what you're doing is you are irritating nerves or injuring nerves. And there are two ways to predominantly to assess them. One is that you take high frequency stimulation and you're trying to understand where these ganglionated plexi are. But you're looking from the inside of the building, but the ganglionated plexi are on the outside wall. So you're trying to find a marker of this with high frequency stimulation, but what you're getting could be muscle, could be nerve connections, could be gap junctions, could be a whole lot of things. So yes, I think there are a lot of very conclusively proved studies that high frequency stimulation definitely affects these ganglia, but exactly what the effect is, is very difficult to know. So one thing that you can do is you can denervate, well, I should say partially denervate the heart. And so you get rid of some of the vagal response, but there are other responses at play too, which we haven't measured. We measure heart rate variability, which is only looking at the efferent input into the SANO really. So extra cardiac vagal stimulation is another way to determine that. And a paper we presented a podcast yesterday looked at comparing different strategies of cardiac neuroablation approach and looking at whether you may be able to limit CNA. And that is a worthy objective because if you ablate or over ablate these ganglionated plexi, you can end up in a bit of trouble. They can be prorythmic. There's animal data to show this. So I think we need to be really very cautious of what we're ablating, why we're ablating it. And that concept of the yin and yang, I think will hold to be untrue. We need to look at the autonomic nervous system as often working in concert. And the adrenergic arm, the cholinergic arms sometimes co-activate to produce AF. Sometimes, you know, it can be prorythmic and ventricular arrhythmias. So a lot of different things happen. And to wrap up the session, Dr. Stuttgart-Brockes, after this very compelling argument that vagal denervation is important for a fibrillation success, comes up and says low-level vagal stimulation is important in controlling it. So clearly, there's a divergence of opinions or a controversy that's emerging. Dr. Zhu is an expert in this field. How do you reconcile these differing views? I think it's a, yeah, it's very interesting. And what makes our field so exciting is that we have these contradictory findings. But it all comes back to what exactly, what is the physiological outcome of what you are doing to this nerve when you're stimulating it? The parameters by which you're electrically zapping a nerve, for lack of a better word, matter a lot. And we know this from a lot of research that was done in Dr. Shivkumar's lab, that depending on the parameters of, in terms of the frequency and the intensity of your electrical stimulation of the vagus nerve, you can actually end up with totally different effects. Certain parameters within a certain range of frequencies and amplitudes can be stimulatory and certain parameters can be inhibitory. So, and we don't know why that is. So I think that it all comes back to what is the protocol? What are the details of the protocol that you are using to modulate these neurons? Pulse field ablation. It seems to be everybody's favorite topic, the neuroselectivity on myocytes. Is there a loss in efficacy? Is there a downside to not partially denervating the heart with pulse field ablation? Where do you see that in affecting the cardiac autonomic system in general? Prakash? It's, I think that's something that we don't understand very well. There was initial studies have shown some significant changes, but then whether it's, you know, like a stunning phenomenon, acute, and then they recover over time. I think we need some targeted studies on this. There's definitely, given the footprint, especially larger footprint of catheters there is more involvement of the autonomic nervous system in these ablation lesions. So, and so I think the jury's still out there is my looking at the data. That's that'd be my thought. I think we need to know more. Dr. Zhu, would you be able to comment on the pulse field ablation aspect as well? Sure, I agree with some of the other comments that have been made so far about pulse field ablation in terms of if it is indeed, and I don't think we know this to be factual 100%. If it is indeed specific for myocytes alone and spares the neurons completely, then it would seem to throw this hypothesis of vaguely mediated atrial fibrillation out the window. But again, we don't know for sure at this point whether it actually does fully spare the neurons. In anecdotal evidence in terms of seeing an increase in the resting heart rate, in the resting sinus heart rate of patients after pulse field ablation, it does seem that there is less of an increase in the resting heart rate after pulse field ablation compared to radiofrequency ablation or cryo-balloon pulmonary vein isolation. So that would seem to support the idea that perhaps you're sparing the vagal innervation to the heart, but we don't know for sure what's going to happen in the long-term. So, Varun, let me come back to your question. So you have been studying the afferent inputs into the autonomic nervous system in AF patients. And we're talking about how do we modulate, and we've got two different concepts. One is of ablation. One is of kind of vagal, it's kind of treat AF type of tragus stimulation for vagal retraining. So I'm after your thoughts. What should we be doing at a clinical level in the AF patient? So the first thing to say is that low-level tragus stimulation is not purely vagal stimulation. So low-level tragus stimulation works really probably in an anti-adrenergic way, and also working on the cholinergic anti-inflammatory pathways. And this is a very key point. We don't know exactly how, but this is the purported mechanisms of low-level tragus stimulation. But from Dr. Stobras' talk yesterday, and I've heard this over many years, and I learn something new every time I listen to him, the one thing that's very evident is that, one, not everybody responds. There are responders, and there are people who don't respond. And choosing which ones is very important. So in terms of neuromodulation, that's a key point clinically. The second thing is that it is really nice to have a non-invasive treatment. And I think he's come far along, he's got some nice data, and I think this holds a lot of problems. So I think low-level tragus stimulation, because of its non-invasive nature, less side effects, I think is not as very controversial, but we need to understand the exact mechanisms by which it occurs, and in whom it responds best. Now, when it comes to low-level tragus stimulation, what is another important point from Dr. Stobras' talk is that a small level of tragus stimulation has a longer effect. So the effect lasts beyond the stimulus. And he showed this very nicely yesterday in some of the brain functional MRI data, and we know this as well from other studies. So where the afferents come in is really key point. One thing that we've noticed with atrial fibrillation is that there's a sympathetic shift in general in clinical patients with atrial fibrillation. And that may actually be a reason why some people have lots of pain. So the afferents work and need normal sinus rhythm. When there's an irregular heartbeat, as occurs in atrial fibrillation, these receptors in the heart, particularly cardiopulmonary or volume-regulating receptors, don't work as well. And we've found in our studies that actually if you cardiovert patients, these receptor responses actually improve. We use a technique of lower body negative pressure, which actually incidentally was also used in returned astronauts in the 60s. And I think it's still used in some places, for example, in Texas. So these techniques can selectively unload bioreceptors in the heart that look at volume with minimal blood pressure changes. And using a lot of reflexes together, even though it's a little bit dirty in terms of exactly doing it in humans, you can get a sense of where the reflex deficits are. And we have shown that there are reflex deficits in atrial fibrillation. They improve with cardioversion. And interestingly, in a small pilot level data, we had a few patients who had tracheostimulation exactly as per Dr. Stavrakis' protocol. And on the same day, repeat testing partly or mostly normalized these reflexes. So neuromodulation, I think, in this space will be very important. One, to look at the burden of AF to try and regress that prevention. So I think that's one avenue where I think it'll be important. And we feel that there'll be a link between the afferent autonomic nervous system, which recognizes volume changes in the heart, and atrial dilatation. So there is more atrial dilatation and progression with AF myopathy, and then development potentially to heart failure, which is why catheter ablation and restoration of sinus rhythm is so important. And the last point that I would like to make is that there are a lot of sequelae of atrial fibrillation that we will uncover in time. Patients that are older with falls risk and syncope risk, orthostatic hypotension, which is a predictor in large scale studies for AF. So these sequelae may be improved by neuromodulation. There is another emerging association epidemiologically of AF and dementia and cognitive decline. And it may well be that volume dysregulation can cause decreases in cerebral blood flow, and there is some data to suggest this. So I think these are the avenues that we would take clinically with cardiac neuroablation with clinical studies. Intrinsically seeing those beautiful pictures that Dr. Shivkumar displayed, intrinsically I feel that taking that away, however you may do it, by sympathectomy or ganglion injection or by ablation, there's gotta be a downside. Evolution didn't make that an error. So what to the panel, all three of you, what are the downsides of removing these autonomic influences? Is that with ganglion added plexi ablation, there are conflicting studies. Some have shown proarrhythmia. Renal denervation, for example, is another example where there may be some proarrhythmia. So I think the downside, the trade-off, is that you may get an autonomic dysregulation within the heart that can promote arrhythmias, particularly ventricular arrhythmias. Now, when we talk about atrial fibrillation and VT, they're different. So the mechanisms are different. When we talk about ventricular tachycardia, there are a lot of feedback, positive loop reflexes between the brain and the spinal cord that really overactive it and they self-propagate. And that is what is being targeted with sympathectomies. Thank you. I think that, and this is a study that Dr. Shukumar actually quoted in his talk, there are dangerous effects potentially to ablating without fully understanding the effects on myocardial electrophysiology. So that AFAC study that he referred to showed that there's a significant increase in sinus node dysfunction requiring pacemaker implantation after ganglionated plexi ablation. And in terms of denervating the ventricles, and I think Dr. Malik was alluding to this as well, we have acquired heart diseases that already do that for us. We know the effects of denervation in some of these structural heart diseases like myocardial infarction and heart failure, there's a significant amount of decrease in sympathetic innervation to the myocardium and that actually has proarrhythmic effects. So it's not as simple as, and it's thought to be due to postsynaptic changes in the adrenergic receptors of the heart. And it's not as simple as simply taking away the nerves will take away the bad autonomic influence that you're hoping for. Rakesh, any comments on this? I'm familiar with this. There was one study that looked at, and the animal study and the sort of the vagal resource, so to speak, that could be a deterrent against something like response to ischemia, and that was kind of diminished. But I think clinically, right now, if you think about, let's say, cardio-neuroablation, it's typically performed in the younger people with patient selection is really important for cardio-neuroablation. I think you have to prove clearly that they either have cardio-inhibitory syncope or reproducible recurrent symptoms and they should fail all the conservative measures and medical therapy to be considered. And they can also be used for other vagally-mediated bradyarrhythmia such as functional AV block and also significant sinus node, significantly slow sinus rates with substantial symptoms. But again, I think I am also cautious. I think we need really a sham control trial to really prove and rule out placebo effect in these patients and also need a long-term registry data to see how this sort of parasympathetic denervation is gonna impact things long-term. We know that there is risk of inappropriate sinus tachycardia, and that's at least, some studies, 2% to 7%, and some of them may need medications. And, but I think long-term, we at least have available registry data that we know. We don't have any ischemia-related complications or long-term. So again, but that's something to watch for and study as we go along. Let me ask this question in a different way. So now we're all treating a lot of patients with atrial fibrillation. Are there any, and how do you select them currently to undertake autonomic modulation as well? I can, what I do, Prash, is that if they have significant bradycardia at baseline, like maybe you get referred patients with potentially, you know, consider pacemaker slash, you know, ablation kind of thing, that may, and so those patients, they have baseline bradycardia, and if they are not significantly older, meaning that they have definite, like degenerative sinus node disease, and if they are, let's say they are relatively younger, 50, you know, early 60s, and have significant sinus bradycardia, I think I would map their ganglia and ablate them, at least the left-sided ganglia, I would ablate them along with that. I think we can definitely get at least, you know, 10, 15% increase in, 15, 20% increase in their heart rate, and potentially could avoid a pacemaker down the road. Right here, and Varun, would you like to comment on that? Look, I think the main comment to make is when you're ablating, what are you actually ablating, right? And so I think that you are targeting high-frequency stimulation areas, sites where you get extra patiobagal response, but in fact, a lot of these tend to be nerves that innervate the sinoatrial node, and so that would be a mechanism by ablating more in the atrium, targeting these areas where there are ganglionated plexi will release some of those nerves that control innervation of the SN node, and thereby improve sinus node activity, so I think that's not unreasonable. Is there anyone else that you would do this in? Or even Trager's stimulation? I think that the most promising neuromodulation therapies that we have, and there's a bit more work to do, are one, low-level Trager's stimulation, and two, I guess, renal denervation, particularly in hypertensives. The trade-off, and Dr. Lloyd talked about this earlier, is that there is a risk, potentially, of proarrhythmia with that second effect. Low-level Trager's stimulation, I see, is quite attractive, but we need to find the right patient cohort, and what really excited me about yesterday's talk, and Dr. Sabarakis led it at the end, is these wearables where you can look at concepts like P-wave alternans, and you can look at ways in which you may determine who would respond in a closed-loop system, and thereby, you could target therapy earlier and use it in those that respond, and I recognize very quickly if they won't respond to that therapy, and I feel that is a very promising avenue for the near future. So, individualized responses came up, and variability. Dr. Xu, how do we get at those individual variations patient by patient? Is it genetics? Is it doing Dr. Pichon's vagal stimulation test and seeing if they pause? Is it just purely anatomic? I think it's probably a combination of everything. I think one of the bigger problems is that the idea of postural orthostatic tachycardia syndrome or sinus node dysfunction or inappropriate sinus tachycardia, we don't fully understand what the disease process actually is. Is it actually even the same disease? Is one patient that's being labeled having vasovagal syncope the same as the other patient? Is that pathophysiology the same? And I think that before we can understand why our treatments have varying effects, we have to understand first whether we're actually using them on the same disease. Well said. In 2025, the community EP, what do we tell our just our workhorse electrophysiologist right now in terms of how to treat the autonomic system? Should we open this up and say, you should map these patients. Should we only give it to the experts, Rakesh? Again, you know, if I, I don't know, it varies quite a bit. I'm sorry, my video has some issues, I apologize. If you, a lot of EPs actually don't feel very, you know, don't want to see these patients, even they may have expertise, but they, you know, this is time consuming. It's abstract and it's, you know, the patients are, you know, they have probably seen three doctors before they get to you. They may already have gone to Mayo Clinic or wherever they are and got like a whole battery of autonomic tests which may or may not tell you anything. And then, so I think the biggest thing is that, you know, I think patients look for validation of their symptoms and some rational explanation for what's going on. And I think I, from my perspective, I see a lot of these patients, I work with them, I see them frequently. We try different things. I think we set expectations at the beginning that this is going to take time and we're going to use a stepwise approach. And depending upon testing we do, you may or may not need an interventional strategy or a medical slash lifestyle strategy. And I think it's, there's a lot of overlap between these syndromes. You know, one patient gets diagnosed at POTS and then one sender comes to us and we do a tilt and there is really no evidence of orthostatic tachycardia and vice versa. And then there are specific, you know, I think if you look at the discrepancy between like our syncope guidelines and also the neurology guidelines, like in our syncope guidelines, hardly mention any autonomic testing, whereas neurology guidelines are completely about autonomic testing. So just, and we don't have any good outcome data that autonomic testing specifically does a whole lot. I mean, there are some situations where there is a specific form of POTS and stuff like that. But I think this is still an EP, EP should take care of these patients. And it's just not, you know, we talk about a lot of interventional approaches to autonomic dysfunction, which is actually really great. But at the end of the, but more than that, I think these are young patients who have debilitating problems without any structural heart disease. And I think we need to listen to them, you know, rather than sort of, you know, dismissing them and then work with them to give them the best quality of life we can, whether it's interventional, whether it's, you know, lifestyle, whether it's medication. So that's kind of my thought. Excellent comments for us to be finishing on. So this has been a tour de force of autonomic dysfunction in arrhythmia and taking us from a simplified description to really complex therapies that are evolving to treat this. And I want to thank our panelists to put this together in terms of what we as treating clinicians should be looking out for in the future and what we should be considering as therapy in the future. So thank you for joining us for an episode of the BEAT webinar.

autonomic nervous system

ablation therapy

heart arrhythmias

atrial fibrillation

vagal nerve stimulation

cardioneuroablation

pulse field ablation